id
stringlengths 2
20
| ch_id
stringlengths 2
20
| keywords
listlengths 0
162
| title
stringlengths 0
130
| authors
stringlengths 0
245
| abstract
stringlengths 0
4.05k
| content
stringlengths 0
197k
| references
listlengths 0
142
| created_date
stringlengths 0
10
| updated_date
stringlengths 0
10
| revised_date
stringlengths 0
10
| journal
stringclasses 1
value | source_url
stringclasses 1
value | publication_types
listlengths 2
2
|
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
lpi
|
lpi
|
[
"Cationic Aminoaciduria",
"Y+L amino acid transporter 1",
"SLC7A7",
"Lysinuric Protein Intolerance"
] |
Lysinuric Protein Intolerance
|
Virginia Nunes, Harri Niinikoski
|
Summary Lysinuric protein intolerance (LPI) typically presents after an infant is weaned from breast milk or formula; variable findings include recurrent vomiting and episodes of diarrhea, episodes of stupor and coma after a protein-rich meal, poor feeding, aversion to protein-rich food, failure to thrive, hepatosplenomegaly, and muscular hypotonia. Over time, findings include: poor growth, osteoporosis, involvement of the lungs (progressive interstitial changes, pulmonary alveolar proteinosis) and of the kidneys (progressive glomerular and proximal tubular disease), hematologic abnormalities (normochromic or hypochromic anemia, leukopenia, thrombocytopenia, erythroblastophagocytosis in the bone marrow aspirate), and a clinical presentation resembling the hemophagocytic lymphohistiocytosis/macrophagic activation syndrome. Hypercholesterolemia, hypertriglyceridemia, and acute pancreatitis can also be seen. The diagnosis is established in an individual with clinical and laboratory features suggestive of LPI including elevated 24-hour urinary excretion of cationic amino acids, especially lysine. Identification of biallelic LPI is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for a pregnancy at increased risk are possible using molecular genetic techniques if both pathogenic variants have been identified in an affected family member.
|
## Diagnosis
Lysinuric protein intolerance (LPI)
Recurrent vomiting with episodes of diarrhea
Episodes of stupor and coma after a protein-rich meal
Poor feeding
Aversion to protein-rich food
Failure to thrive
Enlargement of the liver and spleen
Muscular hypotonia
Poor growth
Early (often severe) osteoporosis
Subclinical or overt pulmonary involvement
Renal involvement
Hemophagocytic lymphohistiocytosis/macrophagic activation syndrome
Elevated plasma ammonia after a protein-rich meal. Fasting values are usually normal.
Increased urinary orotic acid*
Plasma amino acid concentrations:
Cationic amino acid (lysine, arginine, and ornithine) concentrations are usually below normal for age, but may be within the normal range.
Serine, glycine, citrulline, proline, alanine, and glutamine concentrations are increased.
Urinary amino acid excretion. 24-hour urinary excretion of cationic amino acids, especially lysine, is increased.**
*Note: (1) In some affected individuals, elevated urinary orotic acid excretion occurs in the absence of hyperammonemia. (2) Urinary orotic acid excretion may be within the normal range if an untreated person has had a prolonged fast or has excluded protein-rich food from the diet.
**Note: (1) In some affected individuals, calculation of the renal clearances of cationic amino acids (lysine, arginine, and ornithine) may be necessary to clarify the urinary loss of these amino acids. (2) Renal clearance of an amino acid is calculated using the same formula as for creatinine clearance, but substituting creatinine values with values of 24-hour urinary amino acid excretion and of the fasting plasma amino acid concentrations. (3) Mean values and ranges of the renal clearances of cationic amino acids in individuals with LPI were reported in
Plasma concentrations of LDH, ferritin, and zinc are usually elevated.
Normochromic or hypochromic anemia, leukopenia, and thrombocytopenia are nonspecific hematologic findings.
Hypertriglyceridemia and hypercholesterolemia are frequently observed.
The diagnosis of LPI
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of LPI, molecular genetic testing approaches can include
Testing may begin with targeted analysis for the Finnish founder variant
For an introduction to multigene panels click
When the diagnosis of LPI is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Lysinuric Protein Intolerance (LPI)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Presently, of around 400 alleles of persons in whom LPI is suspected, only around 5%-8% have not been characterized, giving a detection rate of approximately 92%-95%.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Recurrent vomiting with episodes of diarrhea
• Episodes of stupor and coma after a protein-rich meal
• Poor feeding
• Aversion to protein-rich food
• Failure to thrive
• Enlargement of the liver and spleen
• Muscular hypotonia
• Poor growth
• Early (often severe) osteoporosis
• Subclinical or overt pulmonary involvement
• Renal involvement
• Hemophagocytic lymphohistiocytosis/macrophagic activation syndrome
• Elevated plasma ammonia after a protein-rich meal. Fasting values are usually normal.
• Increased urinary orotic acid*
• Plasma amino acid concentrations:
• Cationic amino acid (lysine, arginine, and ornithine) concentrations are usually below normal for age, but may be within the normal range.
• Serine, glycine, citrulline, proline, alanine, and glutamine concentrations are increased.
• Cationic amino acid (lysine, arginine, and ornithine) concentrations are usually below normal for age, but may be within the normal range.
• Serine, glycine, citrulline, proline, alanine, and glutamine concentrations are increased.
• Urinary amino acid excretion. 24-hour urinary excretion of cationic amino acids, especially lysine, is increased.**
• Cationic amino acid (lysine, arginine, and ornithine) concentrations are usually below normal for age, but may be within the normal range.
• Serine, glycine, citrulline, proline, alanine, and glutamine concentrations are increased.
• Plasma concentrations of LDH, ferritin, and zinc are usually elevated.
• Normochromic or hypochromic anemia, leukopenia, and thrombocytopenia are nonspecific hematologic findings.
• Hypertriglyceridemia and hypercholesterolemia are frequently observed.
• Testing may begin with targeted analysis for the Finnish founder variant
• For an introduction to multigene panels click
## Suggestive Findings
Lysinuric protein intolerance (LPI)
Recurrent vomiting with episodes of diarrhea
Episodes of stupor and coma after a protein-rich meal
Poor feeding
Aversion to protein-rich food
Failure to thrive
Enlargement of the liver and spleen
Muscular hypotonia
Poor growth
Early (often severe) osteoporosis
Subclinical or overt pulmonary involvement
Renal involvement
Hemophagocytic lymphohistiocytosis/macrophagic activation syndrome
Elevated plasma ammonia after a protein-rich meal. Fasting values are usually normal.
Increased urinary orotic acid*
Plasma amino acid concentrations:
Cationic amino acid (lysine, arginine, and ornithine) concentrations are usually below normal for age, but may be within the normal range.
Serine, glycine, citrulline, proline, alanine, and glutamine concentrations are increased.
Urinary amino acid excretion. 24-hour urinary excretion of cationic amino acids, especially lysine, is increased.**
*Note: (1) In some affected individuals, elevated urinary orotic acid excretion occurs in the absence of hyperammonemia. (2) Urinary orotic acid excretion may be within the normal range if an untreated person has had a prolonged fast or has excluded protein-rich food from the diet.
**Note: (1) In some affected individuals, calculation of the renal clearances of cationic amino acids (lysine, arginine, and ornithine) may be necessary to clarify the urinary loss of these amino acids. (2) Renal clearance of an amino acid is calculated using the same formula as for creatinine clearance, but substituting creatinine values with values of 24-hour urinary amino acid excretion and of the fasting plasma amino acid concentrations. (3) Mean values and ranges of the renal clearances of cationic amino acids in individuals with LPI were reported in
Plasma concentrations of LDH, ferritin, and zinc are usually elevated.
Normochromic or hypochromic anemia, leukopenia, and thrombocytopenia are nonspecific hematologic findings.
Hypertriglyceridemia and hypercholesterolemia are frequently observed.
• Recurrent vomiting with episodes of diarrhea
• Episodes of stupor and coma after a protein-rich meal
• Poor feeding
• Aversion to protein-rich food
• Failure to thrive
• Enlargement of the liver and spleen
• Muscular hypotonia
• Poor growth
• Early (often severe) osteoporosis
• Subclinical or overt pulmonary involvement
• Renal involvement
• Hemophagocytic lymphohistiocytosis/macrophagic activation syndrome
• Elevated plasma ammonia after a protein-rich meal. Fasting values are usually normal.
• Increased urinary orotic acid*
• Plasma amino acid concentrations:
• Cationic amino acid (lysine, arginine, and ornithine) concentrations are usually below normal for age, but may be within the normal range.
• Serine, glycine, citrulline, proline, alanine, and glutamine concentrations are increased.
• Cationic amino acid (lysine, arginine, and ornithine) concentrations are usually below normal for age, but may be within the normal range.
• Serine, glycine, citrulline, proline, alanine, and glutamine concentrations are increased.
• Urinary amino acid excretion. 24-hour urinary excretion of cationic amino acids, especially lysine, is increased.**
• Cationic amino acid (lysine, arginine, and ornithine) concentrations are usually below normal for age, but may be within the normal range.
• Serine, glycine, citrulline, proline, alanine, and glutamine concentrations are increased.
• Plasma concentrations of LDH, ferritin, and zinc are usually elevated.
• Normochromic or hypochromic anemia, leukopenia, and thrombocytopenia are nonspecific hematologic findings.
• Hypertriglyceridemia and hypercholesterolemia are frequently observed.
## Establishing the Diagnosis
The diagnosis of LPI
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of LPI, molecular genetic testing approaches can include
Testing may begin with targeted analysis for the Finnish founder variant
For an introduction to multigene panels click
When the diagnosis of LPI is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Lysinuric Protein Intolerance (LPI)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Presently, of around 400 alleles of persons in whom LPI is suspected, only around 5%-8% have not been characterized, giving a detection rate of approximately 92%-95%.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Testing may begin with targeted analysis for the Finnish founder variant
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of LPI, molecular genetic testing approaches can include
Testing may begin with targeted analysis for the Finnish founder variant
For an introduction to multigene panels click
• Testing may begin with targeted analysis for the Finnish founder variant
• For an introduction to multigene panels click
## Option 2
When the diagnosis of LPI is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Lysinuric Protein Intolerance (LPI)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Presently, of around 400 alleles of persons in whom LPI is suspected, only around 5%-8% have not been characterized, giving a detection rate of approximately 92%-95%.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Usually infants with lysinuric protein intolerance (LPI) present with gastrointestinal symptoms (feeding difficulties, vomiting, and diarrhea) soon after weaning from breast milk or formula.
Most affected infants show failure to thrive early in life. Neurologic presentation with episodes of coma is less common. Moderate hepatosplenomegaly is present. Muscular hypotonia and hypotrophy are observed from early infancy. Poor growth and delayed skeletal maturation are common after the first year of life. Osteoporosis may result in pathologic fractures.
Intellectual development is usually normal unless episodes of prolonged coma cause neurologic damage.
Classic symptoms of protein intolerance may remain unnoticed during the first and second decades of life because of subconscious avoidance of dietary protein.
Treatment with a low-protein diet and supplementation with citrulline and nitrogen-scavenging drugs (see Management,
PAP usually presents with progressive exertional dyspnea, tachypnea, and cough that are exacerbated by respiratory infections and complicated by viral or bacterial pneumonia. Diminished breath sounds, inspiratory crackles, subcostal and suprasternal retractions, cyanosis, and, more rarely, digital clubbing can be found on physical examination.
Diffuse reticulonodular densities are common on radiologic evaluation. Chest high-resolution computed tomography reveals ground-glass opacities with superimposed smooth septal thickening.
The pathogenesis of the PAP in LPI is poorly understood, but may be associated with intracellular nitric oxide accumulation [
Renal tubular acidosis or findings consistent with reduced phosphate reabsorption and generalized aminoaciduria indicate underlying complex proximal tubular disease (Fanconi syndrome).
Kidney histology reveals immune-mediated glomerulonephritis as well as chronic tubulointerstitial nephritis with glomerulosclerosis in the absence of immune deposits [
The pathogenesis of the renal involvement is unknown but may be associated with nitric oxide overproduction [
Erythroblastophagocytosis and decreased megakaryocytes may be found in bone marrow aspirate. Hematologic findings also include slight normochromic or hypochromic anemia, leukopenia, thrombocytopenia, and subclinical intravascular coagulation.
System y
Genotype-phenotype correlations have not been found.
Variable expressivity is observed in individuals of Finnish origin who are homozygous for the same founder variant.
In a large Italian pedigree, homozygosity for
In 35 individuals with LPI of Japanese ancestry, no correlation between genotype and phenotype was observed [
Lysinuric protein intolerance has also been referred to as cationic aminoaciduria.
More than 200 individuals with LPI have been reported; one third are of Finnish origin [
The disorder is found worldwide: individuals with LPI originate from at least 25 countries [
The incidence of LPI has been estimated at 1:60,000 newborns in Finland and 1:57,000 in Japan [
## Clinical Description
Usually infants with lysinuric protein intolerance (LPI) present with gastrointestinal symptoms (feeding difficulties, vomiting, and diarrhea) soon after weaning from breast milk or formula.
Most affected infants show failure to thrive early in life. Neurologic presentation with episodes of coma is less common. Moderate hepatosplenomegaly is present. Muscular hypotonia and hypotrophy are observed from early infancy. Poor growth and delayed skeletal maturation are common after the first year of life. Osteoporosis may result in pathologic fractures.
Intellectual development is usually normal unless episodes of prolonged coma cause neurologic damage.
Classic symptoms of protein intolerance may remain unnoticed during the first and second decades of life because of subconscious avoidance of dietary protein.
Treatment with a low-protein diet and supplementation with citrulline and nitrogen-scavenging drugs (see Management,
## Complications
PAP usually presents with progressive exertional dyspnea, tachypnea, and cough that are exacerbated by respiratory infections and complicated by viral or bacterial pneumonia. Diminished breath sounds, inspiratory crackles, subcostal and suprasternal retractions, cyanosis, and, more rarely, digital clubbing can be found on physical examination.
Diffuse reticulonodular densities are common on radiologic evaluation. Chest high-resolution computed tomography reveals ground-glass opacities with superimposed smooth septal thickening.
The pathogenesis of the PAP in LPI is poorly understood, but may be associated with intracellular nitric oxide accumulation [
Renal tubular acidosis or findings consistent with reduced phosphate reabsorption and generalized aminoaciduria indicate underlying complex proximal tubular disease (Fanconi syndrome).
Kidney histology reveals immune-mediated glomerulonephritis as well as chronic tubulointerstitial nephritis with glomerulosclerosis in the absence of immune deposits [
The pathogenesis of the renal involvement is unknown but may be associated with nitric oxide overproduction [
Erythroblastophagocytosis and decreased megakaryocytes may be found in bone marrow aspirate. Hematologic findings also include slight normochromic or hypochromic anemia, leukopenia, thrombocytopenia, and subclinical intravascular coagulation.
System y
## Genotype-Phenotype Correlations
Genotype-phenotype correlations have not been found.
Variable expressivity is observed in individuals of Finnish origin who are homozygous for the same founder variant.
In a large Italian pedigree, homozygosity for
In 35 individuals with LPI of Japanese ancestry, no correlation between genotype and phenotype was observed [
## Nomenclature
Lysinuric protein intolerance has also been referred to as cationic aminoaciduria.
## Prevalence
More than 200 individuals with LPI have been reported; one third are of Finnish origin [
The disorder is found worldwide: individuals with LPI originate from at least 25 countries [
The incidence of LPI has been estimated at 1:60,000 newborns in Finland and 1:57,000 in Japan [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The phenotypic variability of lysinuric protein intolerance (LPI) has resulted in various misdiagnoses.
## Management
To establish the extent of disease in an individual diagnosed with lysinuric protein intolerance, the following evaluations are recommended if they have not already been completed:
History for evidence of hyperammonemic crises with overt neurologic manifestations (vomiting, drowsiness, coma) and of respiratory involvement (cough, dyspnea, recurrent lower respiratory tract infections)
Neurologic evaluation to detect secondary neurologic damage
Respiratory evaluation including chest x-ray, pulmonary high-resolution computed tomography, and pulmonary function tests
Evaluation and follow up of growth parameters
Liver and spleen ultrasound examination to monitor liver structural changes and spleen enlargement
Hematologic evaluation (bone marrow aspirate may be required)
Immunologic assessment including plasma concentrations of immune globulins and, when clinically indicated, detection of autoimmune antibodies and immune complexes
Renal function studies
Bone density evaluation
Consultation with a biochemical geneticist and/or genetic counselor
The management of individuals with LPI is similar to that described in
Patients should be transitioned from parenteral to enteral feeds as soon as possible. Nasogastric tube feeding may be required to ensure adequate caloric and nutritional intake. Therapy with ondansetron can be started to decrease vomiting.
Complete restriction of protein for more than 24-48 hours is not recommended as the individual will become protein catabolic for essential amino acids.
Measurement of orotic aciduria appears to be a sensitive tool for adjustment of treatment.
While hyperammonemia can be efficiently prevented and treated, no effective therapy has been established for late complications.
In individuals with pulmonary alveolar proteinosis (PAP), treatment with granulocyte/monocyte colony-stimulating factor (GM-CSF) was shown to be ineffective or even to worsen the clinical course [
Heart-lung transplantation was attempted with a temporary successful result, but it did not prevent a fatal return of the lung disease [
Bone marrow transplantation has been discussed as a possible treatment for PAP in LPI. The rationale of this therapeutic approach would rely on the hypothesis of a defective function of lung macrophages [
The prevention of metabolic abnormality is the goal of treatment. Long-term management is based on protein-restricted diet and administration of citrulline (see
The onset and the clinical course of the secondary complications (e.g., lung and renal involvement) appear to be poorly responsive to early treatment.
Efforts to minimize the risk of respiratory infections should be promoted. Vaccination against influenza (and possibly pneumococci) is recommended.
An individual with LPI without previous history of chickenpox or varicella zoster should be vaccinated or, if exposed to varicella, treated as an immune-compromised person.
Some individuals with LPI may respond poorly to polysaccharide-containing vaccines. Therefore, revaccination may be required if specific antibody titers are non-protective.
Individuals with LPI should be referred for follow up to physicians with expertise in the treatment of inborn errors of metabolism. The age of the patient and the severity of the clinical features determine the frequency of clinical visits and monitoring.
Monitoring should include the following:
Plasma concentrations of amino acids to identify deficiencies of essential amino acids induced by the protein-restricted diet (similar to that used in
Attention to early signs of hyperammonemia including lethargy, nausea, vomiting, and poor feeding in young children, and headache and mood changes in older children
Fasting and postprandial blood ammonia concentrations
Urinary orotic acid excretion
Evaluation of renal function
Attention to early clinical signs of lung involvement
Serum concentrations of LDH and ferritin
The development of a multiorgan pathology in LPI requires careful surveillance of several complications including lung and renal diseases and osteoporosis. No specific guidelines have been proposed. Therefore, a tailored approach is necessary for the follow up of a specific complication.
Large boluses of protein or amino acids should be avoided.
It is not clear whether prolonged fasting may trigger hyperammonemic crises.
It is appropriate to evaluate at-risk sibs of a proband in order to reduce morbidity and mortality through early diagnosis and treatment:
If the pathogenic variants in the family are known, molecular genetic testing of at-risk sibs should be performed. Plasma and urine amino acid and urinary orotic acid analyses are recommended in individuals with suspected LPI while awaiting molecular genetic results.
If the pathogenic variants in the family are not known, early diagnosis of at-risk sibs relies on detailed clinical evaluation and determination of plasma and urinary amino acid concentrations and orotic acid urinary excretion.
See
Pregnancy management should be performed in a center familiar with metabolic diseases. Frequent plasma amino acid and ammonia measurements are recommended as well as overall well-being of the mother and fetus. Most infants with LPI are born prematurely (between gestational weeks 31 and 39) [
See
Search
No treatment, including strict compliance with dietary regimen, citrulline supplementation, or high-dose corticosteroids, is effective in influencing the clinical course of the renal disease.
• History for evidence of hyperammonemic crises with overt neurologic manifestations (vomiting, drowsiness, coma) and of respiratory involvement (cough, dyspnea, recurrent lower respiratory tract infections)
• Neurologic evaluation to detect secondary neurologic damage
• Respiratory evaluation including chest x-ray, pulmonary high-resolution computed tomography, and pulmonary function tests
• Evaluation and follow up of growth parameters
• Liver and spleen ultrasound examination to monitor liver structural changes and spleen enlargement
• Hematologic evaluation (bone marrow aspirate may be required)
• Immunologic assessment including plasma concentrations of immune globulins and, when clinically indicated, detection of autoimmune antibodies and immune complexes
• Renal function studies
• Bone density evaluation
• Consultation with a biochemical geneticist and/or genetic counselor
• Plasma concentrations of amino acids to identify deficiencies of essential amino acids induced by the protein-restricted diet (similar to that used in
• Attention to early signs of hyperammonemia including lethargy, nausea, vomiting, and poor feeding in young children, and headache and mood changes in older children
• Fasting and postprandial blood ammonia concentrations
• Urinary orotic acid excretion
• Evaluation of renal function
• Attention to early clinical signs of lung involvement
• Serum concentrations of LDH and ferritin
• If the pathogenic variants in the family are known, molecular genetic testing of at-risk sibs should be performed. Plasma and urine amino acid and urinary orotic acid analyses are recommended in individuals with suspected LPI while awaiting molecular genetic results.
• If the pathogenic variants in the family are not known, early diagnosis of at-risk sibs relies on detailed clinical evaluation and determination of plasma and urinary amino acid concentrations and orotic acid urinary excretion.
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with lysinuric protein intolerance, the following evaluations are recommended if they have not already been completed:
History for evidence of hyperammonemic crises with overt neurologic manifestations (vomiting, drowsiness, coma) and of respiratory involvement (cough, dyspnea, recurrent lower respiratory tract infections)
Neurologic evaluation to detect secondary neurologic damage
Respiratory evaluation including chest x-ray, pulmonary high-resolution computed tomography, and pulmonary function tests
Evaluation and follow up of growth parameters
Liver and spleen ultrasound examination to monitor liver structural changes and spleen enlargement
Hematologic evaluation (bone marrow aspirate may be required)
Immunologic assessment including plasma concentrations of immune globulins and, when clinically indicated, detection of autoimmune antibodies and immune complexes
Renal function studies
Bone density evaluation
Consultation with a biochemical geneticist and/or genetic counselor
• History for evidence of hyperammonemic crises with overt neurologic manifestations (vomiting, drowsiness, coma) and of respiratory involvement (cough, dyspnea, recurrent lower respiratory tract infections)
• Neurologic evaluation to detect secondary neurologic damage
• Respiratory evaluation including chest x-ray, pulmonary high-resolution computed tomography, and pulmonary function tests
• Evaluation and follow up of growth parameters
• Liver and spleen ultrasound examination to monitor liver structural changes and spleen enlargement
• Hematologic evaluation (bone marrow aspirate may be required)
• Immunologic assessment including plasma concentrations of immune globulins and, when clinically indicated, detection of autoimmune antibodies and immune complexes
• Renal function studies
• Bone density evaluation
• Consultation with a biochemical geneticist and/or genetic counselor
## Treatment of Manifestations
The management of individuals with LPI is similar to that described in
Patients should be transitioned from parenteral to enteral feeds as soon as possible. Nasogastric tube feeding may be required to ensure adequate caloric and nutritional intake. Therapy with ondansetron can be started to decrease vomiting.
Complete restriction of protein for more than 24-48 hours is not recommended as the individual will become protein catabolic for essential amino acids.
Measurement of orotic aciduria appears to be a sensitive tool for adjustment of treatment.
While hyperammonemia can be efficiently prevented and treated, no effective therapy has been established for late complications.
In individuals with pulmonary alveolar proteinosis (PAP), treatment with granulocyte/monocyte colony-stimulating factor (GM-CSF) was shown to be ineffective or even to worsen the clinical course [
Heart-lung transplantation was attempted with a temporary successful result, but it did not prevent a fatal return of the lung disease [
Bone marrow transplantation has been discussed as a possible treatment for PAP in LPI. The rationale of this therapeutic approach would rely on the hypothesis of a defective function of lung macrophages [
## Treatment of Acute Hyperammonemic Crises
Patients should be transitioned from parenteral to enteral feeds as soon as possible. Nasogastric tube feeding may be required to ensure adequate caloric and nutritional intake. Therapy with ondansetron can be started to decrease vomiting.
Complete restriction of protein for more than 24-48 hours is not recommended as the individual will become protein catabolic for essential amino acids.
## Long-Term Treatment
Measurement of orotic aciduria appears to be a sensitive tool for adjustment of treatment.
## Treatment of Late Complications
While hyperammonemia can be efficiently prevented and treated, no effective therapy has been established for late complications.
In individuals with pulmonary alveolar proteinosis (PAP), treatment with granulocyte/monocyte colony-stimulating factor (GM-CSF) was shown to be ineffective or even to worsen the clinical course [
Heart-lung transplantation was attempted with a temporary successful result, but it did not prevent a fatal return of the lung disease [
Bone marrow transplantation has been discussed as a possible treatment for PAP in LPI. The rationale of this therapeutic approach would rely on the hypothesis of a defective function of lung macrophages [
## Prevention of Primary Manifestations
The prevention of metabolic abnormality is the goal of treatment. Long-term management is based on protein-restricted diet and administration of citrulline (see
## Prevention of Secondary Complications
The onset and the clinical course of the secondary complications (e.g., lung and renal involvement) appear to be poorly responsive to early treatment.
Efforts to minimize the risk of respiratory infections should be promoted. Vaccination against influenza (and possibly pneumococci) is recommended.
An individual with LPI without previous history of chickenpox or varicella zoster should be vaccinated or, if exposed to varicella, treated as an immune-compromised person.
Some individuals with LPI may respond poorly to polysaccharide-containing vaccines. Therefore, revaccination may be required if specific antibody titers are non-protective.
## Surveillance
Individuals with LPI should be referred for follow up to physicians with expertise in the treatment of inborn errors of metabolism. The age of the patient and the severity of the clinical features determine the frequency of clinical visits and monitoring.
Monitoring should include the following:
Plasma concentrations of amino acids to identify deficiencies of essential amino acids induced by the protein-restricted diet (similar to that used in
Attention to early signs of hyperammonemia including lethargy, nausea, vomiting, and poor feeding in young children, and headache and mood changes in older children
Fasting and postprandial blood ammonia concentrations
Urinary orotic acid excretion
Evaluation of renal function
Attention to early clinical signs of lung involvement
Serum concentrations of LDH and ferritin
The development of a multiorgan pathology in LPI requires careful surveillance of several complications including lung and renal diseases and osteoporosis. No specific guidelines have been proposed. Therefore, a tailored approach is necessary for the follow up of a specific complication.
• Plasma concentrations of amino acids to identify deficiencies of essential amino acids induced by the protein-restricted diet (similar to that used in
• Attention to early signs of hyperammonemia including lethargy, nausea, vomiting, and poor feeding in young children, and headache and mood changes in older children
• Fasting and postprandial blood ammonia concentrations
• Urinary orotic acid excretion
• Evaluation of renal function
• Attention to early clinical signs of lung involvement
• Serum concentrations of LDH and ferritin
## Agents/Circumstances to Avoid
Large boluses of protein or amino acids should be avoided.
It is not clear whether prolonged fasting may trigger hyperammonemic crises.
## Evaluation of Relatives at Risk
It is appropriate to evaluate at-risk sibs of a proband in order to reduce morbidity and mortality through early diagnosis and treatment:
If the pathogenic variants in the family are known, molecular genetic testing of at-risk sibs should be performed. Plasma and urine amino acid and urinary orotic acid analyses are recommended in individuals with suspected LPI while awaiting molecular genetic results.
If the pathogenic variants in the family are not known, early diagnosis of at-risk sibs relies on detailed clinical evaluation and determination of plasma and urinary amino acid concentrations and orotic acid urinary excretion.
See
• If the pathogenic variants in the family are known, molecular genetic testing of at-risk sibs should be performed. Plasma and urine amino acid and urinary orotic acid analyses are recommended in individuals with suspected LPI while awaiting molecular genetic results.
• If the pathogenic variants in the family are not known, early diagnosis of at-risk sibs relies on detailed clinical evaluation and determination of plasma and urinary amino acid concentrations and orotic acid urinary excretion.
## Pregnancy Management
Pregnancy management should be performed in a center familiar with metabolic diseases. Frequent plasma amino acid and ammonia measurements are recommended as well as overall well-being of the mother and fetus. Most infants with LPI are born prematurely (between gestational weeks 31 and 39) [
See
## Therapies Under Investigation
Search
## Other
No treatment, including strict compliance with dietary regimen, citrulline supplementation, or high-dose corticosteroids, is effective in influencing the clinical course of the renal disease.
## Genetic Counseling
Lysinuric protein intolerance (LPI) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Lysinuric protein intolerance (LPI) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier (Heterozygote) Detection
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Diagnosis
## Resources
United Kingdom
Children's National Medical Center
•
•
•
• United Kingdom
•
•
•
•
•
•
•
•
• Children's National Medical Center
•
## Molecular Genetics
Lysinuric Protein Intolerance: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Lysinuric Protein Intolerance (
All types of pathogenic variants have been observed: missense and nonsense variants account for 54.4% and 28.6%, respectively; deletions, insertions, splicing variants, and large genomic rearrangements together account for 3.6%) (
Selected
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Described in Italian and North African individuals; see
Founder variant of Finnish population; previously reported as 1181-2A>T by
## References
## Literature Cited
## Chapter Notes
Spanish Health Institute Carlos III Grants: FIS PI13/00121-R-FEDER and PI16/00267-R-FEDER (to V.N.), Generalitat de Catalunya Grants SGR2009-1490 (to V.N.)
Simona Fecarotta, MD; Federico II University (2006-2011)Harri Niinikoski, MD, PhD (2018-present)Virginia Nunes, PhD (2011-present)Gianfranco Sebastio, MD; Federico Il University (2006-2018)Maria Pia Sperandeo, PhD; Federico Il University (2006-2011)
12 April 2018 (sw) Comprehensive update posted live
13 October 2011 (cd) Revision: targeted mutation analysis for the c.895-2A>T founder mutation available clinically
31 May 2011 (me) Comprehensive update posted live
21 December 2006 (me) Review posted live
22 September 2006 (gs) Original submission
• 12 April 2018 (sw) Comprehensive update posted live
• 13 October 2011 (cd) Revision: targeted mutation analysis for the c.895-2A>T founder mutation available clinically
• 31 May 2011 (me) Comprehensive update posted live
• 21 December 2006 (me) Review posted live
• 22 September 2006 (gs) Original submission
## Acknowledgments
Spanish Health Institute Carlos III Grants: FIS PI13/00121-R-FEDER and PI16/00267-R-FEDER (to V.N.), Generalitat de Catalunya Grants SGR2009-1490 (to V.N.)
## Author History
Simona Fecarotta, MD; Federico II University (2006-2011)Harri Niinikoski, MD, PhD (2018-present)Virginia Nunes, PhD (2011-present)Gianfranco Sebastio, MD; Federico Il University (2006-2018)Maria Pia Sperandeo, PhD; Federico Il University (2006-2011)
## Revision History
12 April 2018 (sw) Comprehensive update posted live
13 October 2011 (cd) Revision: targeted mutation analysis for the c.895-2A>T founder mutation available clinically
31 May 2011 (me) Comprehensive update posted live
21 December 2006 (me) Review posted live
22 September 2006 (gs) Original submission
• 12 April 2018 (sw) Comprehensive update posted live
• 13 October 2011 (cd) Revision: targeted mutation analysis for the c.895-2A>T founder mutation available clinically
• 31 May 2011 (me) Comprehensive update posted live
• 21 December 2006 (me) Review posted live
• 22 September 2006 (gs) Original submission
|
[
"A Barilli, BM Rotoli, R Visigalli, O Bussolati, GC Gazzola, Z Kadija, G Rodi, F Mariani, ML Ruzza, M Luisetti, V Dall'Asta. In lysinuric protein intolerance system y+L activity is defective in monocytes and in GM-CSF-differentiated macrophages.. Orphanet J Rare Dis 2010;5:32",
"G Borsani, MT Bassi, MP Sperandeo, A De Grandi, A Buoninconti, M Riboni, M Manzoni, B Incerti, A Pepe, G Andria, A Ballabio, G Sebastio. SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance.. Nat Genet. 1999;21:297-301",
"D Carpentieri, MF Barnhart, K Aleck, T Miloh, D deMello. Lysinuric protein intolerance in a family of Mexican ancestry with a novel SLC7A7 gene deletion. Case report and review of the literature.. Mol Genet Metab Rep 2015;2:47-50",
"M Ceruti, G Rodi, GM Stella, A Adami, A Bolongaro, A Baritussio, E Pozzi, M Luisetti. Successful whole lung lavage in pulmonary alveolar proteinosis secondary to lysinuric protein intolerance: a case report.. Orphanet J Rare Dis 2007;2:14",
"L Cimbalistiene, W Lehnert, K Huoponen, V Kucinskas. First reported case of lysinuric protein intolerance (LPI) in Lithuania, confirmed biochemically and by DNA analysis.. J Appl Genet 2007;48:277-80",
"DN Douda, N Farmakovski, S Dell, H Grasemann, N Palaniyar. SP-D counteracts GM-CSF-mediated increase of granuloma formation by alveolar macrophages in lysinuric protein intolerance.. Orphanet J Rare Dis 2009;4:29",
"N Esseghir, CS Bouchlaka, SH Fredj, AB Chehida, H Azzouz, M Fontaine, N Tebib, MF Dridi, G Briand, T Messaoud, AB Elgaaied, N Kaabachi. First report of a molecular prenatal diagnosis in a Tunisian family with lysinuric protein intolerance.. JIMD Rep 2011;1:37-8",
"E Estève, P Krug, A Hummel, JB Arnoux, O Boyer, A Brassier, P de Lonlay, V Vuiblet, S Gobin, R Salomon, C Pietrement, JP Bonnefont, A Servais, L Galmiche. Renal involvement in lysinuric protein intolerance: contribution of pathology to assessment of heterogeneity of renal lesions.. Hum Pathol 2017;62:160-9",
"M Font-Llitjós, B Rodriguez-Santiago, M Espino, R Sillue, S Manas, L Gomez, LA Perez-Jurado, M Palacin, V Nunes. Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat.. Eur J Hum Genet 2009;17:71-9",
"J. Häberle. Clinical practice: the management of hyperammonemia.. Eur J Pediatr 2011;170:21-34",
"M Kärki, K Nanto-Salonen, H Niinikoski, LM Tanner. Urine beta2-microglobulin is an early marker of renal involvement in LPI.. JIMD Rep 2016;25:47-55",
"A Koizumi, Y Shoji, J Nozaki, A Noguchi. E X, Dakeishi M, Ohura T, Tsuyoshi K, Yasuhiko W, Manabe M, Takasago Y, Takada G. A cluster of lysinuric protein intolerance (LPI) patients in a northern part of Iwate, Japan due to a founder effect. The Mass Screening Group.. Hum Mutat 2000;16:270-1",
"W Mauhin, F Habarou, S Gobin, A Servais, A Brassier, C Grisel, C Roda, G Pinto, D Moshous, F Ghalim, P Krug, N Deltour, C Pontoizeau, S Dubois, M Assoun, L Galmiche, JP Bonnefont, C Ottolenghi, J de Blic, JB Arnoux, P de Lonlay. Update on lysinuric protein intolerance, a multi-faceted disease retrospective cohort analysis from birth to adulthood.. Orphanet J Rare Dis 2017;12:3",
"J Mykkänen, D Torrents, M Pineda, M Camps, ME Yoldi, N Horelli-Kuitunen, K Huoponen, M Heinonen, J Oksanen, O Simell, ML Savontaus, A Zorzano, M Palacin, P Aula. Functional analysis of novel mutations in y(+)LAT-1 amino acid transporter gene causing lysinuric protein intolerance (LPI).. Hum Mol Genet 2000;9:431-8",
"C Nicolas, N Bednarek, V Vuiblet, O Boyer, A Brassier, P De Lonlay, L Galmiche, P Krug, V Baudouin, S Pichard, M Schiff, C Pietrement. Renal involvement in a French paediatric cohort of patients with lysinuric protein intolerance.. JIMD Rep 2016;29:11-7",
"H Niinikoski, R Lapatto, M Nuutinen, L Tanner, O Simell, K Nanto-Salonen. Growth hormone therapy is safe and effective in patients with lysinuric protein intolerance.. JIMD Rep 2011;1:43-7",
"A Noguchi, K Nakamura, K Murayama, S Yamamoto, H Komatsu, R Kizu, M Takayanagi, T Okuyama, F Endo, Y Takasago, Y Shoji, T. Takahashi. Clinical and genetic features of lysinuric protein intolerance in Japan.. Pediatr Int 2016;58:979-83",
"F Santamaria, G Brancaccio, G Parenti, P Francalanci, C Squitieri, G Sebastio, C Dionisi-Vici, P D'Argenio, G Andria, F Parisi. Recurrent fatal pulmonary alveolar proteinosis after heart-lung transplantation in a child with lysinuric protein intolerance.. J Pediatr 2004;145:268-72",
"F. Scaglia. New insights in nutritional management and amino acid supplementation in urea cycle disorders.. Mol Genet Metab 2010;100:S72-6",
"G Sebastio, MP Sperandeo, G Andria. Lysinuric protein intolerance: reviewing concepts on a multisystem disease.. Am J Med Genet C Semin Med Genet 2011;157C:54-62",
"Y Shoji, A Noguchi, Y Shoji, M Matsumori, Y Takasago, M Takayanagi, Y Yoshida, K Ihara, T Hara, S Yamaguchi, M Yoshino, M Kaji, S Yamamoto, A Nakai, A Koizumi, Y Hokezu, K Nagamatsu, H Mikami, I Kitajima, G. Takada. Five novel SLC7A7 variants and y+L gene-expression pattern in cultured lymphoblasts from Japanese patients with lysinuric protein intolerance.. Hum Mutat 2002;20:375-81",
"MP Sperandeo, G Andria, G Sebastio. Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene.. Hum Mutat 2008;29:14-21",
"MP Sperandeo, P Annunziata, V Ammendola, V Fiorito, A Pepe, MV Soldovieri, M Taglialatela, G Andria, G Sebastio. Lysinuric protein intolerance: identification and functional analysis of mutations of the SLC7A7 gene.. Hum Mutat 2005;25:410",
"MP Sperandeo, MT Bassi, M Riboni, G Parenti, A Buoninconti, M Manzoni, B Incerti, MR Larocca, M Di Rocco, P Strisciuglio, I Dianzani, R Parini, M Candito, F Endo, A Ballabio, G Andria, G Sebastio, G Borsani. Structure of the SLC7A7 gene and mutational analysis of patients affected by lysinuric protein intolerance.. Am J Hum Genet 2000;66:92-9",
"L Tanner, K Nanto-Salonen, H Niinikoski, R Erkkola, K Huoponen, O Simell. Hazards associated with pregnancies and deliveries in lysinuric protein intolerance.. Metabolism 2006;55:224-31",
"LM Tanner, K Nanto-Salonen, MS Rashed, S Kotilainen, M Aalto, J Venetoklis, H Niinikoski, K Huoponen, O Simell. Carnitine deficiency and L-carnitine supplementation in lysinuric protein intolerance.. Metabolism 2008;57:549-54",
"LM Tanner, H Niinikoski, K Nanto-Salonen, O Simell. Combined hyperlipidemia in patients with lysinuric protein intolerance.. J Inherit Metab Dis 2010;33:S145-50",
"D Torrents, J Mykkänen, M Pineda, L Feliubadalo, R Estevez, R de Cid, P Sanjurjo, A Zorzano, V Nunes, K Huoponen, A Reinikainen, O Simell, ML Savontaus, P Aula, M Palacin. Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene.. Nat Genet 1999;21:293-6",
"S Valimahamed-Mitha, L Berteloot, H Ducoin, C Ottolenghi, P de Lonlay, J de Blic. Lung involvement in children with lysinuric protein intolerance.. J Inherit Metab Dis 2015;38:257-63"
] |
21/12/2006
|
12/4/2018
|
13/10/2011
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
lpin2-majeed
|
lpin2-majeed
|
[
"Phosphatidate phosphatase LPIN2",
"LPIN2",
"LPIN2-Related Majeed Syndrome"
] |
Dhanya Lakshmi Narayanan, Kishore Sai Gogineni, Vaishnavi Ashok Badiger
|
Summary Individuals with The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Recurrent bone pain near the joints, often of the long bones of the lower extremities
Joint swelling and subsequent joint contracture
Chronic recurrent multifocal osteomyelitis that is sterile
Neutrophilic dermatosis, which may present as painful erythematous plaques, pustules, or nodules with neutrophilic infiltrates
Note: This finding can be transient.
Failure to thrive
Recurrent fever
Hepatosplenomegaly
Gastrointestinal issues, including recurrent abdominal pain and/or recurrent diarrhea
Elevated erythrocyte sedimentation rate (ESR), typically above 100 mm/hr, and C-reactive protein (CRP), often above 50 mg/L
Neutropenia
Congenital dyserythropoietic, microcytic anemia, ranging from mild to severe, that sometimes requires blood transfusion
Bone marrow biopsy that demonstrates erythroid hyperplasia with binuclearity or multinuclearity suggestive of congenital dyserythropeitic anemia
Note: Bone marrow biopsy is not required to make this diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by periodic fevers and/or autoinflammatory findings, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the authors' observations and the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Recurrent bone pain near the joints, often of the long bones of the lower extremities
• Joint swelling and subsequent joint contracture
• Chronic recurrent multifocal osteomyelitis that is sterile
• Neutrophilic dermatosis, which may present as painful erythematous plaques, pustules, or nodules with neutrophilic infiltrates
• Note: This finding can be transient.
• Failure to thrive
• Recurrent fever
• Hepatosplenomegaly
• Gastrointestinal issues, including recurrent abdominal pain and/or recurrent diarrhea
• Elevated erythrocyte sedimentation rate (ESR), typically above 100 mm/hr, and C-reactive protein (CRP), often above 50 mg/L
• Neutropenia
• Congenital dyserythropoietic, microcytic anemia, ranging from mild to severe, that sometimes requires blood transfusion
• Bone marrow biopsy that demonstrates erythroid hyperplasia with binuclearity or multinuclearity suggestive of congenital dyserythropeitic anemia
• Note: Bone marrow biopsy is not required to make this diagnosis
• For an introduction to multigene panels click
## Suggestive Findings
Recurrent bone pain near the joints, often of the long bones of the lower extremities
Joint swelling and subsequent joint contracture
Chronic recurrent multifocal osteomyelitis that is sterile
Neutrophilic dermatosis, which may present as painful erythematous plaques, pustules, or nodules with neutrophilic infiltrates
Note: This finding can be transient.
Failure to thrive
Recurrent fever
Hepatosplenomegaly
Gastrointestinal issues, including recurrent abdominal pain and/or recurrent diarrhea
Elevated erythrocyte sedimentation rate (ESR), typically above 100 mm/hr, and C-reactive protein (CRP), often above 50 mg/L
Neutropenia
Congenital dyserythropoietic, microcytic anemia, ranging from mild to severe, that sometimes requires blood transfusion
Bone marrow biopsy that demonstrates erythroid hyperplasia with binuclearity or multinuclearity suggestive of congenital dyserythropeitic anemia
Note: Bone marrow biopsy is not required to make this diagnosis
• Recurrent bone pain near the joints, often of the long bones of the lower extremities
• Joint swelling and subsequent joint contracture
• Chronic recurrent multifocal osteomyelitis that is sterile
• Neutrophilic dermatosis, which may present as painful erythematous plaques, pustules, or nodules with neutrophilic infiltrates
• Note: This finding can be transient.
• Failure to thrive
• Recurrent fever
• Hepatosplenomegaly
• Gastrointestinal issues, including recurrent abdominal pain and/or recurrent diarrhea
• Elevated erythrocyte sedimentation rate (ESR), typically above 100 mm/hr, and C-reactive protein (CRP), often above 50 mg/L
• Neutropenia
• Congenital dyserythropoietic, microcytic anemia, ranging from mild to severe, that sometimes requires blood transfusion
• Bone marrow biopsy that demonstrates erythroid hyperplasia with binuclearity or multinuclearity suggestive of congenital dyserythropeitic anemia
• Note: Bone marrow biopsy is not required to make this diagnosis
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by periodic fevers and/or autoinflammatory findings, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the authors' observations and the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by periodic fevers and/or autoinflammatory findings, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the authors' observations and the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Individuals with
To date, 32 individuals from 19 families have been identified with a pathogenic variant in
No genotype-phenotype correlations have been identified.
The prevalence of
## Clinical Description
Individuals with
To date, 32 individuals from 19 families have been identified with a pathogenic variant in
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; MOI = mode of inheritance
SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome
Chronic nonbacterial osteomyelitis
• SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome
• Chronic nonbacterial osteomyelitis
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Community or
Social work involvement for parental support;
Home nursing referral.
CBC = complete blood count; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Treatment of Manifestations in Individuals with
Anakinra 1.5mg/kg/day w/titration as needed
Canakinumab 2mg/kg every 4 or 8 wks
This finding may improve w/anti-inflammatory treatment.
Splenectomy may be considered.
Anti-IL-1 = anti-interleukin-1; PT = physical therapy; OT = occupational therapy
Anti-inflammatory treatment decreases inflammation and reduces flare ups.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Recommended Surveillance for Individuals with
CBC = complete blood count; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate
For affected individuals managed with biologic or immunosuppressive medications, live-attenuated vaccines should be avoided, when possible.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual to identify as early as possible those who would benefit from prompt initiation of anti-inflammatory treatment. Evaluations can include:
Targeted molecular genetic testing if the pathogenic variants in the family are known;
If the pathogenic variants in the family are unknown, clinical assessment (history and physical exam for signs/symptoms of systemic inflammation, full skin examination for rashes, assessment of inflammatory markers [serum C-reactive protein & erythrocyte sedimentation rate], and complete blood count with differential) can be considered.
See
Information regarding the safety of the use of anakinra in human pregnancy is limited; however, based on animal models, the use of such therapy during human pregnancy is not anticipated to lead to an increased risk of congenital anomalies in the fetus. There is no available data on the use of canakinumab during human pregnancy. However, to date there has not been a pattern of birth anomalies reported with anti-interleukin-1 medication classes.
The use of corticosteroids during human pregnancy has been associated with an increased risk of cleft lip with or without cleft palate in exposed fetuses. Medications should be discussed with a health care provider during pregnancy or when planning to conceive [
Methotrexate is known to be harmful to the developing fetus and can lead to pregnancy loss and/or birth defects. Fetal outcome depends on the dose of methotrexate used, the duration of exposure, and the gestational age of the fetus during the exposure period. Methotrexate ideally should be discontinued prior to attempting to conceive.
See
The clinical trial
Search
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Anakinra 1.5mg/kg/day w/titration as needed
• Canakinumab 2mg/kg every 4 or 8 wks
• This finding may improve w/anti-inflammatory treatment.
• Splenectomy may be considered.
• Targeted molecular genetic testing if the pathogenic variants in the family are known;
• If the pathogenic variants in the family are unknown, clinical assessment (history and physical exam for signs/symptoms of systemic inflammation, full skin examination for rashes, assessment of inflammatory markers [serum C-reactive protein & erythrocyte sedimentation rate], and complete blood count with differential) can be considered.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Community or
Social work involvement for parental support;
Home nursing referral.
CBC = complete blood count; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There is no cure for
Treatment of Manifestations in Individuals with
Anakinra 1.5mg/kg/day w/titration as needed
Canakinumab 2mg/kg every 4 or 8 wks
This finding may improve w/anti-inflammatory treatment.
Splenectomy may be considered.
Anti-IL-1 = anti-interleukin-1; PT = physical therapy; OT = occupational therapy
Anti-inflammatory treatment decreases inflammation and reduces flare ups.
• Anakinra 1.5mg/kg/day w/titration as needed
• Canakinumab 2mg/kg every 4 or 8 wks
• This finding may improve w/anti-inflammatory treatment.
• Splenectomy may be considered.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Recommended Surveillance for Individuals with
CBC = complete blood count; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate
## Agents/Circumstances to Avoid
For affected individuals managed with biologic or immunosuppressive medications, live-attenuated vaccines should be avoided, when possible.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual to identify as early as possible those who would benefit from prompt initiation of anti-inflammatory treatment. Evaluations can include:
Targeted molecular genetic testing if the pathogenic variants in the family are known;
If the pathogenic variants in the family are unknown, clinical assessment (history and physical exam for signs/symptoms of systemic inflammation, full skin examination for rashes, assessment of inflammatory markers [serum C-reactive protein & erythrocyte sedimentation rate], and complete blood count with differential) can be considered.
See
• Targeted molecular genetic testing if the pathogenic variants in the family are known;
• If the pathogenic variants in the family are unknown, clinical assessment (history and physical exam for signs/symptoms of systemic inflammation, full skin examination for rashes, assessment of inflammatory markers [serum C-reactive protein & erythrocyte sedimentation rate], and complete blood count with differential) can be considered.
## Pregnancy Management
Information regarding the safety of the use of anakinra in human pregnancy is limited; however, based on animal models, the use of such therapy during human pregnancy is not anticipated to lead to an increased risk of congenital anomalies in the fetus. There is no available data on the use of canakinumab during human pregnancy. However, to date there has not been a pattern of birth anomalies reported with anti-interleukin-1 medication classes.
The use of corticosteroids during human pregnancy has been associated with an increased risk of cleft lip with or without cleft palate in exposed fetuses. Medications should be discussed with a health care provider during pregnancy or when planning to conceive [
Methotrexate is known to be harmful to the developing fetus and can lead to pregnancy loss and/or birth defects. Fetal outcome depends on the dose of methotrexate used, the duration of exposure, and the gestational age of the fetus during the exposure period. Methotrexate ideally should be discontinued prior to attempting to conceive.
See
## Therapies Under Investigation
The clinical trial
Search
## Genetic Counseling
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Phenotypic variability was described in a family with two affected individuals. One of the affected boys had onset of symptoms at age two years and had a severe course of illness compared to his affected first cousin, who had later onset of symptoms and a milder presentation [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Phenotypic variability was described in a family with two affected individuals. One of the affected boys had onset of symptoms at age two years and had a severe course of illness compared to his affected first cousin, who had later onset of symptoms and a milder presentation [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Phenotypic variability was described in a family with two affected individuals. One of the affected boys had onset of symptoms at age two years and had a severe course of illness compared to his affected first cousin, who had later onset of symptoms and a milder presentation [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Phenotypic variability was described in a family with two affected individuals. One of the affected boys had onset of symptoms at age two years and had a severe course of illness compared to his affected first cousin, who had later onset of symptoms and a milder presentation [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Familial Mediterranean Fever & Autoinflammatory Diseases
India
•
•
•
• Familial Mediterranean Fever & Autoinflammatory Diseases
•
•
•
•
•
•
• India
•
## Molecular Genetics
LPIN2-Related Majeed Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for LPIN2-Related Majeed Syndrome (
## Molecular Pathogenesis
## Chapter Notes
Dr Dhanya Narayanan is a DBT Wellcome Trust India Alliance Early Career clinical and Public Health research fellow. For more information on the project, visit
We thank the DBT Wellcome Trust India Alliance for funding the study "Understanding Autoinflammatory Diseases through Clinical, Genomic and Functional Approaches" [IA/CPHE/20/1/505226].
2 March 2023 (ma) Review posted live
6 September 2022 (dln) Original submission
• 2 March 2023 (ma) Review posted live
• 6 September 2022 (dln) Original submission
## Author Notes
Dr Dhanya Narayanan is a DBT Wellcome Trust India Alliance Early Career clinical and Public Health research fellow. For more information on the project, visit
## Acknowledgments
We thank the DBT Wellcome Trust India Alliance for funding the study "Understanding Autoinflammatory Diseases through Clinical, Genomic and Functional Approaches" [IA/CPHE/20/1/505226].
## Revision History
2 March 2023 (ma) Review posted live
6 September 2022 (dln) Original submission
• 2 March 2023 (ma) Review posted live
• 6 September 2022 (dln) Original submission
## References
## Literature Cited
|
[
"F Bhuyan, AA de Jesus, J Mitchell, E Leikina, R VanTries, R Herzog, KB Onel, A Oler, GA Montealegre Sanchez, KA Johnson, L Bichell, B Marrero, LF De Castro, Y Huang, KR Calvo, MT Collins, S Ganesan, LV Chernomordik, PJ Ferguson, R Goldbach-Mansky. Novel Majeed syndrome-causing LPIN2 mutations link bone inflammation to inflammatory M2 macrophages and accelerated osteoclastogenesis.. Arthritis Rheumatol. 2021;73:1021-32",
"PP Chavan, I Aksentijevich, A Daftary, H Panwala, C Khemani, A Khan, R Khubchandani. Majeed syndrome: five cases with novel mutations from unrelated families in India with a review of literature.. J Rheumatol. 2021;48:1850-55",
"PJ Ferguson, H El-Shanti. Majeed syndrome: a review of the clinical, genetic, and immunologic features.. Biomolecules. 2021;11:367",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"G Lordén, I Sanjuán-García, N de Pablo, C Meana, I Alvarez-Miguel, MT Pérez-García, P Pelegrín, J Balsinde, MA Balboa. Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation.. J Exp Med. 2017;214:511-28",
"AP Rao, DB Gopalakrishna, X Bing, PJ Ferguson. Phenotypic variability in Majeed syndrome.. J Rheumatol. 2016;43:1258-9",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"L Sun, P Zhang, Y Song, F Liu, Q. Huang. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2021;38:775-78",
"T Youngstein, P Hoffmann, A Gül, T Lane, R Williams, DM Rowczenio, H Ozdogan, S Ugurlu, J Ryan, L Harty, S Riminton, AP Headley, J Roesler, N Blank, JB Kuemmerle-Deschner, A Simon, AS Woolf, PN Hawkins, HJ Lachmann. International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors.. Rheumatology (Oxford) 2017;56:2102-8"
] |
2/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
lpl
|
lpl
|
[
"Familial LPL Deficiency",
"Type I Hyperlipoproteinemia",
"Familial Chylomicronemia Syndrome",
"Familial LPL Deficiency",
"Lipoprotein lipase",
"LPL",
"Familial Lipoprotein Lipase Deficiency"
] |
Familial Lipoprotein Lipase Deficiency
|
John R Burnett, Amanda J Hooper, Robert A Hegele
|
Summary Familial lipoprotein lipase (LPL) deficiency usually presents in childhood and is characterized by very severe hypertriglyceridemia with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Clearance of chylomicrons from the plasma is impaired, causing triglycerides to accumulate in plasma and the plasma to have a milky (lactescent or lipemic) appearance. Symptoms usually resolve with restriction of total dietary fat to ≤20 g/day. The diagnosis of LPL deficiency is established in a proband by the identification of biallelic pathogenic variants in Familial LPL deficiency is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
|
## Diagnosis
Familial lipoprotein lipase (LPL) deficiency
Recurrent acute pancreatitis
Eruptive cutaneous xanthomata
Hepatosplenomegaly
Impaired clearance of chylomicrons from plasma causing the plasma to have a milky (lactescent or lipemic) appearance
Plasma triglyceride concentrations greater than 2000 mg/dL in the untreated state, regardless of fasting status
The diagnosis of LPL deficiency
A consensus diagnostic algorithm has been published [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Familial Lipoprotein Lipase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
LPL enzyme activity can be assayed in plasma taken ten minutes following intravenous administration of heparin (60 U/kg body weight). The absence of LPL enzyme activity in postheparin plasma is diagnostic of familial LPL deficiency.
LPL enzyme activity may be assayed directly in biopsies of adipose tissue.
• Recurrent acute pancreatitis
• Eruptive cutaneous xanthomata
• Hepatosplenomegaly
• Impaired clearance of chylomicrons from plasma causing the plasma to have a milky (lactescent or lipemic) appearance
• Plasma triglyceride concentrations greater than 2000 mg/dL in the untreated state, regardless of fasting status
• For an introduction to multigene panels click
• LPL enzyme activity can be assayed in plasma taken ten minutes following intravenous administration of heparin (60 U/kg body weight). The absence of LPL enzyme activity in postheparin plasma is diagnostic of familial LPL deficiency.
• LPL enzyme activity may be assayed directly in biopsies of adipose tissue.
## Suggestive Findings
Familial lipoprotein lipase (LPL) deficiency
Recurrent acute pancreatitis
Eruptive cutaneous xanthomata
Hepatosplenomegaly
Impaired clearance of chylomicrons from plasma causing the plasma to have a milky (lactescent or lipemic) appearance
Plasma triglyceride concentrations greater than 2000 mg/dL in the untreated state, regardless of fasting status
• Recurrent acute pancreatitis
• Eruptive cutaneous xanthomata
• Hepatosplenomegaly
• Impaired clearance of chylomicrons from plasma causing the plasma to have a milky (lactescent or lipemic) appearance
• Plasma triglyceride concentrations greater than 2000 mg/dL in the untreated state, regardless of fasting status
## Establishing the Diagnosis
The diagnosis of LPL deficiency
A consensus diagnostic algorithm has been published [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Familial Lipoprotein Lipase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
LPL enzyme activity can be assayed in plasma taken ten minutes following intravenous administration of heparin (60 U/kg body weight). The absence of LPL enzyme activity in postheparin plasma is diagnostic of familial LPL deficiency.
LPL enzyme activity may be assayed directly in biopsies of adipose tissue.
• For an introduction to multigene panels click
• LPL enzyme activity can be assayed in plasma taken ten minutes following intravenous administration of heparin (60 U/kg body weight). The absence of LPL enzyme activity in postheparin plasma is diagnostic of familial LPL deficiency.
• LPL enzyme activity may be assayed directly in biopsies of adipose tissue.
## Clinical Characteristics
Familial lipoprotein lipase (LPL) deficiency usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Males and females are affected equally.
Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age ten years; however, some individuals present for the first time during pregnancy. The severity of symptoms correlates with the degree of chylomicronemia. Chylomicrons are large triglyceride-rich lipoprotein particles that appear in the circulation shortly after the ingestion of dietary fat; normally, they are cleared from plasma after an overnight fast. The degree of chylomicronemia in LPL deficiency varies by dietary fat intake.
The abdominal pain, which can vary from mildly bothersome to incapacitating, is usually mid-epigastric with radiation to the back. It may be diffuse and mimic an acute abdomen, often leading to unnecessary abdominal exploratory surgery. The pain probably results from chylomicronemia leading to pancreatitis.
About 50% of individuals with familial LPL deficiency have eruptive xanthomas, small yellow papules localized over the trunk, buttocks, knees, and extensor surfaces of the arms. Xanthomas are deposits of lipid in the skin that result from the extravascular phagocytosis of chylomicrons by macrophages. They can appear rapidly when plasma triglyceride concentration exceeds 2000 mg/dL and can sometimes regress if plasma triglyceride is normalized.
Xanthomas may become generalized. As a single lesion, they may be several millimeters in diameter; rarely, they may coalesce into plaques. They are usually not tender unless they occur at a site susceptible to repeated abrasion.
Hepatomegaly and splenomegaly often occur when plasma triglyceride concentrations are markedly increased. The organomegaly results from triglyceride uptake by macrophages, which become foam cells.
When triglyceride concentrations exceed 4000 mg/dL, the retinal arterioles and venules, and often the fundus itself, develop a pale pink color ("lipemia retinalis"), caused by light scattering by large chylomicrons. This coloration is reversible and vision is not affected.
Reversible neuropsychiatric findings, including mild dementia, depression, and memory loss, have also been reported with chylomicronemia [
As most pathogenic
Familial LPL deficiency is the most common form of the familial chylomicronemia syndrome, which was formerly known as "type 1 hyperlipoproteinemia."
The prevalence of familial LPL deficiency is approximately one in 1,000,000 in the general US population.
The disease has been described in all races. The prevalence is much higher in some areas of Quebec, Canada as a result of a founder effect.
Consanguinity is observed in some families with familial LPL deficiency caused by homozygous pathogenic
## Clinical Description
Familial lipoprotein lipase (LPL) deficiency usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Males and females are affected equally.
Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age ten years; however, some individuals present for the first time during pregnancy. The severity of symptoms correlates with the degree of chylomicronemia. Chylomicrons are large triglyceride-rich lipoprotein particles that appear in the circulation shortly after the ingestion of dietary fat; normally, they are cleared from plasma after an overnight fast. The degree of chylomicronemia in LPL deficiency varies by dietary fat intake.
The abdominal pain, which can vary from mildly bothersome to incapacitating, is usually mid-epigastric with radiation to the back. It may be diffuse and mimic an acute abdomen, often leading to unnecessary abdominal exploratory surgery. The pain probably results from chylomicronemia leading to pancreatitis.
About 50% of individuals with familial LPL deficiency have eruptive xanthomas, small yellow papules localized over the trunk, buttocks, knees, and extensor surfaces of the arms. Xanthomas are deposits of lipid in the skin that result from the extravascular phagocytosis of chylomicrons by macrophages. They can appear rapidly when plasma triglyceride concentration exceeds 2000 mg/dL and can sometimes regress if plasma triglyceride is normalized.
Xanthomas may become generalized. As a single lesion, they may be several millimeters in diameter; rarely, they may coalesce into plaques. They are usually not tender unless they occur at a site susceptible to repeated abrasion.
Hepatomegaly and splenomegaly often occur when plasma triglyceride concentrations are markedly increased. The organomegaly results from triglyceride uptake by macrophages, which become foam cells.
When triglyceride concentrations exceed 4000 mg/dL, the retinal arterioles and venules, and often the fundus itself, develop a pale pink color ("lipemia retinalis"), caused by light scattering by large chylomicrons. This coloration is reversible and vision is not affected.
Reversible neuropsychiatric findings, including mild dementia, depression, and memory loss, have also been reported with chylomicronemia [
## Genotype-Phenotype Correlations
As most pathogenic
## Nomenclature
Familial LPL deficiency is the most common form of the familial chylomicronemia syndrome, which was formerly known as "type 1 hyperlipoproteinemia."
## Prevalence
The prevalence of familial LPL deficiency is approximately one in 1,000,000 in the general US population.
The disease has been described in all races. The prevalence is much higher in some areas of Quebec, Canada as a result of a founder effect.
Consanguinity is observed in some families with familial LPL deficiency caused by homozygous pathogenic
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Familial lipoprotein lipase (LPL) deficiency should be considered in young persons with the chylomicronemia syndrome, defined as abdominal pain, eruptive xanthomata, plasma triglyceride concentrations greater than 2000 mg/dL, and fasting lipemic plasma. However, the majority of individuals with chylomicronemia and plasma triglyceride concentration greater than 2000 mg/dL do not have familial LPL deficiency; rather, they have one of the more common genetic disorders of triglyceride metabolism (i.e., familial combined hyperlipidemia and monogenic familial hypertriglyceridemia). Hypertriglyceridemia can also be polygenic, due to both heterozygous rare large-effect variants and accumulations of common rare small-effect variants in several genes and loci [
Secondary causes of hypertriglyceridemia include: diabetes mellitus; paraproteinemia and lymphoproliferative disorders; use of alcohol; and therapy with estrogen, glucocorticoids, selective serotonin reuptake inhibitors, atypical antipsychotic agents, isotretinoin, or certain antihypertensive agents. In one series of 123 individuals evaluated for marked hypertriglyceridemia, 110 had an acquired cause of hypertriglyceridemia combined with a common genetic form of hypertriglyceridemia, five had familial LPL deficiency, five had other rare genetic forms of hypertriglyceridemia, and three had an unknown cause [
Other than LPL deficiency, the chylomicronemia syndrome may be caused by biallelic pathogenic variants in apolipoprotein C-II (
Genetic Causes of Primary Monogenic Chylomicronemia
From
apoA-V = apolipoprotein A-V; apoC-II = apolipoprotein C-II; FFA = free fatty acid; GPI-HBP1 = glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1; LMF1 = lipase maturation factor 1; LPL = lipoprotein lipase
## Management
To establish the extent of disease and needs in an individual diagnosed with familial lipoprotein lipase (LPL) deficiency, measurement of plasma triglyceride concentration is recommended.
Consultation with a clinical geneticist and/or genetic counselor may also be considered.
Medium-chain triglycerides may be used for cooking, as they are absorbed directly into the portal vein without becoming incorporated into chylomicron triglyceride.
The success of therapy depends on the individual's acceptance of the fat restriction, including both unsaturated and saturated fat. Note: Fish oil supplements, which are effective in disorders of excess hepatic triglyceride production, are not effective in LPL deficiency and are contraindicated (see
The enlarged liver and spleen can return to normal size within one week of lowering of triglyceride concentrations.
The xanthomas can clear over the course of weeks to months. Recurrent or persistent eruptive xanthomas indicate inadequate therapy.
Pancreatitis associated with the chylomicronemia syndrome is treated in the manner typical for other forms of pancreatitis.
Discontinuation of oral fat intake stops chylomicron triglyceride formation, and replacement with hypocaloric parenteral nutrition decreases VLDL triglyceride production.
Administration of excess calories, as in hyperalimentation, is contraindicated in the acute state. The intravenous administration of lipid emulsions may lead to persistent or recurrent pancreatitis.
If recurrent pancreatitis with severe hypertriglyceridemia occurs, total dietary fat intake needs to be reduced.
See
Prevention of recurrent acute pancreatitis decreases the risk of developing diabetes mellitus. Fat malabsorption is very rare.
Plasma triglyceride levels need to be followed over time to evaluate the affected individual’s success in following the very low-fat dietary recommendations. When the triglyceride level is above 1000 mg/dL, a fasting sample is not required for this evaluation. Other components of the lipid profile do not need to be routinely measured.
Affected individuals who develop abdominal pain need to contact their physician.
Avoidance of agents known to increase endogenous triglyceride concentration such as alcohol, oral estrogens, diuretics, isotretinoin, glucocorticoids, selective serotonin reuptake inhibitors, and beta-adrenergic blocking agents is recommended.
Fish oil supplements are contraindicated as they contribute to chylomicron levels.
It is appropriate to evaluate at-risk sibs during infancy. Early diagnosis and implementation of dietary fat intake restriction can prevent symptoms and related medical complications.
Evaluations can include:
Measurement of plasma triglyceride concentration;
Molecular genetic testing if the pathogenic variants in the family are known.
See
During pregnancy in a woman with LPL deficiency, extreme dietary fat restriction to less than two grams per day during the second and third trimester with close monitoring of plasma triglyceride concentration can result in delivery of a normal infant with normal plasma concentrations of essential fatty acids [
One woman with LPL deficiency delivered a normal child following a one-gram per day fat diet and treatment with gemfibrozil (600 mg/day) [
See
Search
The lipid-lowering drugs that are used to treat other disorders of lipid metabolism are not effective in individuals with familial LPL deficiency.
Although plasmapheresis and antioxidant therapy have been suggested as treatment for pancreatitis, they do not appear to be needed for either acute therapy or long-term care.
• Discontinuation of oral fat intake stops chylomicron triglyceride formation, and replacement with hypocaloric parenteral nutrition decreases VLDL triglyceride production.
• Administration of excess calories, as in hyperalimentation, is contraindicated in the acute state. The intravenous administration of lipid emulsions may lead to persistent or recurrent pancreatitis.
• Measurement of plasma triglyceride concentration;
• Molecular genetic testing if the pathogenic variants in the family are known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with familial lipoprotein lipase (LPL) deficiency, measurement of plasma triglyceride concentration is recommended.
Consultation with a clinical geneticist and/or genetic counselor may also be considered.
## Treatment of Manifestations
Medium-chain triglycerides may be used for cooking, as they are absorbed directly into the portal vein without becoming incorporated into chylomicron triglyceride.
The success of therapy depends on the individual's acceptance of the fat restriction, including both unsaturated and saturated fat. Note: Fish oil supplements, which are effective in disorders of excess hepatic triglyceride production, are not effective in LPL deficiency and are contraindicated (see
The enlarged liver and spleen can return to normal size within one week of lowering of triglyceride concentrations.
The xanthomas can clear over the course of weeks to months. Recurrent or persistent eruptive xanthomas indicate inadequate therapy.
Pancreatitis associated with the chylomicronemia syndrome is treated in the manner typical for other forms of pancreatitis.
Discontinuation of oral fat intake stops chylomicron triglyceride formation, and replacement with hypocaloric parenteral nutrition decreases VLDL triglyceride production.
Administration of excess calories, as in hyperalimentation, is contraindicated in the acute state. The intravenous administration of lipid emulsions may lead to persistent or recurrent pancreatitis.
If recurrent pancreatitis with severe hypertriglyceridemia occurs, total dietary fat intake needs to be reduced.
• Discontinuation of oral fat intake stops chylomicron triglyceride formation, and replacement with hypocaloric parenteral nutrition decreases VLDL triglyceride production.
• Administration of excess calories, as in hyperalimentation, is contraindicated in the acute state. The intravenous administration of lipid emulsions may lead to persistent or recurrent pancreatitis.
## Prevention of Primary Manifestations
See
## Prevention of Secondary Complications
Prevention of recurrent acute pancreatitis decreases the risk of developing diabetes mellitus. Fat malabsorption is very rare.
## Surveillance
Plasma triglyceride levels need to be followed over time to evaluate the affected individual’s success in following the very low-fat dietary recommendations. When the triglyceride level is above 1000 mg/dL, a fasting sample is not required for this evaluation. Other components of the lipid profile do not need to be routinely measured.
Affected individuals who develop abdominal pain need to contact their physician.
## Agents/Circumstances to Avoid
Avoidance of agents known to increase endogenous triglyceride concentration such as alcohol, oral estrogens, diuretics, isotretinoin, glucocorticoids, selective serotonin reuptake inhibitors, and beta-adrenergic blocking agents is recommended.
Fish oil supplements are contraindicated as they contribute to chylomicron levels.
## Evaluation of Relatives at Risk
It is appropriate to evaluate at-risk sibs during infancy. Early diagnosis and implementation of dietary fat intake restriction can prevent symptoms and related medical complications.
Evaluations can include:
Measurement of plasma triglyceride concentration;
Molecular genetic testing if the pathogenic variants in the family are known.
See
• Measurement of plasma triglyceride concentration;
• Molecular genetic testing if the pathogenic variants in the family are known.
## Pregnancy Management
During pregnancy in a woman with LPL deficiency, extreme dietary fat restriction to less than two grams per day during the second and third trimester with close monitoring of plasma triglyceride concentration can result in delivery of a normal infant with normal plasma concentrations of essential fatty acids [
One woman with LPL deficiency delivered a normal child following a one-gram per day fat diet and treatment with gemfibrozil (600 mg/day) [
See
## Therapies Under Investigation
Search
## Other
The lipid-lowering drugs that are used to treat other disorders of lipid metabolism are not effective in individuals with familial LPL deficiency.
Although plasmapheresis and antioxidant therapy have been suggested as treatment for pancreatitis, they do not appear to be needed for either acute therapy or long-term care.
## Genetic Counseling
Familial LPL deficiency is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes are asymptomatic but may have moderately elevated plasma triglyceride concentrations and may be at mild risk for premature atherosclerosis.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes are asymptomatic but may have moderately elevated plasma triglyceride concentrations and may be at mild risk for premature atherosclerosis.
Carrier testing for at-risk relatives requires prior identification of the
See
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. In practice, prenatal testing is rarely requested because of the availability of effective treatment.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes are asymptomatic but may have moderately elevated plasma triglyceride concentrations and may be at mild risk for premature atherosclerosis.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes are asymptomatic but may have moderately elevated plasma triglyceride concentrations and may be at mild risk for premature atherosclerosis.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Familial LPL deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes are asymptomatic but may have moderately elevated plasma triglyceride concentrations and may be at mild risk for premature atherosclerosis.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes are asymptomatic but may have moderately elevated plasma triglyceride concentrations and may be at mild risk for premature atherosclerosis.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes are asymptomatic but may have moderately elevated plasma triglyceride concentrations and may be at mild risk for premature atherosclerosis.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes are asymptomatic but may have moderately elevated plasma triglyceride concentrations and may be at mild risk for premature atherosclerosis.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. In practice, prenatal testing is rarely requested because of the availability of effective treatment.
## Resources
•
•
•
•
## Molecular Genetics
Familial Lipoprotein Lipase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Familial Lipoprotein Lipase Deficiency (
## References
## Literature Cited
## Chapter Notes
John D Brunzell, MD; University of Washington (1999-2017)John R Burnett, MB ChB, MD, PhD, FRCPA (2017-present)Robert A Hegele, MD, FRCPC, FACP (2017-present)Amanda J Hooper, PhD (2017-present)
22 June 2017 (ma) Comprehensive update posted live
15 December 2011 (me) Comprehensive update posted live
28 July 2009 (me) Comprehensive update posted live
1 October 2007 (cd) Revision: deletion/duplication analysis available; prenatal testing available; mutation analysis for p.Gly188Glu done by sequence analysis
24 April 2006 (me) Comprehensive update posted live
9 April 2004 (me) Comprehensive update posted live
18 February 2002 (me) Comprehensive update posted live
12 October 1999 (me) Review posted live
April 1999 (jb) Original submission
• 22 June 2017 (ma) Comprehensive update posted live
• 15 December 2011 (me) Comprehensive update posted live
• 28 July 2009 (me) Comprehensive update posted live
• 1 October 2007 (cd) Revision: deletion/duplication analysis available; prenatal testing available; mutation analysis for p.Gly188Glu done by sequence analysis
• 24 April 2006 (me) Comprehensive update posted live
• 9 April 2004 (me) Comprehensive update posted live
• 18 February 2002 (me) Comprehensive update posted live
• 12 October 1999 (me) Review posted live
• April 1999 (jb) Original submission
## Author History
John D Brunzell, MD; University of Washington (1999-2017)John R Burnett, MB ChB, MD, PhD, FRCPA (2017-present)Robert A Hegele, MD, FRCPC, FACP (2017-present)Amanda J Hooper, PhD (2017-present)
## Revision History
22 June 2017 (ma) Comprehensive update posted live
15 December 2011 (me) Comprehensive update posted live
28 July 2009 (me) Comprehensive update posted live
1 October 2007 (cd) Revision: deletion/duplication analysis available; prenatal testing available; mutation analysis for p.Gly188Glu done by sequence analysis
24 April 2006 (me) Comprehensive update posted live
9 April 2004 (me) Comprehensive update posted live
18 February 2002 (me) Comprehensive update posted live
12 October 1999 (me) Review posted live
April 1999 (jb) Original submission
• 22 June 2017 (ma) Comprehensive update posted live
• 15 December 2011 (me) Comprehensive update posted live
• 28 July 2009 (me) Comprehensive update posted live
• 1 October 2007 (cd) Revision: deletion/duplication analysis available; prenatal testing available; mutation analysis for p.Gly188Glu done by sequence analysis
• 24 April 2006 (me) Comprehensive update posted live
• 9 April 2004 (me) Comprehensive update posted live
• 18 February 2002 (me) Comprehensive update posted live
• 12 October 1999 (me) Review posted live
• April 1999 (jb) Original submission
|
[
"K Al-Shali, J Wang, F Fellows, MW Huff, BM Wolfe, RA Hegele. Successful pregnancy outcome in a patient with severe chylomicronemia due to compound heterozygosity for mutant lipoprotein lipase.. Clin Biochem 2002;35:125-30",
"AP Beigneux, BS Davies, P Gin, MM Weinstein, E Farber, X Qiao, F Peale, S Bunting, RL Walzem, JS Wong, WS Blaner, ZM Ding, K Melford, N Wongsiriroj, X Shu, F de Sauvage, RO Ryan, LG Fong, A Bensadoun, SG Young. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons.. Cell Metab 2007;5:279-91",
"AP Beigneux, R Franssen, A Bensadoun, P Gin, K Melford, J Peter, RL Walzem, MM Weinstein, BS Davies, JA Kuivenhoven, JJ Kastelein, LG Fong, GM Dallinga-Thie, SG Young. Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase.. Arterioscler Thromb Vasc Biol. 2009;29:956-62",
"AP Beigneux, K Miyashita, M Ploug, DJ Blom, M Ai, MF Linton, W Khovidhunkit, R Dufour, A Garg, MA McMahon, CR Pullinger, NP Sandoval, X Hu, CM Allan, M Larsson, T Machida, M Murakami, K Reue, P Tontonoz, IJ Goldberg, P Moulin, S Charrière, LG Fong, K Nakajima, SG Young. Autoantibodies against GPIHBP1 as a cause of hypertriglyceridemia.. N Engl J Med 2017;376:1647-58",
"AJ Brahm, RA Hegele. Chylomicronaemia–current diagnosis and future therapies.. Nat Rev Endocrinol 2015;11:352-62",
"S Calandra, C Priore Oliva, P Tarugi, S Bertolini. APOA5 and triglyceride metabolism, lesson from human APOA5 deficiency.. Curr. Opin. Lipidol 2006;17:122-7",
"A Chait, JD Brunzell. Severe hypertriglyceridemia: role of familial and acquired disorders.. Metabolism 1983;32:209-14",
"A Chait, HT Robertson, JD Brunzell. Chylomicronemia syndrome in diabetes mellitus.. Diabetes Care 1981;4:343-8",
"D Gaudet, D Brisson, K Tremblay, VJ Alexander, W Singleton, SG Hughes, RS Geary, BF Baker, MJ Graham, RM Crooke, JL Witztum. Targeting APOC3 in the familial chylomicronemia syndrome.. N Engl J Med 2014;371:2200-6",
"D Gaudet, J Méthot, S Déry, D Brisson, C Essiembre, G Tremblay, K Tremblay, J de Wal, J Twisk, N van den Bulk, V Sier-Ferreira, S van Deventer. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial.. Gene Ther 2013;20:361-9",
"B Gilbert, M Rouis, S Griglio, L de Lumley, P Laplaud, B Gilbert, M Rouis, S Griglio, L de Lumley, P Laplaud. Lipoprotein lipase (LPL) deficiency: a new patient homozygote for the preponderant mutation Gly188Glu in the human LPL gene and review of reported mutations: 75% are clustered in exons 5 and 6.. Ann Genet 2001;44:25-32",
"P Gin, CN Goulbourne, O Adeyo, AP Beigneux, BS Davies, S Tat, CV Voss, A Bensadoun, LG Fong, SG Young. Chylomicronemia mutations yield new insights into interactions between lipoprotein lipase and GPIHBP1.. Hum Mol Genet 2012;21:2961-72",
"T Gotoda, K Shirai, T Ohta, J Kobayashi, S Yokoyama, S Oikawa, H Bujo, S Ishibashi, H Arai, S Yamashita, M Harada-Shiba, M Eto, T Hayashi, H Sone, H Suzuki, N Yamada. Diagnosis and management of type I and type V hyperlipoproteinemia.. J Atheroscler Thromb 2012;19:1-12",
"SE Gryn, RA Hegele. Novel therapeutics in hypertriglyceridemia.. Curr Opin Lipidol 2015;26:484-91",
"RA Hegele, HN Ginsberg, MJ Chapman, BG Nordestgaard, JA Kuivenhoven, M Averna, J Borén, E Bruckert, AL Catapano, OS Descamps, GK Hovingh, SE Humphries, PT Kovanen, L Masana, P Pajukanta, KG Parhofer, FJ Raal, KK Ray, RD Santos, AF Stalenhoef, E Stroes, MR Taskinen, A Tybjærg-Hansen, GF Watts, O Wiklund. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management.. Lancet Diabetes Endocrinol. 2014;2:655-66",
"KM Heilman, WR Fisher. Hyperlipidemic dementia.. Arch Neurol 1974;31:67-8",
"TS Jap, SF Jenq, YC Wu, CY Chiu, HM Cheng. Mutations in the lipoprotein lipase gene as a cause of hypertriglyceridemia and pancreatitis in Taiwan.. Pancreas 2003;27:122-6",
"MA Kawashiri, T Higashikata, M Mizuno, M Takata, S Katsuda, K Miwa, T Nozue, A Nohara, A Inazu, J Kobayashi, J Koizumi, H Mabuchi. Long-term course of lipoprotein lipase (LPL) deficiency due to homozygous LPL(Arita) in a patient with recurrent pancreatitis, retained glucose tolerance, and atherosclerosis.. J Clin Endocrinol Metab 2005;90:6541-4",
"JM Martín-Campos, J Julve, R Roig, S Martínez, TL Errico, S Martínez-Couselo, JC Escolà-Gil, J Méndez-González, F Blanco-Vaca. Molecular analysis of chylomicronemia in a clinical laboratory setting: diagnosis of 13 cases of lipoprotein lipase deficiency.. Clin Chim Acta 2014;429:61-8",
"CD Meyers, K Tremblay, A Amer, J Chen, L Jiang, D Gaudet. Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome.. Lipids Health Dis 2015;14:8",
"V Murthy, P Julien, C Gagne. Molecular pathobiology of the human lipoprotein lipase gene.. Pharmacol Ther 1996;70:101-35",
"SK Nilsson, J Heeren, G Olivecrona, M Merkel. Apolipoprotein A-V; a potent triglyceride reducer.. Atherosclerosis 2011;219:15-21",
"M Okubo, A Toromanovic, T Ebara, T Murase. Apolipoprotein C-II: a novel large deletion in APOC2 caused by Alu–Alu homologous recombination in an infant with apolipoprotein C-II deficiency.. Clin Chim Acta 2015;438:148-53",
"M Péterfy. Lipase maturation factor 1: a lipase chaperone involved in lipid metabolism.. Biochim Biophys Acta 2012;1821:790-4",
"M Péterfy, O Ben-Zeev, HZ Mao, D Weissglas-Volkov, BE Aouizerat, CR Pullinger, PH Frost, JP Kane, MJ Malloy, K Reue, P Pajukanta, MH Doolittle. Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia.. Nat Genet 2007;39:1483-7",
"FM Sacks, M Stanesa, RA Hegele. Severe hypertriglyceridemia with pancreatitis: thirteen years' treatment with lomitapide.. JAMA Intern Med 2014;174:443-7",
"E Stroes, P Moulin, KG Parhofer, V Rebours, JM Lӧhr, M Averna. Diagnostic algorithm for familial chylomicronemia syndrome.. Atheroscler Suppl 2017;23:1-7",
"EC Tsai, JA Brown, MY Veldee, GJ Anderson, A Chait, JD Brunzell. Potential of essential fatty acid deficiency with extremely low fat diet in lipoprotein lipase deficiency during pregnancy: A case report.. BMC Pregnancy Childbirth 2004;4:27",
"A Viljoen, AS Wierzbicki. Diagnosis and treatment of severe hypertriglyceridemia.. Expert Rev Cardiovasc Ther 2012;10:505-14"
] |
12/10/1999
|
22/6/2017
|
1/10/2007
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
lrrk2
|
lrrk2
|
[
"Leucine-rich repeat serine/threonine-protein kinase 2",
"LRRK2",
"LRRK2 Parkinson Disease"
] |
Rachel Saunders-Pullman, Deborah Raymond, Sonya Elango
|
Summary * Idiopathic PD refers to the presence of signs and symptoms of PD for which the etiology is currently unknown and in which there is no known family history of PD. The diagnosis of
|
## Diagnosis
While there are subtle group differences between
Note: "Idiopathic Parkinson disease" and "sporadic Parkinson disease" are terms used in the Parkinson disease medical literature to describe Parkinson disease of unknown cause diagnosed in an individual with a negative family history. Future advances in the understanding of genetic risk factors are likely to identify genetic causes / risk factors for some Parkinson disease currently considered "idiopathic" or "sporadic."
Bradykinesia (slowness of movement) with decrements in speed or amplitude as movements are continued
AND
Rest tremor (4-6-Hz tremor in a fully resting limb) and/or rigidity.
To meet Movement Disorders Society clinical diagnostic criteria [
Clear and dramatic beneficial response to dopaminergic therapy
Levodopa-induced dyskinesias
Rest tremor in a limb (prior or current)
Positive results from an ancillary diagnostic test (e.g.):
Cardiac metaiodobenzylguanidine (MIBG) scintigraphy
Olfactory abnormality
However: (1) Early and untreated individuals with PD may not meet the supportive criteria, as dopaminergic therapy may not have been tried, and thus no response or dyskinesias documented; (2) attributing olfactory abnormality to
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
C
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, no deletions or duplications involving
Homozygous
• Bradykinesia (slowness of movement) with decrements in speed or amplitude as movements are continued
• AND
• Rest tremor (4-6-Hz tremor in a fully resting limb) and/or rigidity.
• Clear and dramatic beneficial response to dopaminergic therapy
• Levodopa-induced dyskinesias
• Rest tremor in a limb (prior or current)
• Positive results from an ancillary diagnostic test (e.g.):
• Cardiac metaiodobenzylguanidine (MIBG) scintigraphy
• Olfactory abnormality
• Cardiac metaiodobenzylguanidine (MIBG) scintigraphy
• Olfactory abnormality
• Cardiac metaiodobenzylguanidine (MIBG) scintigraphy
• Olfactory abnormality
## Suggestive Findings
Bradykinesia (slowness of movement) with decrements in speed or amplitude as movements are continued
AND
Rest tremor (4-6-Hz tremor in a fully resting limb) and/or rigidity.
To meet Movement Disorders Society clinical diagnostic criteria [
Clear and dramatic beneficial response to dopaminergic therapy
Levodopa-induced dyskinesias
Rest tremor in a limb (prior or current)
Positive results from an ancillary diagnostic test (e.g.):
Cardiac metaiodobenzylguanidine (MIBG) scintigraphy
Olfactory abnormality
However: (1) Early and untreated individuals with PD may not meet the supportive criteria, as dopaminergic therapy may not have been tried, and thus no response or dyskinesias documented; (2) attributing olfactory abnormality to
• Bradykinesia (slowness of movement) with decrements in speed or amplitude as movements are continued
• AND
• Rest tremor (4-6-Hz tremor in a fully resting limb) and/or rigidity.
• Clear and dramatic beneficial response to dopaminergic therapy
• Levodopa-induced dyskinesias
• Rest tremor in a limb (prior or current)
• Positive results from an ancillary diagnostic test (e.g.):
• Cardiac metaiodobenzylguanidine (MIBG) scintigraphy
• Olfactory abnormality
• Cardiac metaiodobenzylguanidine (MIBG) scintigraphy
• Olfactory abnormality
• Cardiac metaiodobenzylguanidine (MIBG) scintigraphy
• Olfactory abnormality
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
C
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, no deletions or duplications involving
Homozygous
## Clinical Characteristics
Age at onset is typically in the 50s and 60s but varies, even within the same family. The range of disease onset is 28-95 years with a mean of 58-61 years – similar to or slightly younger than in individuals with IPD [
The percentage of men and women with
Clinical features are overall similar in men and women; however, women may have more complications related to therapy [
Slowness and difficulty with dexterity (bradykinesia)
Tremor, which may occur at rest or during action, although this sign may not be present
Slow walk or shuffling gait
Unsteadiness and falls
Low vocal volume, with difficulty projecting
Facial hypomimia (masking)
As with other forms of Parkinson disease, the disorder is slowly progressive, and generally spreads from unilateral to bilateral involvement. Disease progression varies significantly among individuals and is related to age of onset.
Cognitive decline, including mild cognitive impairment and dementia
Constipation
Hyposmia/anosmia
Depression, anxiety, and other neuropsychiatric features [
Seborrhea
Sexual dysfunction
Sleep complaints, including poor sleep quality, excessive daytime sleepiness, sleep fragmentation, early awakening, daytime sleepiness, and insomnia [
Urinary frequency
Orthostatic hypotension
An association between melanoma and PD of any etiology has been reported [
Non-skin cancer, especially leukemia and colon cancer, may be increased in individuals with a heterozygous pathogenic variant in
There is typically significant reduction in uptake of
Studies of these and other tracers support abnormalities of both dopaminergic and serotonergic metabolism [
Infrequently, normal PET scanning early in the disease course has been observed in both
Click
Among the confirmed pathogenic variants in
Most studies have shown that individual clinical features are indistinguishable between individuals with
While
Affected male-to-female ratio is similar, compared to 60% male and 40% female for IPD [
Overall survival is longer in those with
Generally a milder motor course, including slower motor progression, reported in those with
Note: Some longitudinal studies do not support this finding [
Postural instability and gait difficulty may be slightly worse in individuals with
Note: Some studies have not found any significant differences in cognition between individuals with
More difficulty with
Possibly a slightly lower risk of
Among 12 Ashkenazi Jewish individuals who had both the
Differences in phenotype have been observed for the rarer pathogenic
Individuals with the
However, one systematic review found more frequent tremor in individuals with the
The same review found that individuals with a pathogenic variant at residue 1441 (p.Arg1441Gly,
Individuals with a p.Gly2385Arg variant appear to have more rapidly progressive parkinsonism with greater subjective and objective scores of motor decline, as well as more motor fluctuations, compared to individuals with the p.Gly2019Ser variant [
Individuals with at least one risk-factor variant (p.Gly2385Arg, p.Arg1628Pro, or p.Ser1647Thr) showed greater motor progression over a four-year period than those with the
Individuals with the pathogenic
Penetrance of
The most frequent variant is
In Ashkenazi Jews with this variant, penetrance is estimated at 25%-30% up to age 80 [
In North African Berbers, lifetime penetrance is estimated at 45% [
In non-Jewish individuals, penetrance associated with this variant is estimated at 42% by age 80 [
The
A study of the original
Alternate nomenclature for
PARK8, which refers to the chromosomal region of 12q12 linked to disease in a large Japanese PD kindred [
"Dardarin," the Basque word for "tremor," has been used to refer to
In the US,
A founder effect exists for certain pathogenic variants, such as
A founder effect exists for the
Further information about the prevalence of certain variants in different populations can be accessed
• Age at onset is typically in the 50s and 60s but varies, even within the same family. The range of disease onset is 28-95 years with a mean of 58-61 years – similar to or slightly younger than in individuals with IPD [
• The percentage of men and women with
• Clinical features are overall similar in men and women; however, women may have more complications related to therapy [
• Slowness and difficulty with dexterity (bradykinesia)
• Tremor, which may occur at rest or during action, although this sign may not be present
• Slow walk or shuffling gait
• Unsteadiness and falls
• Low vocal volume, with difficulty projecting
• Facial hypomimia (masking)
• Cognitive decline, including mild cognitive impairment and dementia
• Constipation
• Hyposmia/anosmia
• Depression, anxiety, and other neuropsychiatric features [
• Seborrhea
• Sexual dysfunction
• Sleep complaints, including poor sleep quality, excessive daytime sleepiness, sleep fragmentation, early awakening, daytime sleepiness, and insomnia [
• Urinary frequency
• Orthostatic hypotension
• An association between melanoma and PD of any etiology has been reported [
• Non-skin cancer, especially leukemia and colon cancer, may be increased in individuals with a heterozygous pathogenic variant in
• There is typically significant reduction in uptake of
• Studies of these and other tracers support abnormalities of both dopaminergic and serotonergic metabolism [
• Generally a milder motor course, including slower motor progression, reported in those with
• Note: Some longitudinal studies do not support this finding [
• Postural instability and gait difficulty may be slightly worse in individuals with
• Note: Some studies have not found any significant differences in cognition between individuals with
• More difficulty with
• Possibly a slightly lower risk of
• Individuals with the
• However, one systematic review found more frequent tremor in individuals with the
• The same review found that individuals with a pathogenic variant at residue 1441 (p.Arg1441Gly,
• Individuals with a p.Gly2385Arg variant appear to have more rapidly progressive parkinsonism with greater subjective and objective scores of motor decline, as well as more motor fluctuations, compared to individuals with the p.Gly2019Ser variant [
• Individuals with at least one risk-factor variant (p.Gly2385Arg, p.Arg1628Pro, or p.Ser1647Thr) showed greater motor progression over a four-year period than those with the
• Individuals with the pathogenic
• In Ashkenazi Jews with this variant, penetrance is estimated at 25%-30% up to age 80 [
• In North African Berbers, lifetime penetrance is estimated at 45% [
• In non-Jewish individuals, penetrance associated with this variant is estimated at 42% by age 80 [
• The
• A study of the original
• PARK8, which refers to the chromosomal region of 12q12 linked to disease in a large Japanese PD kindred [
• "Dardarin," the Basque word for "tremor," has been used to refer to
• A founder effect exists for certain pathogenic variants, such as
• A founder effect exists for the
## Clinical Description
Age at onset is typically in the 50s and 60s but varies, even within the same family. The range of disease onset is 28-95 years with a mean of 58-61 years – similar to or slightly younger than in individuals with IPD [
The percentage of men and women with
Clinical features are overall similar in men and women; however, women may have more complications related to therapy [
Slowness and difficulty with dexterity (bradykinesia)
Tremor, which may occur at rest or during action, although this sign may not be present
Slow walk or shuffling gait
Unsteadiness and falls
Low vocal volume, with difficulty projecting
Facial hypomimia (masking)
As with other forms of Parkinson disease, the disorder is slowly progressive, and generally spreads from unilateral to bilateral involvement. Disease progression varies significantly among individuals and is related to age of onset.
Cognitive decline, including mild cognitive impairment and dementia
Constipation
Hyposmia/anosmia
Depression, anxiety, and other neuropsychiatric features [
Seborrhea
Sexual dysfunction
Sleep complaints, including poor sleep quality, excessive daytime sleepiness, sleep fragmentation, early awakening, daytime sleepiness, and insomnia [
Urinary frequency
Orthostatic hypotension
An association between melanoma and PD of any etiology has been reported [
Non-skin cancer, especially leukemia and colon cancer, may be increased in individuals with a heterozygous pathogenic variant in
There is typically significant reduction in uptake of
Studies of these and other tracers support abnormalities of both dopaminergic and serotonergic metabolism [
Infrequently, normal PET scanning early in the disease course has been observed in both
Click
• Age at onset is typically in the 50s and 60s but varies, even within the same family. The range of disease onset is 28-95 years with a mean of 58-61 years – similar to or slightly younger than in individuals with IPD [
• The percentage of men and women with
• Clinical features are overall similar in men and women; however, women may have more complications related to therapy [
• Slowness and difficulty with dexterity (bradykinesia)
• Tremor, which may occur at rest or during action, although this sign may not be present
• Slow walk or shuffling gait
• Unsteadiness and falls
• Low vocal volume, with difficulty projecting
• Facial hypomimia (masking)
• Cognitive decline, including mild cognitive impairment and dementia
• Constipation
• Hyposmia/anosmia
• Depression, anxiety, and other neuropsychiatric features [
• Seborrhea
• Sexual dysfunction
• Sleep complaints, including poor sleep quality, excessive daytime sleepiness, sleep fragmentation, early awakening, daytime sleepiness, and insomnia [
• Urinary frequency
• Orthostatic hypotension
• An association between melanoma and PD of any etiology has been reported [
• Non-skin cancer, especially leukemia and colon cancer, may be increased in individuals with a heterozygous pathogenic variant in
• There is typically significant reduction in uptake of
• Studies of these and other tracers support abnormalities of both dopaminergic and serotonergic metabolism [
## Phenotype Correlations by Cause
Among the confirmed pathogenic variants in
Most studies have shown that individual clinical features are indistinguishable between individuals with
While
Affected male-to-female ratio is similar, compared to 60% male and 40% female for IPD [
Overall survival is longer in those with
Generally a milder motor course, including slower motor progression, reported in those with
Note: Some longitudinal studies do not support this finding [
Postural instability and gait difficulty may be slightly worse in individuals with
Note: Some studies have not found any significant differences in cognition between individuals with
More difficulty with
Possibly a slightly lower risk of
Among 12 Ashkenazi Jewish individuals who had both the
• Generally a milder motor course, including slower motor progression, reported in those with
• Note: Some longitudinal studies do not support this finding [
• Postural instability and gait difficulty may be slightly worse in individuals with
• Note: Some studies have not found any significant differences in cognition between individuals with
• More difficulty with
• Possibly a slightly lower risk of
## Reported Clinical Differences Between Individuals with
While
Affected male-to-female ratio is similar, compared to 60% male and 40% female for IPD [
Overall survival is longer in those with
Generally a milder motor course, including slower motor progression, reported in those with
Note: Some longitudinal studies do not support this finding [
Postural instability and gait difficulty may be slightly worse in individuals with
Note: Some studies have not found any significant differences in cognition between individuals with
More difficulty with
Possibly a slightly lower risk of
• Generally a milder motor course, including slower motor progression, reported in those with
• Note: Some longitudinal studies do not support this finding [
• Postural instability and gait difficulty may be slightly worse in individuals with
• Note: Some studies have not found any significant differences in cognition between individuals with
• More difficulty with
• Possibly a slightly lower risk of
## Co-Occurring Pathogenic Variants in
Among 12 Ashkenazi Jewish individuals who had both the
## Genotype-Phenotype Correlations
Differences in phenotype have been observed for the rarer pathogenic
Individuals with the
However, one systematic review found more frequent tremor in individuals with the
The same review found that individuals with a pathogenic variant at residue 1441 (p.Arg1441Gly,
Individuals with a p.Gly2385Arg variant appear to have more rapidly progressive parkinsonism with greater subjective and objective scores of motor decline, as well as more motor fluctuations, compared to individuals with the p.Gly2019Ser variant [
Individuals with at least one risk-factor variant (p.Gly2385Arg, p.Arg1628Pro, or p.Ser1647Thr) showed greater motor progression over a four-year period than those with the
Individuals with the pathogenic
• Individuals with the
• However, one systematic review found more frequent tremor in individuals with the
• The same review found that individuals with a pathogenic variant at residue 1441 (p.Arg1441Gly,
• Individuals with a p.Gly2385Arg variant appear to have more rapidly progressive parkinsonism with greater subjective and objective scores of motor decline, as well as more motor fluctuations, compared to individuals with the p.Gly2019Ser variant [
• Individuals with at least one risk-factor variant (p.Gly2385Arg, p.Arg1628Pro, or p.Ser1647Thr) showed greater motor progression over a four-year period than those with the
• Individuals with the pathogenic
## Penetrance
Penetrance of
The most frequent variant is
In Ashkenazi Jews with this variant, penetrance is estimated at 25%-30% up to age 80 [
In North African Berbers, lifetime penetrance is estimated at 45% [
In non-Jewish individuals, penetrance associated with this variant is estimated at 42% by age 80 [
The
A study of the original
• In Ashkenazi Jews with this variant, penetrance is estimated at 25%-30% up to age 80 [
• In North African Berbers, lifetime penetrance is estimated at 45% [
• In non-Jewish individuals, penetrance associated with this variant is estimated at 42% by age 80 [
• The
• A study of the original
## Nomenclature
Alternate nomenclature for
PARK8, which refers to the chromosomal region of 12q12 linked to disease in a large Japanese PD kindred [
"Dardarin," the Basque word for "tremor," has been used to refer to
• PARK8, which refers to the chromosomal region of 12q12 linked to disease in a large Japanese PD kindred [
• "Dardarin," the Basque word for "tremor," has been used to refer to
## Prevalence
In the US,
A founder effect exists for certain pathogenic variants, such as
A founder effect exists for the
Further information about the prevalence of certain variants in different populations can be accessed
• A founder effect exists for certain pathogenic variants, such as
• A founder effect exists for the
## Differential Diagnosis
The differential diagnosis of
## Management
To establish the extent of disease and needs in an individual diagnosed with
Assessment of motor symptoms and signs, including motor functioning and falls
Assessment of nonmotor symptoms and signs, including:
Cognition
Constipation
Mood
Illusions/hallucinations
Sexual dysfunction
Pain
Sleep disturbance
Urinary difficulties, including frequency
Orthostatic hypotension
Baseline skin evaluation for evidence of melanoma
Consider referral to a clinical geneticist and/or genetic counselor.
The treatment of individuals with
Pharmacologic replacement of dopamine
Different formulations of levodopa may be considered, including l-dopa combined with cardi-dopa.
Multiple formulations of l-dopa (which may be immediate release or longer acting) exist, as well as multiple routes of delivery, including oral (the major one), sublingual, and enteric.
Utilization of l-dopa should be driven by clinical need, and the clinician should consider using the lowest dose that yields a satisfactory clinical effect [
Monoamine oxidate B (MAO-B) inhibitors, including selegiline and rasagiline
Amantadine (Symmetrel
Dopamine receptor agonists
Anticholinergics
Exercise, as safe for the particular affected individual; often recommended [
Physical and occupational therapy
Voice therapy, particularly the Lee Silverman Voice Treatment
Cognitive behavioral therapy; potentially beneficial either with or without pharmacologic treatment
For those with hallucinations, consideration of non-dopamine-blocking medications (particularly pimavanserin; see
Troubling dyskinesias
Dyskinesias in individuals with
In general, women with
While dyskinesia is related to l-dopa dose, decisions regarding dosing should be guided by the clinician [
Significant wearing-off of doses
Delayed onset of medication action
Refractory rest tremor
Neurosurgical procedures such as deep brain stimulation (DBS) of the subthalamic nucleus (STN) / globus pallidus interna (GPi) may be considered if there is good response to but complications from l-dopa therapy.
Whether target selection should be guided by
Response to both STN and GPi have been reported in individuals with
Further, disease-modifying clinical trials are under way for
Recommended Surveillance for Individuals with
To assess effect of motor therapies (including wearing off and dyskinesias) and need for symptomatic treatment
Systematic assessment of history of motor and nonmotor features including associated disability as well as examination of motor features are captured in the Movement Disorder Society Sponsored Revision of the
Dopamine-blocking therapies (both typical and atypical dopamine-blocking psychiatric medications as well as dopamine blockers for gastrointestinal causes) may exacerbate parkinsonism in
See
While the data are restricted to case reports and registries, most support treatment with L-dopa during pregnancy (reviewed by
See
The Lrrk2 protein is a fusion of Rab (Roc), COR, and kinase (MAPK) domains, and pathogenic variants are postulated to augment kinase activity [
In addition to kinase inhibitors,
Search
• Assessment of motor symptoms and signs, including motor functioning and falls
• Assessment of nonmotor symptoms and signs, including:
• Cognition
• Constipation
• Mood
• Illusions/hallucinations
• Sexual dysfunction
• Pain
• Sleep disturbance
• Urinary difficulties, including frequency
• Orthostatic hypotension
• Baseline skin evaluation for evidence of melanoma
• Cognition
• Constipation
• Mood
• Illusions/hallucinations
• Sexual dysfunction
• Pain
• Sleep disturbance
• Urinary difficulties, including frequency
• Orthostatic hypotension
• Baseline skin evaluation for evidence of melanoma
• Consider referral to a clinical geneticist and/or genetic counselor.
• Cognition
• Constipation
• Mood
• Illusions/hallucinations
• Sexual dysfunction
• Pain
• Sleep disturbance
• Urinary difficulties, including frequency
• Orthostatic hypotension
• Baseline skin evaluation for evidence of melanoma
• Pharmacologic replacement of dopamine
• Different formulations of levodopa may be considered, including l-dopa combined with cardi-dopa.
• Multiple formulations of l-dopa (which may be immediate release or longer acting) exist, as well as multiple routes of delivery, including oral (the major one), sublingual, and enteric.
• Utilization of l-dopa should be driven by clinical need, and the clinician should consider using the lowest dose that yields a satisfactory clinical effect [
• Different formulations of levodopa may be considered, including l-dopa combined with cardi-dopa.
• Multiple formulations of l-dopa (which may be immediate release or longer acting) exist, as well as multiple routes of delivery, including oral (the major one), sublingual, and enteric.
• Utilization of l-dopa should be driven by clinical need, and the clinician should consider using the lowest dose that yields a satisfactory clinical effect [
• Monoamine oxidate B (MAO-B) inhibitors, including selegiline and rasagiline
• Amantadine (Symmetrel
• Dopamine receptor agonists
• Anticholinergics
• Different formulations of levodopa may be considered, including l-dopa combined with cardi-dopa.
• Multiple formulations of l-dopa (which may be immediate release or longer acting) exist, as well as multiple routes of delivery, including oral (the major one), sublingual, and enteric.
• Utilization of l-dopa should be driven by clinical need, and the clinician should consider using the lowest dose that yields a satisfactory clinical effect [
• Exercise, as safe for the particular affected individual; often recommended [
• Physical and occupational therapy
• Voice therapy, particularly the Lee Silverman Voice Treatment
• Cognitive behavioral therapy; potentially beneficial either with or without pharmacologic treatment
• For those with hallucinations, consideration of non-dopamine-blocking medications (particularly pimavanserin; see
• Troubling dyskinesias
• Dyskinesias in individuals with
• In general, women with
• While dyskinesia is related to l-dopa dose, decisions regarding dosing should be guided by the clinician [
• Dyskinesias in individuals with
• In general, women with
• While dyskinesia is related to l-dopa dose, decisions regarding dosing should be guided by the clinician [
• Significant wearing-off of doses
• Delayed onset of medication action
• Refractory rest tremor
• Dyskinesias in individuals with
• In general, women with
• While dyskinesia is related to l-dopa dose, decisions regarding dosing should be guided by the clinician [
• Whether target selection should be guided by
• Response to both STN and GPi have been reported in individuals with
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Assessment of motor symptoms and signs, including motor functioning and falls
Assessment of nonmotor symptoms and signs, including:
Cognition
Constipation
Mood
Illusions/hallucinations
Sexual dysfunction
Pain
Sleep disturbance
Urinary difficulties, including frequency
Orthostatic hypotension
Baseline skin evaluation for evidence of melanoma
Consider referral to a clinical geneticist and/or genetic counselor.
• Assessment of motor symptoms and signs, including motor functioning and falls
• Assessment of nonmotor symptoms and signs, including:
• Cognition
• Constipation
• Mood
• Illusions/hallucinations
• Sexual dysfunction
• Pain
• Sleep disturbance
• Urinary difficulties, including frequency
• Orthostatic hypotension
• Baseline skin evaluation for evidence of melanoma
• Cognition
• Constipation
• Mood
• Illusions/hallucinations
• Sexual dysfunction
• Pain
• Sleep disturbance
• Urinary difficulties, including frequency
• Orthostatic hypotension
• Baseline skin evaluation for evidence of melanoma
• Consider referral to a clinical geneticist and/or genetic counselor.
• Cognition
• Constipation
• Mood
• Illusions/hallucinations
• Sexual dysfunction
• Pain
• Sleep disturbance
• Urinary difficulties, including frequency
• Orthostatic hypotension
• Baseline skin evaluation for evidence of melanoma
## Treatment of Manifestations
The treatment of individuals with
Pharmacologic replacement of dopamine
Different formulations of levodopa may be considered, including l-dopa combined with cardi-dopa.
Multiple formulations of l-dopa (which may be immediate release or longer acting) exist, as well as multiple routes of delivery, including oral (the major one), sublingual, and enteric.
Utilization of l-dopa should be driven by clinical need, and the clinician should consider using the lowest dose that yields a satisfactory clinical effect [
Monoamine oxidate B (MAO-B) inhibitors, including selegiline and rasagiline
Amantadine (Symmetrel
Dopamine receptor agonists
Anticholinergics
Exercise, as safe for the particular affected individual; often recommended [
Physical and occupational therapy
Voice therapy, particularly the Lee Silverman Voice Treatment
Cognitive behavioral therapy; potentially beneficial either with or without pharmacologic treatment
For those with hallucinations, consideration of non-dopamine-blocking medications (particularly pimavanserin; see
Troubling dyskinesias
Dyskinesias in individuals with
In general, women with
While dyskinesia is related to l-dopa dose, decisions regarding dosing should be guided by the clinician [
Significant wearing-off of doses
Delayed onset of medication action
Refractory rest tremor
Neurosurgical procedures such as deep brain stimulation (DBS) of the subthalamic nucleus (STN) / globus pallidus interna (GPi) may be considered if there is good response to but complications from l-dopa therapy.
Whether target selection should be guided by
Response to both STN and GPi have been reported in individuals with
Further, disease-modifying clinical trials are under way for
• Pharmacologic replacement of dopamine
• Different formulations of levodopa may be considered, including l-dopa combined with cardi-dopa.
• Multiple formulations of l-dopa (which may be immediate release or longer acting) exist, as well as multiple routes of delivery, including oral (the major one), sublingual, and enteric.
• Utilization of l-dopa should be driven by clinical need, and the clinician should consider using the lowest dose that yields a satisfactory clinical effect [
• Different formulations of levodopa may be considered, including l-dopa combined with cardi-dopa.
• Multiple formulations of l-dopa (which may be immediate release or longer acting) exist, as well as multiple routes of delivery, including oral (the major one), sublingual, and enteric.
• Utilization of l-dopa should be driven by clinical need, and the clinician should consider using the lowest dose that yields a satisfactory clinical effect [
• Monoamine oxidate B (MAO-B) inhibitors, including selegiline and rasagiline
• Amantadine (Symmetrel
• Dopamine receptor agonists
• Anticholinergics
• Different formulations of levodopa may be considered, including l-dopa combined with cardi-dopa.
• Multiple formulations of l-dopa (which may be immediate release or longer acting) exist, as well as multiple routes of delivery, including oral (the major one), sublingual, and enteric.
• Utilization of l-dopa should be driven by clinical need, and the clinician should consider using the lowest dose that yields a satisfactory clinical effect [
• Exercise, as safe for the particular affected individual; often recommended [
• Physical and occupational therapy
• Voice therapy, particularly the Lee Silverman Voice Treatment
• Cognitive behavioral therapy; potentially beneficial either with or without pharmacologic treatment
• For those with hallucinations, consideration of non-dopamine-blocking medications (particularly pimavanserin; see
• Troubling dyskinesias
• Dyskinesias in individuals with
• In general, women with
• While dyskinesia is related to l-dopa dose, decisions regarding dosing should be guided by the clinician [
• Dyskinesias in individuals with
• In general, women with
• While dyskinesia is related to l-dopa dose, decisions regarding dosing should be guided by the clinician [
• Significant wearing-off of doses
• Delayed onset of medication action
• Refractory rest tremor
• Dyskinesias in individuals with
• In general, women with
• While dyskinesia is related to l-dopa dose, decisions regarding dosing should be guided by the clinician [
• Whether target selection should be guided by
• Response to both STN and GPi have been reported in individuals with
## Surveillance
Recommended Surveillance for Individuals with
To assess effect of motor therapies (including wearing off and dyskinesias) and need for symptomatic treatment
Systematic assessment of history of motor and nonmotor features including associated disability as well as examination of motor features are captured in the Movement Disorder Society Sponsored Revision of the
## Agents/Circumstances to Avoid
Dopamine-blocking therapies (both typical and atypical dopamine-blocking psychiatric medications as well as dopamine blockers for gastrointestinal causes) may exacerbate parkinsonism in
## Evaluation of Relatives at Risk
See
## Pregnancy Management
While the data are restricted to case reports and registries, most support treatment with L-dopa during pregnancy (reviewed by
See
## Therapies Under Investigation
The Lrrk2 protein is a fusion of Rab (Roc), COR, and kinase (MAPK) domains, and pathogenic variants are postulated to augment kinase activity [
In addition to kinase inhibitors,
Search
## Genetic Counseling
To date, all individuals with
The probability that an asymptomatic parent with a pathogenic variant will become symptomatic increases with age.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include germline mosaicism in a parent or a
Although no instances of germline mosaicism have been reported, it remains a possibility.
Similarly,
The family history of some individuals diagnosed with
If a parent of the proband is affected or has an
The probability that an asymptomatic sib who has the pathogenic variant will become symptomatic increases with age.
Each child of an individual with
The probability that an offspring with a pathogenic variant will become symptomatic increases with age.
Testing for at-risk relatives is possible once the
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result), as well as the capabilities and limitations of such testing, should be discussed in the context of formal genetic counseling prior to testing. The Genetic Information Non-Discrimination Act (GINA) does not provide protection against genetic discrimination for life insurance, long-term insurance, or disability insurance.
Testing of asymptomatic minors for adult-onset disorders for which treatment of an asymptomatic individual does not decrease morbidity or mortality is not considered appropriate. Such testing negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• To date, all individuals with
• The probability that an asymptomatic parent with a pathogenic variant will become symptomatic increases with age.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include germline mosaicism in a parent or a
• Although no instances of germline mosaicism have been reported, it remains a possibility.
• Similarly,
• Although no instances of germline mosaicism have been reported, it remains a possibility.
• Similarly,
• The family history of some individuals diagnosed with
• Although no instances of germline mosaicism have been reported, it remains a possibility.
• Similarly,
• If a parent of the proband is affected or has an
• The probability that an asymptomatic sib who has the pathogenic variant will become symptomatic increases with age.
• Each child of an individual with
• The probability that an offspring with a pathogenic variant will become symptomatic increases with age.
• Testing for at-risk relatives is possible once the
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result), as well as the capabilities and limitations of such testing, should be discussed in the context of formal genetic counseling prior to testing. The Genetic Information Non-Discrimination Act (GINA) does not provide protection against genetic discrimination for life insurance, long-term insurance, or disability insurance.
• Testing of asymptomatic minors for adult-onset disorders for which treatment of an asymptomatic individual does not decrease morbidity or mortality is not considered appropriate. Such testing negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
## Risk to Family Members
To date, all individuals with
The probability that an asymptomatic parent with a pathogenic variant will become symptomatic increases with age.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include germline mosaicism in a parent or a
Although no instances of germline mosaicism have been reported, it remains a possibility.
Similarly,
The family history of some individuals diagnosed with
If a parent of the proband is affected or has an
The probability that an asymptomatic sib who has the pathogenic variant will become symptomatic increases with age.
Each child of an individual with
The probability that an offspring with a pathogenic variant will become symptomatic increases with age.
• To date, all individuals with
• The probability that an asymptomatic parent with a pathogenic variant will become symptomatic increases with age.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include germline mosaicism in a parent or a
• Although no instances of germline mosaicism have been reported, it remains a possibility.
• Similarly,
• Although no instances of germline mosaicism have been reported, it remains a possibility.
• Similarly,
• The family history of some individuals diagnosed with
• Although no instances of germline mosaicism have been reported, it remains a possibility.
• Similarly,
• If a parent of the proband is affected or has an
• The probability that an asymptomatic sib who has the pathogenic variant will become symptomatic increases with age.
• Each child of an individual with
• The probability that an offspring with a pathogenic variant will become symptomatic increases with age.
## Related Genetic Counseling Issues
Testing for at-risk relatives is possible once the
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result), as well as the capabilities and limitations of such testing, should be discussed in the context of formal genetic counseling prior to testing. The Genetic Information Non-Discrimination Act (GINA) does not provide protection against genetic discrimination for life insurance, long-term insurance, or disability insurance.
Testing of asymptomatic minors for adult-onset disorders for which treatment of an asymptomatic individual does not decrease morbidity or mortality is not considered appropriate. Such testing negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Testing for at-risk relatives is possible once the
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result), as well as the capabilities and limitations of such testing, should be discussed in the context of formal genetic counseling prior to testing. The Genetic Information Non-Discrimination Act (GINA) does not provide protection against genetic discrimination for life insurance, long-term insurance, or disability insurance.
• Testing of asymptomatic minors for adult-onset disorders for which treatment of an asymptomatic individual does not decrease morbidity or mortality is not considered appropriate. Such testing negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
LRRK2 Parkinson Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for LRRK2 Parkinson Disease (
Ankyrin repeat
Leucine-rich repeat
Roc
COR
Kinase
WD40
See
Several biochemical studies have confirmed kinase activity for LRRK2 wild type protein [
Abnormal LRRK2 has been implicated in a number of different pathways [
Autophagy
Endosomal-lysosomal function
Mitochondrial dysfunction
Immune signaling microglial motility
Synaptic vesicle trafficking and Wnt signaling
While the precise mechanism of action of
Of note, reported risk-factor variants (which are not associated with mendelian disease) include p.Arg1628Pro, p.Ser1647Thr, and p.Gly2385Arg [
Notable
Founder variant in the Basque population– see
Associated with excessive tremor – see
Most frequent pathogenic variant – see
See
Variants listed in the table have been provided by the authors.
• Ankyrin repeat
• Leucine-rich repeat
• Roc
• COR
• Kinase
• WD40
• Autophagy
• Endosomal-lysosomal function
• Mitochondrial dysfunction
• Immune signaling microglial motility
• Synaptic vesicle trafficking and Wnt signaling
• Founder variant in the Basque population– see
• Associated with excessive tremor – see
• Most frequent pathogenic variant – see
• See
## Molecular Pathogenesis
Ankyrin repeat
Leucine-rich repeat
Roc
COR
Kinase
WD40
See
Several biochemical studies have confirmed kinase activity for LRRK2 wild type protein [
Abnormal LRRK2 has been implicated in a number of different pathways [
Autophagy
Endosomal-lysosomal function
Mitochondrial dysfunction
Immune signaling microglial motility
Synaptic vesicle trafficking and Wnt signaling
While the precise mechanism of action of
Of note, reported risk-factor variants (which are not associated with mendelian disease) include p.Arg1628Pro, p.Ser1647Thr, and p.Gly2385Arg [
Notable
Founder variant in the Basque population– see
Associated with excessive tremor – see
Most frequent pathogenic variant – see
See
Variants listed in the table have been provided by the authors.
• Ankyrin repeat
• Leucine-rich repeat
• Roc
• COR
• Kinase
• WD40
• Autophagy
• Endosomal-lysosomal function
• Mitochondrial dysfunction
• Immune signaling microglial motility
• Synaptic vesicle trafficking and Wnt signaling
• Founder variant in the Basque population– see
• Associated with excessive tremor – see
• Most frequent pathogenic variant – see
• See
## Chapter Notes
Dr Saunders-Pullman is the Bachmann-Strauss Chair of Neurology at Mount Sinai. Her research interests focus on the clinical-genetic spectrum of Parkinson disease (PD) and dystonia, including the study of biomarkers and molecular pathways implicated in PD. Ms Raymond is a genetic counselor and clinical research manager. Ms Elango is also a genetic counselor at Mount Sinai. The authors have no financial disclosures.
Current research is supported through the National Institutes of Health (NINDS U01-NS107016-01A1U01 U01-NS094148-02), the Bigglesworth Family Foundation, and the Michael J Fox Foundation.
We are grateful to the individuals involved in our research, including the many scientists, clinicians, and especially the patients and their families.
Sonya Elango, MS (2019-present)Matthew Farrer, PhD; University of British Columbia (2006-2019)Ilaria Guella, PhD; University of British Columbia (2014-2019)Deborah Raymond, MS (2019-present)Owen A Ross, PhD; Mayo Clinic (2006-2019)Rachel Saunders-Pullman, MD, MPH (2019-present)Jeremy T Stone, BSc; Mayo Clinic (2006-2010)Joanne Trinh, BSc; University of British Columbia (2014-2019)
6 July 2023 (sw) Revision: information about
24 October 2019 (ma) Comprehensive update posted live
11 December 2014 (me) Comprehensive update posted live
13 September 2012 (me) Comprehensive update posted live
29 April 2010 (me) Comprehensive update posted live
2 November 2006 (me) Review posted live
6 July 2006 (mf) Original submission
• 6 July 2023 (sw) Revision: information about
• 24 October 2019 (ma) Comprehensive update posted live
• 11 December 2014 (me) Comprehensive update posted live
• 13 September 2012 (me) Comprehensive update posted live
• 29 April 2010 (me) Comprehensive update posted live
• 2 November 2006 (me) Review posted live
• 6 July 2006 (mf) Original submission
## Author Notes
Dr Saunders-Pullman is the Bachmann-Strauss Chair of Neurology at Mount Sinai. Her research interests focus on the clinical-genetic spectrum of Parkinson disease (PD) and dystonia, including the study of biomarkers and molecular pathways implicated in PD. Ms Raymond is a genetic counselor and clinical research manager. Ms Elango is also a genetic counselor at Mount Sinai. The authors have no financial disclosures.
## Acknowledgments
Current research is supported through the National Institutes of Health (NINDS U01-NS107016-01A1U01 U01-NS094148-02), the Bigglesworth Family Foundation, and the Michael J Fox Foundation.
We are grateful to the individuals involved in our research, including the many scientists, clinicians, and especially the patients and their families.
## Author History
Sonya Elango, MS (2019-present)Matthew Farrer, PhD; University of British Columbia (2006-2019)Ilaria Guella, PhD; University of British Columbia (2014-2019)Deborah Raymond, MS (2019-present)Owen A Ross, PhD; Mayo Clinic (2006-2019)Rachel Saunders-Pullman, MD, MPH (2019-present)Jeremy T Stone, BSc; Mayo Clinic (2006-2010)Joanne Trinh, BSc; University of British Columbia (2014-2019)
## Revision History
6 July 2023 (sw) Revision: information about
24 October 2019 (ma) Comprehensive update posted live
11 December 2014 (me) Comprehensive update posted live
13 September 2012 (me) Comprehensive update posted live
29 April 2010 (me) Comprehensive update posted live
2 November 2006 (me) Review posted live
6 July 2006 (mf) Original submission
• 6 July 2023 (sw) Revision: information about
• 24 October 2019 (ma) Comprehensive update posted live
• 11 December 2014 (me) Comprehensive update posted live
• 13 September 2012 (me) Comprehensive update posted live
• 29 April 2010 (me) Comprehensive update posted live
• 2 November 2006 (me) Review posted live
• 6 July 2006 (mf) Original submission
## References
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Published Guidelines / Consensus Statements
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Literature Cited
Schematic representation of the 144-kb
ANK = ankyrin repeat region
LRR = leucine-rich repeat
Roc = Ras of complex; GTPase
COR = C terminal of Ras
MAPKKK = MAPK kinase kinase
WD40
|
[] |
2/11/2006
|
24/10/2019
|
6/7/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
ltbp4-cutis-laxa
|
ltbp4-cutis-laxa
|
[
"Autosomal Recessive Cutis Laxa Type 1C (ARCL1C)",
"Urban-Rifkin-Davis Syndrome (URDS)",
"Autosomal Recessive Cutis Laxa Type 1C (ARCL1C)",
"Urban-Rifkin-Davis Syndrome (URDS)",
"Latent-transforming growth factor beta-binding protein 4",
"LTBP4",
"LTBP4-Related Cutis Laxa"
] |
Bert L Callewaert, Zsolt Urban
|
Summary The diagnosis of
|
## Diagnosis
No formal clinical diagnostic criteria have been established for
Loose redundant skin folds (cutis laxa)
Pulmonary emphysema
Gastrointestinal and/or urinary tract diverticula
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Loose redundant skin folds (cutis laxa)
• Pulmonary emphysema
• Gastrointestinal and/or urinary tract diverticula
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Loose redundant skin folds (cutis laxa)
Pulmonary emphysema
Gastrointestinal and/or urinary tract diverticula
• Loose redundant skin folds (cutis laxa)
• Pulmonary emphysema
• Gastrointestinal and/or urinary tract diverticula
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
The skin may show thinning and visible veins, as well as small wrinkles on the dorsum of hands and feet.
Hair may be sparse and slowly growing, especially temporally.
Precipitating/aggravating factors may include bronchiolitis, pneumonia, and positive pressure ventilation. Tracheomalacia, pulmonary hypertension, and congenital diaphragmatic hernia may worsen the respiratory problems.
In three individuals who survived beyond age five years, pulmonary emphysema was clinically less severe. In one of these individuals CT of the lungs showed emphysema, and lung function tests were consistent with severe obstructive lung disease (FEV
Newborns are at risk for pyloric stenosis (3/25 individuals).
Diaphragmatic involvement includes sliding hernias, congenital hernias, hiatal hernia, and diaphragmatic eventration (12/25 individuals). Often gastroesophageal reflux is associated with diaphragmatic insufficiency (sliding hernia). These hernias are rarely encountered in other types of cutis laxa.
Rectal prolapse may occur.
Diverticula, elongation, and dilatation of the gastrointestinal tract increase the risk for intestinal wall fragility, rupture, and necrosis.
Hydronephrosis, which is also frequent, may result from inherent weakness of the collecting system and/or vesicoureteral reflux.
Both incomplete voiding and dilatation of the collecting system may predispose to urinary tract infections.
Congenital stenosis of the peripheral pulmonary arteries
Septal defects
Atrial aneurysm (in 1 individual)
Valvular dysfunction (including dysplasia of any valve that may result in stenosis or regurgitation)
Arterial tortuosity and aortic root widening at the upper limit of normal (reported in 2 individuals) [
Pulmonary hypertension is a common complication that further impairs oxygenation. It is likely that emphysema and peripheral arterial stenoses contribute to the pulmonary hypertension.
No long-term follow-up data are available on the aortic root or the arterial tree.
Cognitive functioning is expected to be within the normal range; however, experience is limited because most affected individuals have died early or were critically ill. Of four children who survived longer than five years, one had slightly delayed expressive language development. Two affected individuals who survived to adulthood had normal cognitive function.
One child had a late-onset infection with group B streptococcus; one died from brain abscesses.
No immunologic tests have been performed in these children.
Inguinal and umbilical hernias can be present.
Postnatal growth delay may occur, but may be secondary to failure to thrive due to chronic, critical illness and respiratory problems rather than inherent to the condition.
One proband was reported to have a coagulopathy with subhyaloid hemorrhage [
Electron microscopy shows elastic fiber anomalies specific for this type of cutis laxa: very small amounts of elastin within the microfibrillar network and large globular elastin deposits that are separate from the microfibrillar bundles.
No genotype-phenotype correlations have been identified.
The prevalence is unknown, but the disorder is expected to be very rare (<1:1,000,000) with only 20 families reported to date.
There are no data on specific populations in which the prevalence may be greater or less than expected for the general population.
• Newborns are at risk for pyloric stenosis (3/25 individuals).
• Diaphragmatic involvement includes sliding hernias, congenital hernias, hiatal hernia, and diaphragmatic eventration (12/25 individuals). Often gastroesophageal reflux is associated with diaphragmatic insufficiency (sliding hernia). These hernias are rarely encountered in other types of cutis laxa.
• Rectal prolapse may occur.
• Diverticula, elongation, and dilatation of the gastrointestinal tract increase the risk for intestinal wall fragility, rupture, and necrosis.
• Congenital stenosis of the peripheral pulmonary arteries
• Septal defects
• Atrial aneurysm (in 1 individual)
• Valvular dysfunction (including dysplasia of any valve that may result in stenosis or regurgitation)
• Arterial tortuosity and aortic root widening at the upper limit of normal (reported in 2 individuals) [
• Inguinal and umbilical hernias can be present.
• Postnatal growth delay may occur, but may be secondary to failure to thrive due to chronic, critical illness and respiratory problems rather than inherent to the condition.
• One proband was reported to have a coagulopathy with subhyaloid hemorrhage [
## Clinical Description
The skin may show thinning and visible veins, as well as small wrinkles on the dorsum of hands and feet.
Hair may be sparse and slowly growing, especially temporally.
Precipitating/aggravating factors may include bronchiolitis, pneumonia, and positive pressure ventilation. Tracheomalacia, pulmonary hypertension, and congenital diaphragmatic hernia may worsen the respiratory problems.
In three individuals who survived beyond age five years, pulmonary emphysema was clinically less severe. In one of these individuals CT of the lungs showed emphysema, and lung function tests were consistent with severe obstructive lung disease (FEV
Newborns are at risk for pyloric stenosis (3/25 individuals).
Diaphragmatic involvement includes sliding hernias, congenital hernias, hiatal hernia, and diaphragmatic eventration (12/25 individuals). Often gastroesophageal reflux is associated with diaphragmatic insufficiency (sliding hernia). These hernias are rarely encountered in other types of cutis laxa.
Rectal prolapse may occur.
Diverticula, elongation, and dilatation of the gastrointestinal tract increase the risk for intestinal wall fragility, rupture, and necrosis.
Hydronephrosis, which is also frequent, may result from inherent weakness of the collecting system and/or vesicoureteral reflux.
Both incomplete voiding and dilatation of the collecting system may predispose to urinary tract infections.
Congenital stenosis of the peripheral pulmonary arteries
Septal defects
Atrial aneurysm (in 1 individual)
Valvular dysfunction (including dysplasia of any valve that may result in stenosis or regurgitation)
Arterial tortuosity and aortic root widening at the upper limit of normal (reported in 2 individuals) [
Pulmonary hypertension is a common complication that further impairs oxygenation. It is likely that emphysema and peripheral arterial stenoses contribute to the pulmonary hypertension.
No long-term follow-up data are available on the aortic root or the arterial tree.
Cognitive functioning is expected to be within the normal range; however, experience is limited because most affected individuals have died early or were critically ill. Of four children who survived longer than five years, one had slightly delayed expressive language development. Two affected individuals who survived to adulthood had normal cognitive function.
One child had a late-onset infection with group B streptococcus; one died from brain abscesses.
No immunologic tests have been performed in these children.
Inguinal and umbilical hernias can be present.
Postnatal growth delay may occur, but may be secondary to failure to thrive due to chronic, critical illness and respiratory problems rather than inherent to the condition.
One proband was reported to have a coagulopathy with subhyaloid hemorrhage [
Electron microscopy shows elastic fiber anomalies specific for this type of cutis laxa: very small amounts of elastin within the microfibrillar network and large globular elastin deposits that are separate from the microfibrillar bundles.
• Newborns are at risk for pyloric stenosis (3/25 individuals).
• Diaphragmatic involvement includes sliding hernias, congenital hernias, hiatal hernia, and diaphragmatic eventration (12/25 individuals). Often gastroesophageal reflux is associated with diaphragmatic insufficiency (sliding hernia). These hernias are rarely encountered in other types of cutis laxa.
• Rectal prolapse may occur.
• Diverticula, elongation, and dilatation of the gastrointestinal tract increase the risk for intestinal wall fragility, rupture, and necrosis.
• Congenital stenosis of the peripheral pulmonary arteries
• Septal defects
• Atrial aneurysm (in 1 individual)
• Valvular dysfunction (including dysplasia of any valve that may result in stenosis or regurgitation)
• Arterial tortuosity and aortic root widening at the upper limit of normal (reported in 2 individuals) [
• Inguinal and umbilical hernias can be present.
• Postnatal growth delay may occur, but may be secondary to failure to thrive due to chronic, critical illness and respiratory problems rather than inherent to the condition.
• One proband was reported to have a coagulopathy with subhyaloid hemorrhage [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Prevalence
The prevalence is unknown, but the disorder is expected to be very rare (<1:1,000,000) with only 20 families reported to date.
There are no data on specific populations in which the prevalence may be greater or less than expected for the general population.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The primary clinical differential diagnoses to consider are autosomal recessive cutis laxa type 1A (ARCL1A), autosomal recessive cutis laxa type 1B (ARCL1B), and autosomal dominant cutis laxa type 1 (ADCL1):
ARCL1A, ARCL1B, ADCL1 and other disorders to consider in the differential diagnosis of
Disorders to Consider in the Differential Diagnosis of
ADCL = autosomal dominant cutis laxa; ARCL = autosomal recessive cutis laxa; CDG = congenital disorder of glycosylation; CHD = congenital heart disease; DD = developmental delay; ID = intellectual disability; MACS =
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Chest radiograph or high-resolution CT scan
Bronchoscopy if clinically indicated
Visualization of GI tract by gastrographin ingestion or enema may be needed.
Diaphragmatic hernia should be excluded.
Community or
Social work involvement for parental support;
Home nursing referral to stimulate motor development & assist w/potential feeding difficulties &/or oxygen supplementation.
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Experience in treating individuals with
Treatment of Manifestations in Individuals with
Symptomatic treatment w/inhaled corticosteroids, atropine & selective β2-adrenergic bronchodilation
Oxygen supplementation if necessary
Surgical treatment of congenital diaphragmatic hernia or severe hiatal hernia
Medical treatment of gastroesophageal reflux to ↓ discomfort & reactive bronchospasms
Mother's milk in infants to maximize passive immunization
Gastrostomy tube may be needed to ensure nutrition in infants w/severe feeding difficulty.
Dietary advice, sufficient fluid intake & (if needed) osmotic laxatives to avoid chronic constipation
Education on complete bladder emptying when voiding
Antibiotic prophylaxis in case of incomplete voiding & recurrent urinary tract infections
Pelvic floor strengthening by PT may help to prevent prolapse of pelvic organs.
PT = physical therapist/therapy; RSV = respiratory syncytial virus
Recommended Surveillance for Individuals with
Due to avoidance of sunlight; see
Avoid the following:
Positive pressure ventilation unless needed to treat life-threatening conditions
People with respiratory infections
Tobacco smoking, which can result in rapid, severe loss of lung function in persons with
Isometric exercise and contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain
Sunbathing or tanning in order to preserve any residual skin elasticity
See
Pregnancy has been observed in one affected female with an unaffected fetus. The pregnancy was uneventful, but delivery was induced because of elevated maternal blood pressure. Delivery was vaginal with normal healing and no signs of prolapse. Two years after delivery both the mother and her son were doing well.
Despite evidence for the possibility of relatively normal pregnancy, a risk of aggravation of cardiopulmonary manifestations, worsening of diaphragmatic hernia, and increased risk of both uterine rupture and exacerbation of pelvic floor/organ insufficiency including uterine, bladder, and rectal prolapse cannot be excluded based on this single case. Therefore, it is recommended that follow up of pregnancy and the postnatal period be done in a high-risk obstetric care unit with experience in connective tissue disorders.
Search
• Chest radiograph or high-resolution CT scan
• Bronchoscopy if clinically indicated
• Visualization of GI tract by gastrographin ingestion or enema may be needed.
• Diaphragmatic hernia should be excluded.
• Community or
• Social work involvement for parental support;
• Home nursing referral to stimulate motor development & assist w/potential feeding difficulties &/or oxygen supplementation.
• Symptomatic treatment w/inhaled corticosteroids, atropine & selective β2-adrenergic bronchodilation
• Oxygen supplementation if necessary
• Surgical treatment of congenital diaphragmatic hernia or severe hiatal hernia
• Medical treatment of gastroesophageal reflux to ↓ discomfort & reactive bronchospasms
• Mother's milk in infants to maximize passive immunization
• Gastrostomy tube may be needed to ensure nutrition in infants w/severe feeding difficulty.
• Dietary advice, sufficient fluid intake & (if needed) osmotic laxatives to avoid chronic constipation
• Education on complete bladder emptying when voiding
• Antibiotic prophylaxis in case of incomplete voiding & recurrent urinary tract infections
• Pelvic floor strengthening by PT may help to prevent prolapse of pelvic organs.
• Positive pressure ventilation unless needed to treat life-threatening conditions
• People with respiratory infections
• Tobacco smoking, which can result in rapid, severe loss of lung function in persons with
• Isometric exercise and contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain
• Sunbathing or tanning in order to preserve any residual skin elasticity
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Chest radiograph or high-resolution CT scan
Bronchoscopy if clinically indicated
Visualization of GI tract by gastrographin ingestion or enema may be needed.
Diaphragmatic hernia should be excluded.
Community or
Social work involvement for parental support;
Home nursing referral to stimulate motor development & assist w/potential feeding difficulties &/or oxygen supplementation.
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Chest radiograph or high-resolution CT scan
• Bronchoscopy if clinically indicated
• Visualization of GI tract by gastrographin ingestion or enema may be needed.
• Diaphragmatic hernia should be excluded.
• Community or
• Social work involvement for parental support;
• Home nursing referral to stimulate motor development & assist w/potential feeding difficulties &/or oxygen supplementation.
## Treatment of Manifestations
Experience in treating individuals with
Treatment of Manifestations in Individuals with
Symptomatic treatment w/inhaled corticosteroids, atropine & selective β2-adrenergic bronchodilation
Oxygen supplementation if necessary
Surgical treatment of congenital diaphragmatic hernia or severe hiatal hernia
Medical treatment of gastroesophageal reflux to ↓ discomfort & reactive bronchospasms
Mother's milk in infants to maximize passive immunization
Gastrostomy tube may be needed to ensure nutrition in infants w/severe feeding difficulty.
Dietary advice, sufficient fluid intake & (if needed) osmotic laxatives to avoid chronic constipation
Education on complete bladder emptying when voiding
Antibiotic prophylaxis in case of incomplete voiding & recurrent urinary tract infections
Pelvic floor strengthening by PT may help to prevent prolapse of pelvic organs.
PT = physical therapist/therapy; RSV = respiratory syncytial virus
• Symptomatic treatment w/inhaled corticosteroids, atropine & selective β2-adrenergic bronchodilation
• Oxygen supplementation if necessary
• Surgical treatment of congenital diaphragmatic hernia or severe hiatal hernia
• Medical treatment of gastroesophageal reflux to ↓ discomfort & reactive bronchospasms
• Mother's milk in infants to maximize passive immunization
• Gastrostomy tube may be needed to ensure nutrition in infants w/severe feeding difficulty.
• Dietary advice, sufficient fluid intake & (if needed) osmotic laxatives to avoid chronic constipation
• Education on complete bladder emptying when voiding
• Antibiotic prophylaxis in case of incomplete voiding & recurrent urinary tract infections
• Pelvic floor strengthening by PT may help to prevent prolapse of pelvic organs.
## Surveillance
Recommended Surveillance for Individuals with
Due to avoidance of sunlight; see
## Agents/Circumstances to Avoid
Avoid the following:
Positive pressure ventilation unless needed to treat life-threatening conditions
People with respiratory infections
Tobacco smoking, which can result in rapid, severe loss of lung function in persons with
Isometric exercise and contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain
Sunbathing or tanning in order to preserve any residual skin elasticity
• Positive pressure ventilation unless needed to treat life-threatening conditions
• People with respiratory infections
• Tobacco smoking, which can result in rapid, severe loss of lung function in persons with
• Isometric exercise and contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain
• Sunbathing or tanning in order to preserve any residual skin elasticity
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Pregnancy has been observed in one affected female with an unaffected fetus. The pregnancy was uneventful, but delivery was induced because of elevated maternal blood pressure. Delivery was vaginal with normal healing and no signs of prolapse. Two years after delivery both the mother and her son were doing well.
Despite evidence for the possibility of relatively normal pregnancy, a risk of aggravation of cardiopulmonary manifestations, worsening of diaphragmatic hernia, and increased risk of both uterine rupture and exacerbation of pelvic floor/organ insufficiency including uterine, bladder, and rectal prolapse cannot be excluded based on this single case. Therefore, it is recommended that follow up of pregnancy and the postnatal period be done in a high-risk obstetric care unit with experience in connective tissue disorders.
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
New Zealand
France
•
• New Zealand
•
•
•
•
•
• France
•
## Molecular Genetics
LTBP4-Related Cutis Laxa: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for LTBP4-Related Cutis Laxa (
Latent-transforming growth factor β-binding protein 4 (LTBP4) belongs to a family of four extracellular matrix proteins that are structurally related to fibrillins. LTBP4 has multiple isoforms with the long (LTBP4L) and short (LTBP4S) being the major isoforms. The third 8-cys domain of LTBP4 covalently binds the small latent complex consisting of the homodimer TGFβ1 and its propeptide (also known as latency-associated peptide). This interaction allows LTBP4 to sequester TGFβ1 and control its activation. However, the in vivo significance of this function has been called into question by the normal phenotype of mice with variants that prevent the binding of TGFβ1 to LTBP4 [
Evidence suggests that LTBP4 enhances elastogenesis by regulating the incorporation of elastin-fibulin-5 complexes into the microfibrillar bundles to form elastic fibers [
In addition to its function in TGFβ1 sequestration and elastic fiber formation, LTBP4 stabilized the TGFβ receptors TGFBR1 and TGFBR2 [
In mice and humans with LTBP4 deficiency, emphysema results from impaired terminal air sac septation [
## Molecular Pathogenesis
Latent-transforming growth factor β-binding protein 4 (LTBP4) belongs to a family of four extracellular matrix proteins that are structurally related to fibrillins. LTBP4 has multiple isoforms with the long (LTBP4L) and short (LTBP4S) being the major isoforms. The third 8-cys domain of LTBP4 covalently binds the small latent complex consisting of the homodimer TGFβ1 and its propeptide (also known as latency-associated peptide). This interaction allows LTBP4 to sequester TGFβ1 and control its activation. However, the in vivo significance of this function has been called into question by the normal phenotype of mice with variants that prevent the binding of TGFβ1 to LTBP4 [
Evidence suggests that LTBP4 enhances elastogenesis by regulating the incorporation of elastin-fibulin-5 complexes into the microfibrillar bundles to form elastic fibers [
In addition to its function in TGFβ1 sequestration and elastic fiber formation, LTBP4 stabilized the TGFβ receptors TGFBR1 and TGFBR2 [
In mice and humans with LTBP4 deficiency, emphysema results from impaired terminal air sac septation [
## Chapter Notes
Bert Callewaert is an Associate Professor at Ghent University and a pediatrician/clinical geneticist at the Center for Medical Genetics of the Ghent University Hospital. His research focuses on connective tissue disorders (including arterial tortuosity syndrome, cutis laxa syndromes, and familial thoracic aortic aneurysms). Both zebrafish and mouse models are used to gain insight into the pathogenesis of these disorders.
Website:
Zsolt Urban is an Associate Professor of Human Genetics at the Graduate School of Public Health of the University of Pittsburgh. His research is focused on cutis laxa and related disorders. His research team pursues clinical, cell culture, and animal model studies to characterize the natural history of cutis laxa and identify the genetic causes and underlying molecular mechanisms responsible for this group of diseases. For more information, go to the
Dr Callewaert ([email protected]) is actively involved in clinical research regarding individuals with
Contact Dr Callewaert at [email protected] to inquire about the interpretation of
Dr Callewaert ([email protected]) is also interested in hearing from clinicians treating families affected by cutis laxa in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Bert Callewaert is a Senior Clinical Investigator of the Fund for Scientific Research-Flanders. Zsolt Urban is funded by a National Institutes of Health grant HL090648.
23 February 2023 (aa) Revision: clarified age of onset of emphysema in
14 July 2022 (blc) Revision: contact information for questions about
22 July 2021 (ha) Comprehensive update posted live
11 February 2016 (bp) Review posted live
1 December 2014 (zu) Original submission
• 23 February 2023 (aa) Revision: clarified age of onset of emphysema in
• 14 July 2022 (blc) Revision: contact information for questions about
• 22 July 2021 (ha) Comprehensive update posted live
• 11 February 2016 (bp) Review posted live
• 1 December 2014 (zu) Original submission
## Author Notes
Bert Callewaert is an Associate Professor at Ghent University and a pediatrician/clinical geneticist at the Center for Medical Genetics of the Ghent University Hospital. His research focuses on connective tissue disorders (including arterial tortuosity syndrome, cutis laxa syndromes, and familial thoracic aortic aneurysms). Both zebrafish and mouse models are used to gain insight into the pathogenesis of these disorders.
Website:
Zsolt Urban is an Associate Professor of Human Genetics at the Graduate School of Public Health of the University of Pittsburgh. His research is focused on cutis laxa and related disorders. His research team pursues clinical, cell culture, and animal model studies to characterize the natural history of cutis laxa and identify the genetic causes and underlying molecular mechanisms responsible for this group of diseases. For more information, go to the
Dr Callewaert ([email protected]) is actively involved in clinical research regarding individuals with
Contact Dr Callewaert at [email protected] to inquire about the interpretation of
Dr Callewaert ([email protected]) is also interested in hearing from clinicians treating families affected by cutis laxa in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
## Acknowledgments
Bert Callewaert is a Senior Clinical Investigator of the Fund for Scientific Research-Flanders. Zsolt Urban is funded by a National Institutes of Health grant HL090648.
## Revision History
23 February 2023 (aa) Revision: clarified age of onset of emphysema in
14 July 2022 (blc) Revision: contact information for questions about
22 July 2021 (ha) Comprehensive update posted live
11 February 2016 (bp) Review posted live
1 December 2014 (zu) Original submission
• 23 February 2023 (aa) Revision: clarified age of onset of emphysema in
• 14 July 2022 (blc) Revision: contact information for questions about
• 22 July 2021 (ha) Comprehensive update posted live
• 11 February 2016 (bp) Review posted live
• 1 December 2014 (zu) Original submission
## References
## Literature Cited
|
[
"CS Adamo, A Beyens, A Schiavinato, DR Keene, SF Tufa, M Mörgelin, J Brinckmann, T Sasaki, A Niehoff, M Dreiner, L Pottie, L Muiño-Mosquera, EY Gulec, A Gezdirici, P Braghetta, P Bonaldo, R Wagener, M Paulsson, H Bornaun, R De Rycke, M De Bruyne, F Baeke, WP Devine, B Gangaram, A Tam, M Balasubramanian, S Ellard, S Moore, S Symoens, J Shen, S Cole, U Schwarze, KW Holmes, SJ Hayflick, W Wiszniewski, S Nampoothiri, EC Davis, LY Sakai, G Sengle, B Callewaert. EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis.. Am J Hum Genet. 2022;109:2230-52",
"L Basel-Vanagaite, O Sarig, D Hershkovitz, D Fuchs-Telem, D Rapaport, A Gat, G Isman, I Shirazi, M Shohat, CD Enk, E Birk, J Kohlhase, U Matysiak-Scholze, I Maya, C Knopf, A Peffekoven, HC Hennies, R Bergman, M Horowitz, A Ishida-Yamamoto, E Sprecher. RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome.. Am J Hum Genet. 2009;85:254-63",
"A Beyens, K Van Meensel, L Pottie, R De Rycke, M De Bruyne, F Baeke, P Hoebeke, F Plasschaert, B Loeys, S De Schepper, S Symoens, B Callewaert. Defining the clinical, molecular and ultrastructural characteristics in occipital horn syndrome: two new cases and review of the literature.. Genes (Basel) 2019;10:528",
"I Bultmann-Mellin, A Conradi, AC Maul, K Dinger, F Wempe, AP Wohl, T Imhof, FT Wunderlich, AC Bunck, T Nakamura, K Koli, W Bloch, A Ghanem, A Heinz, H von Melchner, G Sengle, A Sterner-Kock. Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms.. Dis Model Mech. 2015;8:403-15",
"I Bultmann-Mellin, K Dinger, C Debuschewitz, KMA Loewe, Y Melcher, MTW Plum, S Appel, G Rappl, S Willenborg, AC Schauss, C Jüngst, M Krüger, S Dressler, T Nakamura, F Wempe, MA Alejandre Alcázar, A Sterner-Kock. Role of LTBP4 in alveolarization, angiogenesis, and fibrosis in lungs.. Am J Physiol Lung Cell Mol Physiol. 2017;313:L687-L698",
"I Bultmann-Mellin, J Essers, PM van Heijingen, H von Melchner, G Sengle, A Sterner-Kock. Function of Ltbp-4L and fibulin-4 in survival and elastogenesis in mice.. Dis Model Mech. 2016;9:1367-74",
"B Callewaert, M Renard, V Hucthagowder, B Albrecht, I Hausser, E Blair, C Dias, A Albino, H Wachi, F Sato, RP Mecham, B Loeys, PJ Coucke, A De Paepe, Z Urban. New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.. Hum Mutat. 2011;32:445-55",
"B Callewaert, CT Su, T Van Damme, P Vlummens, F Malfait, O Vanakker, B Schulz, M Mac Neal, EC Davis, JG Lee, A Salhi, S Unger, K Heimdal, S De Almeida, U Kornak, H Gaspar, JL Bresson, K Prescott, ME Gosendi, S Mansour, GE Piérard, S Madan-Khetarpal, FC Sciurba, S Symoens, PJ Coucke, L Van Maldergem, Z Urban, A De Paepe. Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.. Hum Mutat. 2013;34:111-21",
"B Dabovic, Y Chen, J Choi, M Vassallo, HC Dietz, F Ramirez, H von Melchner, EC Davis, DB Rifkin. Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-beta activity.. J Cell Physiol. 2009;219:14-22",
"B Dabovic, IB Robertson, L Zilberberg, M Vassallo, EC Davis, DB Rifkin. Function of latent TGFβ binding protein 4 and fibulin 5 in elastogenesis and lung development.. J Cell Physiol. 2015;230:226-36",
"N Gupta, N Langeh, A Sridharan, M Kabra. Identification of a novel 19-bp deletion mutation in LTBP4 using exome sequencing in two siblings with autosomal recessive cutis laxa type 1C.. J Pediatr Genet. 2020;9:125-31",
"S Hadj-Rabia, BL Callewaert, E Bourrat, M Kempers, AS Plomp, V Layet, D Bartholdi, M Renard, J De Backer, F Malfait, OM Vanakker, PJ Coucke, AM De Paepe, C Bodemer. Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.. Orphanet J Rare Dis. 2013;8:36",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"C Karakurt, G Koçak, O Elkiran, PJ Coucke, L Van Maldergem. Arterial tortuosity syndrome: case report.. Genet Couns. 2012;23:477-82",
"F McKenzie, K Mina, B Callewaert, A Beyens, JE Dickinson, G Jevon, J Papadimitriou, BR Diness, JN Steensberg, J Ek, G Baynam. Severe congenital cutis laxa: Identification of novel homozygous LOX gene variants in two families.. Clin Genet. 2021;100:168-75",
"K Noda, B Dabovic, K Takagi, T Inoue, M Horiguchi, M Hirai, Y Fujikawa, TO Akama, K Kusumoto, L Zilberberg, LY Sakai, K Koli, M Naitoh, H von Melchner, S Suzuki, DB Rifkin, T Nakamura. Latent TGF-β binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5.. Proc Natl Acad Sci U S A. 2013;110:2852-7",
"J Piard, J Lespinasse, M Vlckova, MA Mensah, S Iurian, M Simandlova, M Malikova, O Bartsch, M Rossi, M Lenoir, F Nugues, S Mundlos, U Kornak, P Stanier, SB Sousa, L Van Maldergem. Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1.. Am J Med Genet A. 2018;176:668-75",
"L Pottie, CS Adamo, A Beyens, S Lütke, P Tapaneeyaphan, A De Clercq, PL Salmon, R De Rycke, A Gezdirici, EY Gulec, N Khan, JE Urquhart, WG Newman, K Metcalfe, S Efthymiou, R Maroofian, N Anwar, S Maqbool, F Rahman, I Altweijri, M Alsaleh, SM Abdullah, M Al-Owain, M Hashem, H Houlden, FS Alkuraya, P Sips, G Sengle, B Callewaert. Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome.. Am J Hum Genet. 2021;108:1095-114",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"M Ritelli, F Cammarata-Scalisi, V Cinquina, M Colombi. Clinical and molecular characterization of an 18-month-old infant with autosomal recessive cutis laxa type 1C due to a novel LTBP4 pathogenic variant, and literature review.. Mol Genet Genomic Med. 2019;7",
"SB Sousa, D Jenkins, E Chanudet, G Tasseva, M Ishida, G Anderson, J Docker, M Ryten, J Sa, JM Saraiva, A Barnicoat, R Scott, A Calder, D Wattanasirichaigoon, K Chrzanowska, M Simandlová, L Van Maldergem, P Stanier, PL Beales, JE Vance, GE Moore. Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome.. Nat Genet. 2014;46:70-6",
"A Sterner-Kock, IS Thorey, K Koli, F Wempe, J Otte, T Bangsow, K Kuhlmeier, T Kirchner, S Jin, J Keski-Oja, H von Melchner. Disruption of the gene encoding the latent transforming growth factor beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer.. Genes Dev. 2002;16:2264-73",
"CT Su, JW Huang, CK Chiang, EC Lawrence, KL Levine, B Dabovic, C Jung, EC Davis, S Madan-Khetarpal, Z Urban. Latent transforming growth factor binding protein 4 regulates transforming growth factor beta receptor stability.. Hum Mol Genet. 2015;24:4024-36",
"Z Szabo, MW Crepeau, AL Mitchell, MJ Stephan, RA Puntel, K Yin Loke, RC Kirk, Z Urban. Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene.. J Med Genet. 2006;43:255-8",
"Z Urban, V Hucthagowder, N Schürmann, V Todorovic, L Zilberberg, J Choi, C Sens, CW Brown, RD Clark, KE Holland, M Marble, LY Sakai, B Dabovic, DB Rifkin, EC Davis. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development.. Am J Hum Genet. 2009;85:593-605",
"M Verlee, A Beyens, A Gezdirici, EY Gulec, L Pottie, S De Feyter, M Vanhooydonck, P Tapaneeyaphan, S Symoens, B Callewaert. Loss-of-function variants in. Genes (Basel) 2021;12:510",
"Q Zhang, Z Qin, S Yi, H Wei, XZ Zhou, J Su. Two novel compound heterozygous variants of LTBP4 in a Chinese infant with cutis laxa type IC and a review of the related literature.. BMC Med Genomics. 2020;13:183"
] |
11/2/2016
|
22/7/2021
|
23/2/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
lwd
|
lwd
|
[
"Leri-Weill Dyschondrosteosis (LWD)",
"SHOX-Deficient Short Stature",
"Short stature homeobox protein",
"SHOX",
"SHOX Deficiency Disorders"
] |
SHOX Deficiency Disorders
|
Gerhard Binder, Gudrun A Rappold
|
Summary The phenotypic spectrum of SHOX deficiency disorders, caused by haploinsufficiency of the The diagnosis of SHOX deficiency is established in a proband with either a pathogenic SHOX deficiency disorders are inherited in a pseudoautosomal dominant manner. In pseudoautosomal dominant inheritance, homologous genes located on the short arm of the X chromosome (Xp) and the short arm of the Y chromosome (Yp) follow the rules of autosomal inheritance; thus, a Each child of an individual with a SHOX deficiency disorder has a 50% chance of inheriting the
|
Leri-Weill dyschondrosteosis (LWD)
SHOX-deficient short stature
For other genetic causes of these phenotypes, see
• Leri-Weill dyschondrosteosis (LWD)
• SHOX-deficient short stature
## Diagnosis
The phenotypic spectrum of SHOX deficiency disorders, caused by haploinsufficiency of the
This shortening of the forearm and lower leg can be assessed by two ratios:
The radiographic criteria for Madelung deformity [
Triangulation of the distal epiphysis
Early fusion of the ulnar half of the distal epiphysis
Localized lucency at the distal ulnar border
Decreased length
Dorsal and ulnar curve
Decreased length
Dorsal subluxation
Triangular deformity of the epiphysis
Disproportionate short stature (young school age)
Madelung deformity (older school age)
Short stature and specific minor abnormalities (See Clinical Characteristics,
The following two testing algorithms have been proposed:
A scoring system based on various clinical signs including body disproportion, arm span:height ratio 55.5%, body mass index >50th centile, the presence of cubitus valgus, short forearm, bowing of the forearm, appearance of muscular hypertrophy, and/or dislocation of the ulna [
While the values for body disproportions in children and adults are useful, they may not apply to very young children [
A diagnostic algorithm (not yet evaluated) based on clinical, auxologic, and radiologic criteria [
Note: The absence of the above signs does not exclude the diagnosis of SHOX deficiency, especially in very young children.
The diagnosis of SHOX deficiency
A heterozygous
In females, one copy is present on the short arm of each X chromosome (Xp).
In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
Deletions can encompass all or part of
A
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SHOX deficiency is broad, individuals with the distinctive findings of Leri-Weill dyschondrosteosis (LWD) described in
When the phenotypic and laboratory findings suggest the diagnosis of Leri-Weill dyschondrosteosis (LWD) or SHOX-deficient short stature, molecular genetic testing approaches can include
If a large
Deletions can also be detected using
For an introduction to multigene panels click
When SHOX-deficient short stature is indistinguishable from many other inherited disorders characterized by short stature,
Exome array (when clinically available) or alternatively CMA – if not previously performed – may be considered if exome sequencing is nondiagnostic.
For an introduction to comprehensive genomic testing click
Balanced and unbalanced translocations involving X, Y, and other chromosomes [
Other complex sex-chromosome abnormalities [
Molecular Genetic Testing Used in SHOX Deficiency
See
See
Currently, about 10% of individuals with LWD do not have a demonstrable
Numbers vary between laboratories using different methodologies. Numbers also differ in patients from different ethnic origins.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon (e.g., those described by
Gene-targeted deletion/duplication analysis should be able to detect all pathogenic deletions or duplications that are detected by CMA / SNP array, although it may also detect smaller deletions or duplications that are outside of the sensitivity of the specific CMA / SNP platform, depending on the probe and SNP coverage through the Xp22.32;Yp11.3 region on the CMA / SNP platform used.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Balanced and unbalanced chromosome rearrangements disrupting
•
• Triangulation of the distal epiphysis
• Early fusion of the ulnar half of the distal epiphysis
• Localized lucency at the distal ulnar border
• Decreased length
• Dorsal and ulnar curve
• Triangulation of the distal epiphysis
• Early fusion of the ulnar half of the distal epiphysis
• Localized lucency at the distal ulnar border
• Decreased length
• Dorsal and ulnar curve
•
• Decreased length
• Dorsal subluxation
• Triangular deformity of the epiphysis
• Decreased length
• Dorsal subluxation
• Triangular deformity of the epiphysis
• Triangulation of the distal epiphysis
• Early fusion of the ulnar half of the distal epiphysis
• Localized lucency at the distal ulnar border
• Decreased length
• Dorsal and ulnar curve
• Decreased length
• Dorsal subluxation
• Triangular deformity of the epiphysis
• Disproportionate short stature (young school age)
• Madelung deformity (older school age)
• Short stature and specific minor abnormalities (See Clinical Characteristics,
• A scoring system based on various clinical signs including body disproportion, arm span:height ratio 55.5%, body mass index >50th centile, the presence of cubitus valgus, short forearm, bowing of the forearm, appearance of muscular hypertrophy, and/or dislocation of the ulna [
• While the values for body disproportions in children and adults are useful, they may not apply to very young children [
• A diagnostic algorithm (not yet evaluated) based on clinical, auxologic, and radiologic criteria [
• A heterozygous
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• Deletions can encompass all or part of
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• Deletions can encompass all or part of
• A
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• Deletions can encompass all or part of
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• If a large
• Deletions can also be detected using
• For an introduction to multigene panels click
• Balanced and unbalanced translocations involving X, Y, and other chromosomes [
• Other complex sex-chromosome abnormalities [
## Suggestive Findings
This shortening of the forearm and lower leg can be assessed by two ratios:
The radiographic criteria for Madelung deformity [
Triangulation of the distal epiphysis
Early fusion of the ulnar half of the distal epiphysis
Localized lucency at the distal ulnar border
Decreased length
Dorsal and ulnar curve
Decreased length
Dorsal subluxation
Triangular deformity of the epiphysis
Disproportionate short stature (young school age)
Madelung deformity (older school age)
Short stature and specific minor abnormalities (See Clinical Characteristics,
The following two testing algorithms have been proposed:
A scoring system based on various clinical signs including body disproportion, arm span:height ratio 55.5%, body mass index >50th centile, the presence of cubitus valgus, short forearm, bowing of the forearm, appearance of muscular hypertrophy, and/or dislocation of the ulna [
While the values for body disproportions in children and adults are useful, they may not apply to very young children [
A diagnostic algorithm (not yet evaluated) based on clinical, auxologic, and radiologic criteria [
Note: The absence of the above signs does not exclude the diagnosis of SHOX deficiency, especially in very young children.
•
• Triangulation of the distal epiphysis
• Early fusion of the ulnar half of the distal epiphysis
• Localized lucency at the distal ulnar border
• Decreased length
• Dorsal and ulnar curve
• Triangulation of the distal epiphysis
• Early fusion of the ulnar half of the distal epiphysis
• Localized lucency at the distal ulnar border
• Decreased length
• Dorsal and ulnar curve
•
• Decreased length
• Dorsal subluxation
• Triangular deformity of the epiphysis
• Decreased length
• Dorsal subluxation
• Triangular deformity of the epiphysis
• Triangulation of the distal epiphysis
• Early fusion of the ulnar half of the distal epiphysis
• Localized lucency at the distal ulnar border
• Decreased length
• Dorsal and ulnar curve
• Decreased length
• Dorsal subluxation
• Triangular deformity of the epiphysis
• Disproportionate short stature (young school age)
• Madelung deformity (older school age)
• Short stature and specific minor abnormalities (See Clinical Characteristics,
• A scoring system based on various clinical signs including body disproportion, arm span:height ratio 55.5%, body mass index >50th centile, the presence of cubitus valgus, short forearm, bowing of the forearm, appearance of muscular hypertrophy, and/or dislocation of the ulna [
• While the values for body disproportions in children and adults are useful, they may not apply to very young children [
• A diagnostic algorithm (not yet evaluated) based on clinical, auxologic, and radiologic criteria [
## Clinical Findings of LWD
This shortening of the forearm and lower leg can be assessed by two ratios:
## Radiographic Findings of LWD
The radiographic criteria for Madelung deformity [
Triangulation of the distal epiphysis
Early fusion of the ulnar half of the distal epiphysis
Localized lucency at the distal ulnar border
Decreased length
Dorsal and ulnar curve
Decreased length
Dorsal subluxation
Triangular deformity of the epiphysis
Disproportionate short stature (young school age)
Madelung deformity (older school age)
Short stature and specific minor abnormalities (See Clinical Characteristics,
The following two testing algorithms have been proposed:
A scoring system based on various clinical signs including body disproportion, arm span:height ratio 55.5%, body mass index >50th centile, the presence of cubitus valgus, short forearm, bowing of the forearm, appearance of muscular hypertrophy, and/or dislocation of the ulna [
While the values for body disproportions in children and adults are useful, they may not apply to very young children [
A diagnostic algorithm (not yet evaluated) based on clinical, auxologic, and radiologic criteria [
Note: The absence of the above signs does not exclude the diagnosis of SHOX deficiency, especially in very young children.
•
• Triangulation of the distal epiphysis
• Early fusion of the ulnar half of the distal epiphysis
• Localized lucency at the distal ulnar border
• Decreased length
• Dorsal and ulnar curve
• Triangulation of the distal epiphysis
• Early fusion of the ulnar half of the distal epiphysis
• Localized lucency at the distal ulnar border
• Decreased length
• Dorsal and ulnar curve
•
• Decreased length
• Dorsal subluxation
• Triangular deformity of the epiphysis
• Decreased length
• Dorsal subluxation
• Triangular deformity of the epiphysis
• Triangulation of the distal epiphysis
• Early fusion of the ulnar half of the distal epiphysis
• Localized lucency at the distal ulnar border
• Decreased length
• Dorsal and ulnar curve
• Decreased length
• Dorsal subluxation
• Triangular deformity of the epiphysis
• Disproportionate short stature (young school age)
• Madelung deformity (older school age)
• Short stature and specific minor abnormalities (See Clinical Characteristics,
• A scoring system based on various clinical signs including body disproportion, arm span:height ratio 55.5%, body mass index >50th centile, the presence of cubitus valgus, short forearm, bowing of the forearm, appearance of muscular hypertrophy, and/or dislocation of the ulna [
• While the values for body disproportions in children and adults are useful, they may not apply to very young children [
• A diagnostic algorithm (not yet evaluated) based on clinical, auxologic, and radiologic criteria [
## Establishing the Diagnosis
The diagnosis of SHOX deficiency
A heterozygous
In females, one copy is present on the short arm of each X chromosome (Xp).
In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
Deletions can encompass all or part of
A
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SHOX deficiency is broad, individuals with the distinctive findings of Leri-Weill dyschondrosteosis (LWD) described in
When the phenotypic and laboratory findings suggest the diagnosis of Leri-Weill dyschondrosteosis (LWD) or SHOX-deficient short stature, molecular genetic testing approaches can include
If a large
Deletions can also be detected using
For an introduction to multigene panels click
When SHOX-deficient short stature is indistinguishable from many other inherited disorders characterized by short stature,
Exome array (when clinically available) or alternatively CMA – if not previously performed – may be considered if exome sequencing is nondiagnostic.
For an introduction to comprehensive genomic testing click
Balanced and unbalanced translocations involving X, Y, and other chromosomes [
Other complex sex-chromosome abnormalities [
Molecular Genetic Testing Used in SHOX Deficiency
See
See
Currently, about 10% of individuals with LWD do not have a demonstrable
Numbers vary between laboratories using different methodologies. Numbers also differ in patients from different ethnic origins.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon (e.g., those described by
Gene-targeted deletion/duplication analysis should be able to detect all pathogenic deletions or duplications that are detected by CMA / SNP array, although it may also detect smaller deletions or duplications that are outside of the sensitivity of the specific CMA / SNP platform, depending on the probe and SNP coverage through the Xp22.32;Yp11.3 region on the CMA / SNP platform used.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Balanced and unbalanced chromosome rearrangements disrupting
• A heterozygous
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• Deletions can encompass all or part of
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• Deletions can encompass all or part of
• A
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• Deletions can encompass all or part of
• In females, one copy is present on the short arm of each X chromosome (Xp).
• In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called
• If a large
• Deletions can also be detected using
• For an introduction to multigene panels click
• Balanced and unbalanced translocations involving X, Y, and other chromosomes [
• Other complex sex-chromosome abnormalities [
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Leri-Weill dyschondrosteosis (LWD) or SHOX-deficient short stature, molecular genetic testing approaches can include
If a large
Deletions can also be detected using
For an introduction to multigene panels click
• If a large
• Deletions can also be detected using
• For an introduction to multigene panels click
## Option 2
When SHOX-deficient short stature is indistinguishable from many other inherited disorders characterized by short stature,
Exome array (when clinically available) or alternatively CMA – if not previously performed – may be considered if exome sequencing is nondiagnostic.
For an introduction to comprehensive genomic testing click
Balanced and unbalanced translocations involving X, Y, and other chromosomes [
Other complex sex-chromosome abnormalities [
Molecular Genetic Testing Used in SHOX Deficiency
See
See
Currently, about 10% of individuals with LWD do not have a demonstrable
Numbers vary between laboratories using different methodologies. Numbers also differ in patients from different ethnic origins.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon (e.g., those described by
Gene-targeted deletion/duplication analysis should be able to detect all pathogenic deletions or duplications that are detected by CMA / SNP array, although it may also detect smaller deletions or duplications that are outside of the sensitivity of the specific CMA / SNP platform, depending on the probe and SNP coverage through the Xp22.32;Yp11.3 region on the CMA / SNP platform used.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Balanced and unbalanced chromosome rearrangements disrupting
• Balanced and unbalanced translocations involving X, Y, and other chromosomes [
• Other complex sex-chromosome abnormalities [
## Clinical Characteristics
The phenotypic spectrum of SHOX deficiency disorders ranges from Leri-Weill dyschondrosteosis (LWD) at the severe end of the spectrum to SHOX-deficient short stature (without mesomelia or Madelung deformity) at the mild end. In adults with SHOX deficiency, the proportion of LWD versus SHOX-deficient short stature is not well defined. In LWD the classic clinical triad is short stature, mesomelia, and Madelung deformity. Mesomelia, in which the middle portion of a limb is shortened in relation to the proximal portion, can be evident first in school-aged children and increases with age in frequency and severity. Madelung deformity (abnormal alignment of the radius, ulna, and carpal bones at the wrist) typically develops in mid-to-late childhood and is more common and severe in females. The phenotype of SHOX-deficient short stature is highly variable, even within the same family.
Antenatally detected shortening of the long bones attributable to SHOX deficiency was reported in five infants. In four of the five, SHOX deficiency was inherited from a previously undiagnosed parent with final height z score between -1.2 and -1.9, suggesting that SHOX deficiency can be well tolerated within a favorable genetic context [
Mean birth length is only mildly reduced, at 0.6-0.9 standard deviations (SD) below the mean [
Infancy is characterized by significant growth failure resulting in short stature in early childhood with mean heights of 2.1-2.2 SD below the mean [
During childhood, there is probably no relevant additional loss of height.
The pubertal growth spurt, however, appears to be blunted, resulting in an additional height deficit.
Madelung deformity typically develops in mid-to-late childhood. The first common sign is a subtle reduction in pronation and supination of the forearm. The complete deformity with distal subluxation of the ulna (dinner fork sign) evolves during puberty and is associated with further restriction of forearm supination and pronation [
Rarely, Madelung deformity causes joint pain in adolescence [
Hypertrophy of calf muscles
Short fourth metacarpals
Increased carrying angle of the elbow
High-arched palate
Scoliosis
High body mass index (not caused by excess of fat mass)
No other visceral involvement occurs. Intellect is normal.
When SHOX deficiency occurs in the absence of Madelung deformity and mesomelia excludes the diagnosis of LWD; in these instances, the diagnosis is SHOX-deficient short stature. The phenotype is highly variable, even within the same family [
No correlation has been established between the severity of phenotype and the underlying
Based on a limited number of studies, the frequency of LWS is greater than SHOX-deficient short stature caused by a
While the penetrance of SHOX deficiency is high, its clinical expression is highly variable, becomes more pronounced with age, and is more severe in females.
For reasons unknown, the female-to-male ratio in studied cohorts with SHOX deficiency is increased.
Estimates of the prevalence of SHOX deficiency depend on the inclusion criteria used for the selection of persons tested, the size of the cohort tested, and the genetic tests available for detecting pathogenic variants of
Given the results of studies of
• Antenatally detected shortening of the long bones attributable to SHOX deficiency was reported in five infants. In four of the five, SHOX deficiency was inherited from a previously undiagnosed parent with final height z score between -1.2 and -1.9, suggesting that SHOX deficiency can be well tolerated within a favorable genetic context [
• Mean birth length is only mildly reduced, at 0.6-0.9 standard deviations (SD) below the mean [
• Infancy is characterized by significant growth failure resulting in short stature in early childhood with mean heights of 2.1-2.2 SD below the mean [
• During childhood, there is probably no relevant additional loss of height.
• The pubertal growth spurt, however, appears to be blunted, resulting in an additional height deficit.
• Hypertrophy of calf muscles
• Short fourth metacarpals
• Increased carrying angle of the elbow
• High-arched palate
• Scoliosis
• High body mass index (not caused by excess of fat mass)
## Clinical Description
The phenotypic spectrum of SHOX deficiency disorders ranges from Leri-Weill dyschondrosteosis (LWD) at the severe end of the spectrum to SHOX-deficient short stature (without mesomelia or Madelung deformity) at the mild end. In adults with SHOX deficiency, the proportion of LWD versus SHOX-deficient short stature is not well defined. In LWD the classic clinical triad is short stature, mesomelia, and Madelung deformity. Mesomelia, in which the middle portion of a limb is shortened in relation to the proximal portion, can be evident first in school-aged children and increases with age in frequency and severity. Madelung deformity (abnormal alignment of the radius, ulna, and carpal bones at the wrist) typically develops in mid-to-late childhood and is more common and severe in females. The phenotype of SHOX-deficient short stature is highly variable, even within the same family.
Antenatally detected shortening of the long bones attributable to SHOX deficiency was reported in five infants. In four of the five, SHOX deficiency was inherited from a previously undiagnosed parent with final height z score between -1.2 and -1.9, suggesting that SHOX deficiency can be well tolerated within a favorable genetic context [
Mean birth length is only mildly reduced, at 0.6-0.9 standard deviations (SD) below the mean [
Infancy is characterized by significant growth failure resulting in short stature in early childhood with mean heights of 2.1-2.2 SD below the mean [
During childhood, there is probably no relevant additional loss of height.
The pubertal growth spurt, however, appears to be blunted, resulting in an additional height deficit.
Madelung deformity typically develops in mid-to-late childhood. The first common sign is a subtle reduction in pronation and supination of the forearm. The complete deformity with distal subluxation of the ulna (dinner fork sign) evolves during puberty and is associated with further restriction of forearm supination and pronation [
Rarely, Madelung deformity causes joint pain in adolescence [
Hypertrophy of calf muscles
Short fourth metacarpals
Increased carrying angle of the elbow
High-arched palate
Scoliosis
High body mass index (not caused by excess of fat mass)
No other visceral involvement occurs. Intellect is normal.
When SHOX deficiency occurs in the absence of Madelung deformity and mesomelia excludes the diagnosis of LWD; in these instances, the diagnosis is SHOX-deficient short stature. The phenotype is highly variable, even within the same family [
• Antenatally detected shortening of the long bones attributable to SHOX deficiency was reported in five infants. In four of the five, SHOX deficiency was inherited from a previously undiagnosed parent with final height z score between -1.2 and -1.9, suggesting that SHOX deficiency can be well tolerated within a favorable genetic context [
• Mean birth length is only mildly reduced, at 0.6-0.9 standard deviations (SD) below the mean [
• Infancy is characterized by significant growth failure resulting in short stature in early childhood with mean heights of 2.1-2.2 SD below the mean [
• During childhood, there is probably no relevant additional loss of height.
• The pubertal growth spurt, however, appears to be blunted, resulting in an additional height deficit.
• Hypertrophy of calf muscles
• Short fourth metacarpals
• Increased carrying angle of the elbow
• High-arched palate
• Scoliosis
• High body mass index (not caused by excess of fat mass)
## Leri-Weill Dyschondrosteosis (LWD)
Antenatally detected shortening of the long bones attributable to SHOX deficiency was reported in five infants. In four of the five, SHOX deficiency was inherited from a previously undiagnosed parent with final height z score between -1.2 and -1.9, suggesting that SHOX deficiency can be well tolerated within a favorable genetic context [
Mean birth length is only mildly reduced, at 0.6-0.9 standard deviations (SD) below the mean [
Infancy is characterized by significant growth failure resulting in short stature in early childhood with mean heights of 2.1-2.2 SD below the mean [
During childhood, there is probably no relevant additional loss of height.
The pubertal growth spurt, however, appears to be blunted, resulting in an additional height deficit.
Madelung deformity typically develops in mid-to-late childhood. The first common sign is a subtle reduction in pronation and supination of the forearm. The complete deformity with distal subluxation of the ulna (dinner fork sign) evolves during puberty and is associated with further restriction of forearm supination and pronation [
Rarely, Madelung deformity causes joint pain in adolescence [
Hypertrophy of calf muscles
Short fourth metacarpals
Increased carrying angle of the elbow
High-arched palate
Scoliosis
High body mass index (not caused by excess of fat mass)
No other visceral involvement occurs. Intellect is normal.
• Antenatally detected shortening of the long bones attributable to SHOX deficiency was reported in five infants. In four of the five, SHOX deficiency was inherited from a previously undiagnosed parent with final height z score between -1.2 and -1.9, suggesting that SHOX deficiency can be well tolerated within a favorable genetic context [
• Mean birth length is only mildly reduced, at 0.6-0.9 standard deviations (SD) below the mean [
• Infancy is characterized by significant growth failure resulting in short stature in early childhood with mean heights of 2.1-2.2 SD below the mean [
• During childhood, there is probably no relevant additional loss of height.
• The pubertal growth spurt, however, appears to be blunted, resulting in an additional height deficit.
• Hypertrophy of calf muscles
• Short fourth metacarpals
• Increased carrying angle of the elbow
• High-arched palate
• Scoliosis
• High body mass index (not caused by excess of fat mass)
## SHOX-Deficient Short Stature
When SHOX deficiency occurs in the absence of Madelung deformity and mesomelia excludes the diagnosis of LWD; in these instances, the diagnosis is SHOX-deficient short stature. The phenotype is highly variable, even within the same family [
## Genotype-Phenotype Correlations
No correlation has been established between the severity of phenotype and the underlying
Based on a limited number of studies, the frequency of LWS is greater than SHOX-deficient short stature caused by a
## Penetrance
While the penetrance of SHOX deficiency is high, its clinical expression is highly variable, becomes more pronounced with age, and is more severe in females.
For reasons unknown, the female-to-male ratio in studied cohorts with SHOX deficiency is increased.
## Prevalence
Estimates of the prevalence of SHOX deficiency depend on the inclusion criteria used for the selection of persons tested, the size of the cohort tested, and the genetic tests available for detecting pathogenic variants of
Given the results of studies of
## Genetically Related (Allelic) Disorders
Note: In the case of isolated Xp deletions, the diagnosis of TS is reserved for deletions larger than Xp22.3 [
Characteristic physical features of TS are nonfamilial short stature with or without skeletal disproportion, pubertal delay because of primary hypogonadism, peripheral lymphedema, nuchal folds, left-sided cardiac anomalies (especially coarctation of the aorta or hypoplastic left heart), low hairline, low-set ears, small mandible, cubitus valgus, nail dysplasia, multiple pigmented nevi, characteristic facies, short fourth metacarpal, and chronic otitis media [
The phenotype is variable and somewhat related to the karyotype; some individuals manifest only short stature or primary amenorrhea. Short stature, the most constant feature, is present in at least 95% of individuals with TS [
LMD is a much more severe skeletal dysplasia than LWD and typically results in severe short stature with final heights ranging from 5.5 to 8.9 SD below the mean (data from case reports reviewed by
## Differential Diagnosis
The differential diagnosis of isolated SHOX-deficient short stature includes the following:
Turner syndrome in females (See
Children of both sexes with short stature of unknown cause (often called idiopathic short stature [ISS]). ISS is defined as height below the third centile in an individual for whom no skeletal, hormonal, chromosomal, or genetic etiology [
The differential diagnosis of LWD caused by SHOX deficiency includes the following:
Turner syndrome (See
LWD caused by pathogenic variants at an unidentified alternate locus or in gene(s) outside the
Trauma to, infection of, or tumors in the distal radial growth plate
• Turner syndrome in females (See
• Children of both sexes with short stature of unknown cause (often called idiopathic short stature [ISS]). ISS is defined as height below the third centile in an individual for whom no skeletal, hormonal, chromosomal, or genetic etiology [
• Turner syndrome (See
• LWD caused by pathogenic variants at an unidentified alternate locus or in gene(s) outside the
• Trauma to, infection of, or tumors in the distal radial growth plate
## Management
To establish the extent of disease and needs in an individual diagnosed with SHOX deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended [
For prepubertal children with short stature, recombinant human growth hormone (rhGH therapy) (dose 50 µg/kg body weight/day) should be offered. The therapeutic effect is a gain in final height of 7 to 10 cm. Hand/wrist radiographs for bone age determination should be taken at the initial visit and annually during rhGH therapy to assess maturation tempo.
Treatment with high-dose rhGH augments the growth of children with SHOX deficiency to the same extent as in Turner syndrome according to a two-year randomized controlled trial [
The growth of a child with SHOX deficiency should be monitored every six months.
In case of growth failure or short stature, treatment with recombinant human growth hormone is an option to increase growth rate and adult height; consultation with a pediatric endocrinologist is recommended.
If Madelung deformity is associated with discomfort, physical activities such as lifting, gripping, writing, typing, and sports that strain the wrist should be limited and ergonomic aids sought [
It is appropriate to clarify the genetic status of the sibs of an affected individual in order to identify as early as possible those who would also benefit from recombinant human growth hormone (rhGH) treatment.
See
Search
•
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SHOX deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended [
•
## Treatment of Manifestations
For prepubertal children with short stature, recombinant human growth hormone (rhGH therapy) (dose 50 µg/kg body weight/day) should be offered. The therapeutic effect is a gain in final height of 7 to 10 cm. Hand/wrist radiographs for bone age determination should be taken at the initial visit and annually during rhGH therapy to assess maturation tempo.
Treatment with high-dose rhGH augments the growth of children with SHOX deficiency to the same extent as in Turner syndrome according to a two-year randomized controlled trial [
## Short Stature
For prepubertal children with short stature, recombinant human growth hormone (rhGH therapy) (dose 50 µg/kg body weight/day) should be offered. The therapeutic effect is a gain in final height of 7 to 10 cm. Hand/wrist radiographs for bone age determination should be taken at the initial visit and annually during rhGH therapy to assess maturation tempo.
Treatment with high-dose rhGH augments the growth of children with SHOX deficiency to the same extent as in Turner syndrome according to a two-year randomized controlled trial [
## Painful Bilateral Madelung Deformity (uncommon)
## Surveillance
The growth of a child with SHOX deficiency should be monitored every six months.
In case of growth failure or short stature, treatment with recombinant human growth hormone is an option to increase growth rate and adult height; consultation with a pediatric endocrinologist is recommended.
## Agents/Circumstances to Avoid
If Madelung deformity is associated with discomfort, physical activities such as lifting, gripping, writing, typing, and sports that strain the wrist should be limited and ergonomic aids sought [
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of the sibs of an affected individual in order to identify as early as possible those who would also benefit from recombinant human growth hormone (rhGH) treatment.
See
## Therapies Under Investigation
Search
## Genetic Counseling
SHOX deficiency disorders are inherited in a pseudoautosomal dominant manner. In pseudoautosomal dominant inheritance, homologous genes located on the short arm of the X chromosome (Xp) and the short arm of the Y chromosome (Yp) follow the rules of autosomal inheritance; thus, a
Many individuals diagnosed with SHOX deficiency have an affected parent.
A proband with SHOX deficiency may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
In males an obligatory crossover during meiosis I results in transfer of genes located within pseudoautosomal region 1 from the Y chromosome to the X chromosome and vice versa. Because of the high recombination frequency in pseudoautosomal region 1 on Xp and Yp, males produce a mixture of sperm in which some harbor a Y-linked
The LWD phenotype (e.g., a father bearing a Y-linked
Father-to-son transmission.
The family history of some individuals diagnosed with SHOX deficiency may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations and molecular genetic testing have been performed on the parents of the proband.
Note: If the parent is the individual in whom the
If a parent of the proband is affected and/or is known to have the
If the
If the parents have not been tested for the
Each child of an individual with SHOX deficiency has a 50% chance of inheriting the
If both parents have SHOX deficiency, the offspring have a 50% chance of inheriting one pathogenic variant and having SHOX deficiency, a 25% chance of inheriting two pathogenic variants and having Langer type of mesomelic dwarfism (see
Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with SHOX deficiency may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are usually distinct from those of the parents [
If both parents have a dominantly inherited bone growth disorder, the offspring have a 25% chance of having the maternal bone growth disorder, a 25% chance of having the paternal bone growth disorder, a 25% chance of having normal stature and bone growth, and a 25% chance of having double heterozygosity for both disorders.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
Once the
• Many individuals diagnosed with SHOX deficiency have an affected parent.
• A proband with SHOX deficiency may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• In males an obligatory crossover during meiosis I results in transfer of genes located within pseudoautosomal region 1 from the Y chromosome to the X chromosome and vice versa. Because of the high recombination frequency in pseudoautosomal region 1 on Xp and Yp, males produce a mixture of sperm in which some harbor a Y-linked
• The LWD phenotype (e.g., a father bearing a Y-linked
• Father-to-son transmission.
• The LWD phenotype (e.g., a father bearing a Y-linked
• Father-to-son transmission.
• The family history of some individuals diagnosed with SHOX deficiency may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations and molecular genetic testing have been performed on the parents of the proband.
• Note: If the parent is the individual in whom the
• The LWD phenotype (e.g., a father bearing a Y-linked
• Father-to-son transmission.
• If a parent of the proband is affected and/or is known to have the
• If the
• If the parents have not been tested for the
• Each child of an individual with SHOX deficiency has a 50% chance of inheriting the
• If both parents have SHOX deficiency, the offspring have a 50% chance of inheriting one pathogenic variant and having SHOX deficiency, a 25% chance of inheriting two pathogenic variants and having Langer type of mesomelic dwarfism (see
• Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with SHOX deficiency may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are usually distinct from those of the parents [
• If both parents have a dominantly inherited bone growth disorder, the offspring have a 25% chance of having the maternal bone growth disorder, a 25% chance of having the paternal bone growth disorder, a 25% chance of having normal stature and bone growth, and a 25% chance of having double heterozygosity for both disorders.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Mode of Inheritance
SHOX deficiency disorders are inherited in a pseudoautosomal dominant manner. In pseudoautosomal dominant inheritance, homologous genes located on the short arm of the X chromosome (Xp) and the short arm of the Y chromosome (Yp) follow the rules of autosomal inheritance; thus, a
## Risk to Family Members
Many individuals diagnosed with SHOX deficiency have an affected parent.
A proband with SHOX deficiency may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
In males an obligatory crossover during meiosis I results in transfer of genes located within pseudoautosomal region 1 from the Y chromosome to the X chromosome and vice versa. Because of the high recombination frequency in pseudoautosomal region 1 on Xp and Yp, males produce a mixture of sperm in which some harbor a Y-linked
The LWD phenotype (e.g., a father bearing a Y-linked
Father-to-son transmission.
The family history of some individuals diagnosed with SHOX deficiency may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations and molecular genetic testing have been performed on the parents of the proband.
Note: If the parent is the individual in whom the
If a parent of the proband is affected and/or is known to have the
If the
If the parents have not been tested for the
Each child of an individual with SHOX deficiency has a 50% chance of inheriting the
If both parents have SHOX deficiency, the offspring have a 50% chance of inheriting one pathogenic variant and having SHOX deficiency, a 25% chance of inheriting two pathogenic variants and having Langer type of mesomelic dwarfism (see
Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with SHOX deficiency may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are usually distinct from those of the parents [
If both parents have a dominantly inherited bone growth disorder, the offspring have a 25% chance of having the maternal bone growth disorder, a 25% chance of having the paternal bone growth disorder, a 25% chance of having normal stature and bone growth, and a 25% chance of having double heterozygosity for both disorders.
• Many individuals diagnosed with SHOX deficiency have an affected parent.
• A proband with SHOX deficiency may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• In males an obligatory crossover during meiosis I results in transfer of genes located within pseudoautosomal region 1 from the Y chromosome to the X chromosome and vice versa. Because of the high recombination frequency in pseudoautosomal region 1 on Xp and Yp, males produce a mixture of sperm in which some harbor a Y-linked
• The LWD phenotype (e.g., a father bearing a Y-linked
• Father-to-son transmission.
• The LWD phenotype (e.g., a father bearing a Y-linked
• Father-to-son transmission.
• The family history of some individuals diagnosed with SHOX deficiency may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations and molecular genetic testing have been performed on the parents of the proband.
• Note: If the parent is the individual in whom the
• The LWD phenotype (e.g., a father bearing a Y-linked
• Father-to-son transmission.
• If a parent of the proband is affected and/or is known to have the
• If the
• If the parents have not been tested for the
• Each child of an individual with SHOX deficiency has a 50% chance of inheriting the
• If both parents have SHOX deficiency, the offspring have a 50% chance of inheriting one pathogenic variant and having SHOX deficiency, a 25% chance of inheriting two pathogenic variants and having Langer type of mesomelic dwarfism (see
• Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with SHOX deficiency may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are usually distinct from those of the parents [
• If both parents have a dominantly inherited bone growth disorder, the offspring have a 25% chance of having the maternal bone growth disorder, a 25% chance of having the paternal bone growth disorder, a 25% chance of having normal stature and bone growth, and a 25% chance of having double heterozygosity for both disorders.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
## Resources
Leinestrasse 2
28199 Bremen
Germany
•
• Leinestrasse 2
• 28199 Bremen
• Germany
•
•
•
•
•
•
•
•
•
## Molecular Genetics
SHOX Deficiency Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SHOX Deficiency Disorders (
The short stature homeobox-containing gene
The majority of
Partial and complete duplications of
SHOXa, a 292-amino-acid protein [
SHOXb, a 225-amino-acid protein [
Because there is no
In human embryos
SHOX acts as a nuclear transcription factor that inhibits cellular growth and apoptosis, possibly through the upregulation of p53 [
Direct and indirect targets of the SHOX transcription factor have been described. The targets
An influence of SHOX as a regulator on FGFR3 signaling, CNP/Npr2 signaling and Bmp4 signaling and RUNX activity have been described (for a review see
Recently, the first genetic modifier of SHOX deficiency,
• SHOXa, a 292-amino-acid protein [
• SHOXb, a 225-amino-acid protein [
## Molecular Pathogenesis
The short stature homeobox-containing gene
The majority of
Partial and complete duplications of
SHOXa, a 292-amino-acid protein [
SHOXb, a 225-amino-acid protein [
Because there is no
In human embryos
SHOX acts as a nuclear transcription factor that inhibits cellular growth and apoptosis, possibly through the upregulation of p53 [
Direct and indirect targets of the SHOX transcription factor have been described. The targets
An influence of SHOX as a regulator on FGFR3 signaling, CNP/Npr2 signaling and Bmp4 signaling and RUNX activity have been described (for a review see
Recently, the first genetic modifier of SHOX deficiency,
• SHOXa, a 292-amino-acid protein [
• SHOXb, a 225-amino-acid protein [
## Chapter Notes
Gerhard Binder, MD (2015-present)Ian Glass, MBChB, MD, FRCP, FACMG; University of Washington (2005-2015)Craig Munns, MBBS, PhD, FRACP; The Children's Hospital at Westmead (2005-2015)Gudrun A Rappold, PhD (2015-present)
23 May 2024 (ma) Revision: clarified proportion of pathogenic variants identified by gene-targeted deletion/duplication analysis (
28 June 2018 (bp) Comprehensive update posted live
20 August 2015 (me) Comprehensive update posted live
12 December 2005 (me) Review posted live
25 October 2004 (cm) Original submission
• 23 May 2024 (ma) Revision: clarified proportion of pathogenic variants identified by gene-targeted deletion/duplication analysis (
• 28 June 2018 (bp) Comprehensive update posted live
• 20 August 2015 (me) Comprehensive update posted live
• 12 December 2005 (me) Review posted live
• 25 October 2004 (cm) Original submission
## Author History
Gerhard Binder, MD (2015-present)Ian Glass, MBChB, MD, FRCP, FACMG; University of Washington (2005-2015)Craig Munns, MBBS, PhD, FRACP; The Children's Hospital at Westmead (2005-2015)Gudrun A Rappold, PhD (2015-present)
## Revision History
23 May 2024 (ma) Revision: clarified proportion of pathogenic variants identified by gene-targeted deletion/duplication analysis (
28 June 2018 (bp) Comprehensive update posted live
20 August 2015 (me) Comprehensive update posted live
12 December 2005 (me) Review posted live
25 October 2004 (cm) Original submission
• 23 May 2024 (ma) Revision: clarified proportion of pathogenic variants identified by gene-targeted deletion/duplication analysis (
• 28 June 2018 (bp) Comprehensive update posted live
• 20 August 2015 (me) Comprehensive update posted live
• 12 December 2005 (me) Review posted live
• 25 October 2004 (cm) Original submission
## References
## Literature Cited
This schema provides an algorithmic approach to
Used by permission
|
[] |
12/12/2005
|
28/6/2018
|
23/5/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
m-hfm-ov
|
m-hfm-ov
|
[
"Goldenhar Syndrome",
"First and Second Branchial Arch Syndrome",
"Otomandibular Dysostosis",
"Oculo-auriculo-vertebral Spectrum",
"Facio-auriculo-vertebral Syndrome",
"Hemifacial Microsomia",
"Lateral Facial Dysplasia",
"Craniofacial Microsomia",
"Overview"
] |
Craniofacial Microsomia Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Carrie L Heike, Daniela V Luquetti, Anne V Hing
|
Summary Craniofacial microsomia (CFM) includes a spectrum of malformations primarily involving structures derived from the first and second branchial arches. Characteristic findings include facial asymmetry resulting from maxillary and/or mandibular hypoplasia; preauricular or facial tags; ear malformations that can include microtia (hypoplasia of the external ear), anotia (absence of the external ear), or aural atresia (absence of the external ear canal); and hearing loss. Severity can range from subtle facial asymmetry with a small skin tag in front of an otherwise normal-appearing ear to bilateral involvement (typically asymmetric), microtia/anotia with atresia of the ear canals, microphthalmia, and respiratory compromise from severe mandibular hypoplasia. Other craniofacial malformations including cleft lip and/or palate can be seen. Non-craniofacial malformations, especially vertebral, renal, cardiac, and limb, can be seen. The diagnosis of CFM is based on clinical findings. CFM most frequently occurs as a simplex case (i.e., occurrence in a single individual in a family) with unknown etiology; recurrence risks are empiric. If an individual with CFM is found to have an inherited or
|
Hemifacial microsomia
Oculo-auriculo-vertebral spectrum
Goldenhar syndrome
First and second branchial arch syndrome
Otomandibular dysostosis
Facio-auriculo-vertebral syndrome
Lateral facial dysplasia
• Hemifacial microsomia
• Oculo-auriculo-vertebral spectrum
• Goldenhar syndrome
• First and second branchial arch syndrome
• Otomandibular dysostosis
• Facio-auriculo-vertebral syndrome
• Lateral facial dysplasia
## Definition
Craniofacial microsomia (CFM) includes a spectrum of malformations primarily involving structures derived from the first and second branchial arches.
Characteristic findings (
Facial asymmetry, a hallmark of this condition; common even when individuals demonstrate bilateral features
Mandibular hypoplasia, also called micrognathia (see
Preauricular or facial tags and/or pits. Tags are common, variable in size, and generally distributed along the skin overlying the mandibular ramus. These branchial remnants can be simple skin tags, but may also contain cartilaginous structures that grow over time.
Microtia (hypoplasia of the external ear) (see
Anotia (absence of the external ear)
Aural atresia (absence of the external ear canal and associated middle ear anomalies)
Conductive, sensorineural, or mixed hearing loss
No diagnostic criteria have been established; thus, CFM is often a diagnosis of exclusion (see
Proposed minimal diagnostic criteria [
Hemifacial microsomia (asymmetric hypoplasia of facial structures) with preauricular tags
OR
Microtia (with or without preauricular skin tags)
The following evidence supports the notion that isolated microtia (i.e., microtia with no other malformations) may be a part of the continuum of CFM [
The ear malformations in isolated microtia and CFM are similar.
The proposed causes for isolated microtia and CFM are similar.
Mild features of CFM are frequently noted in individuals with the diagnosis of isolated microtia [
The prevalence of isolated microtia is much higher in family members of individuals with CFM than in the general population [
Several systems have been designed to define the spectrum of anomalies seen in CFM [
Note: Individuals with features of CFM have been classified under a number of different diagnoses. It has not yet been established whether these diagnoses are distinct entities or represent the phenotypic continuum of CFM. In this
Hemifacial microsomia (asymmetric hypoplasia of facial structures)
Note: The term CFM is more inclusive than the term "hemifacial microsomia" because the term CFM includes the large percent of individuals with bilateral involvement, including those diagnosed with hemifacial microsomia who have subtle differences in the "non-affected" side.
Oculo-auriculo-vertebral spectrum
Goldenhar syndrome
First and second branchial arch syndrome
Otomandibular dysostosis
Facio-auriculo-vertebral syndrome
Lateral facial dysplasia
The head and neck originate from six embryonic structures called the pharyngeal apparati (see
The spectrum of anomalies involved in CFM may result from an embryonic "developmental field" functioning as a unit that responds in a similar manner to different insults such as chromosome abnormalities, mutation in a single gene, vascular disruption, and teratogens [
The clinical findings in individuals with craniofacial microsomia can overlap with those observed in syndromes, developmental anomaly associations, and sequences. Examples include:
VATER (expanded to VACTERL:
CHARGE (
MURCS (variable developmental anomalies of the
OEIS (
This overlap has led investigators to hypothesize that these conditions may represent developmental abnormalities which result in anomalies that may be a part of a broad spectrum, such as the axial mesodermal dysplasia spectrum [
Phenotypic variability is common in CFM. Whereas some individuals have subtle facial asymmetry with a small skin tag in front of an otherwise typical-appearing ear, others have bilateral involvement (commonly asymmetric), microtia/anotia with atresia of the ear canals, microphthalmia, and possibly respiratory compromise from severe mandibular hypoplasia (see
In addition to the features that define CFM, the following are commonly observed in affected individuals:
Midface hypoplasia (underdevelopment of the midface, usually asymmetric)
Ankylosis (limited opening of the mouth)
Malocclusion
Epibulbar dermoid
Vertical displacement of the orbit
Microphthalmia/anophthalmia (rare)
Coloboma of the upper eye lid and/or iris
Macrostomia (lateral oral clefting). Unilateral macrostomia is the most common form of facial clefting associated with CFM, though all types of clefts can be observed.
Cleft lip and/or palate
Malformed and/or fused cervical vertebrae are common, though anomalies can be noted throughout the spine.
Hemivertebrae are also common.
Facial palsy (unilateral or bilateral involvement of either part or all branches of cranial nerve VII)
Sensorineural hearing loss
Asymmetric palatal elevation
Impairment of extraocular movements
An estimated 65% of individuals with CFM have some degree of facial asymmetry [
Of those individuals with bilateral facial involvement (e.g., left microtia and a right preauricular tag), most demonstrate asymmetric involvement [
Less common additional malformations:
Prevalence of Selected Anomalies in Craniofacial Microsomia
Adapted from
Prevalence rates from more than 20 reports published between 1983 and 2014 are summarized. Studies based on selected samples were omitted to minimize selection bias.
The diagnosis of CFM can be established based on clinical examination alone.
As discussed in
At least three individuals with predominant features of CFM had mutation of
Of note, one individual with a diagnosis of oculo-auriculo-vertebral spectrum (unilateral microtia, aural atresia, and unilateral mandibular hypoplasia with an absent zygomatic arch) had a
In another study, two individuals diagnosed with Goldenhar syndrome had silent (Glu621Glu; Gln54Gln)
Comparison of Phenotypic Characteristics Among Conditions in the Differential Diagnosis of CFM
X indicates presence of phenotypic characteristic.
CFM has an estimated prevalence of between 1:5600 and 1:26,550 live births – possibly an underestimate because of varying criteria used to define the disorder and underdiagnosis of milder cases.
The male to female ratio is 3:2 [
• Facial asymmetry, a hallmark of this condition; common even when individuals demonstrate bilateral features
• Mandibular hypoplasia, also called micrognathia (see
• Preauricular or facial tags and/or pits. Tags are common, variable in size, and generally distributed along the skin overlying the mandibular ramus. These branchial remnants can be simple skin tags, but may also contain cartilaginous structures that grow over time.
• Microtia (hypoplasia of the external ear) (see
• Anotia (absence of the external ear)
• Aural atresia (absence of the external ear canal and associated middle ear anomalies)
• Conductive, sensorineural, or mixed hearing loss
• Hemifacial microsomia (asymmetric hypoplasia of facial structures) with preauricular tags
• OR
• Microtia (with or without preauricular skin tags)
• The ear malformations in isolated microtia and CFM are similar.
• The proposed causes for isolated microtia and CFM are similar.
• Mild features of CFM are frequently noted in individuals with the diagnosis of isolated microtia [
• The prevalence of isolated microtia is much higher in family members of individuals with CFM than in the general population [
• Hemifacial microsomia (asymmetric hypoplasia of facial structures)
• Note: The term CFM is more inclusive than the term "hemifacial microsomia" because the term CFM includes the large percent of individuals with bilateral involvement, including those diagnosed with hemifacial microsomia who have subtle differences in the "non-affected" side.
• Oculo-auriculo-vertebral spectrum
• Goldenhar syndrome
• First and second branchial arch syndrome
• Otomandibular dysostosis
• Facio-auriculo-vertebral syndrome
• Lateral facial dysplasia
• VATER (expanded to VACTERL:
• CHARGE (
• MURCS (variable developmental anomalies of the
• OEIS (
• Midface hypoplasia (underdevelopment of the midface, usually asymmetric)
• Ankylosis (limited opening of the mouth)
• Malocclusion
• Epibulbar dermoid
• Vertical displacement of the orbit
• Microphthalmia/anophthalmia (rare)
• Coloboma of the upper eye lid and/or iris
• Macrostomia (lateral oral clefting). Unilateral macrostomia is the most common form of facial clefting associated with CFM, though all types of clefts can be observed.
• Cleft lip and/or palate
• Malformed and/or fused cervical vertebrae are common, though anomalies can be noted throughout the spine.
• Hemivertebrae are also common.
• Facial palsy (unilateral or bilateral involvement of either part or all branches of cranial nerve VII)
• Sensorineural hearing loss
• Asymmetric palatal elevation
• Impairment of extraocular movements
## Embryology
The head and neck originate from six embryonic structures called the pharyngeal apparati (see
The spectrum of anomalies involved in CFM may result from an embryonic "developmental field" functioning as a unit that responds in a similar manner to different insults such as chromosome abnormalities, mutation in a single gene, vascular disruption, and teratogens [
The clinical findings in individuals with craniofacial microsomia can overlap with those observed in syndromes, developmental anomaly associations, and sequences. Examples include:
VATER (expanded to VACTERL:
CHARGE (
MURCS (variable developmental anomalies of the
OEIS (
This overlap has led investigators to hypothesize that these conditions may represent developmental abnormalities which result in anomalies that may be a part of a broad spectrum, such as the axial mesodermal dysplasia spectrum [
• VATER (expanded to VACTERL:
• CHARGE (
• MURCS (variable developmental anomalies of the
• OEIS (
## Clinical Manifestations of CFM
Phenotypic variability is common in CFM. Whereas some individuals have subtle facial asymmetry with a small skin tag in front of an otherwise typical-appearing ear, others have bilateral involvement (commonly asymmetric), microtia/anotia with atresia of the ear canals, microphthalmia, and possibly respiratory compromise from severe mandibular hypoplasia (see
In addition to the features that define CFM, the following are commonly observed in affected individuals:
Midface hypoplasia (underdevelopment of the midface, usually asymmetric)
Ankylosis (limited opening of the mouth)
Malocclusion
Epibulbar dermoid
Vertical displacement of the orbit
Microphthalmia/anophthalmia (rare)
Coloboma of the upper eye lid and/or iris
Macrostomia (lateral oral clefting). Unilateral macrostomia is the most common form of facial clefting associated with CFM, though all types of clefts can be observed.
Cleft lip and/or palate
Malformed and/or fused cervical vertebrae are common, though anomalies can be noted throughout the spine.
Hemivertebrae are also common.
Facial palsy (unilateral or bilateral involvement of either part or all branches of cranial nerve VII)
Sensorineural hearing loss
Asymmetric palatal elevation
Impairment of extraocular movements
An estimated 65% of individuals with CFM have some degree of facial asymmetry [
Of those individuals with bilateral facial involvement (e.g., left microtia and a right preauricular tag), most demonstrate asymmetric involvement [
Less common additional malformations:
Prevalence of Selected Anomalies in Craniofacial Microsomia
Adapted from
Prevalence rates from more than 20 reports published between 1983 and 2014 are summarized. Studies based on selected samples were omitted to minimize selection bias.
• Midface hypoplasia (underdevelopment of the midface, usually asymmetric)
• Ankylosis (limited opening of the mouth)
• Malocclusion
• Epibulbar dermoid
• Vertical displacement of the orbit
• Microphthalmia/anophthalmia (rare)
• Coloboma of the upper eye lid and/or iris
• Macrostomia (lateral oral clefting). Unilateral macrostomia is the most common form of facial clefting associated with CFM, though all types of clefts can be observed.
• Cleft lip and/or palate
• Malformed and/or fused cervical vertebrae are common, though anomalies can be noted throughout the spine.
• Hemivertebrae are also common.
• Facial palsy (unilateral or bilateral involvement of either part or all branches of cranial nerve VII)
• Sensorineural hearing loss
• Asymmetric palatal elevation
• Impairment of extraocular movements
## Establishing the Diagnosis of CFM
The diagnosis of CFM can be established based on clinical examination alone.
## Differential Diagnosis of CFM
As discussed in
At least three individuals with predominant features of CFM had mutation of
Of note, one individual with a diagnosis of oculo-auriculo-vertebral spectrum (unilateral microtia, aural atresia, and unilateral mandibular hypoplasia with an absent zygomatic arch) had a
In another study, two individuals diagnosed with Goldenhar syndrome had silent (Glu621Glu; Gln54Gln)
Comparison of Phenotypic Characteristics Among Conditions in the Differential Diagnosis of CFM
X indicates presence of phenotypic characteristic.
## Prevalence of CFM
CFM has an estimated prevalence of between 1:5600 and 1:26,550 live births – possibly an underestimate because of varying criteria used to define the disorder and underdiagnosis of milder cases.
The male to female ratio is 3:2 [
## Causes of CFM
The causes of craniofacial microsomia (CFM) can be divided into environmental, heritable, multifactorial, and unknown (the largest category).
Several studies have assessed the maternal environmental risk factors that may be associated with CFM in offspring. Because each study used different inclusion criteria, the authors have summarized the patient characteristics for each study in
Minimal Diagnostic Criteria Used in Select Studies Assessing Risk Factors for CFM
Reported risk factors include:
Maternal use of vasoactive drugs
Maternal second trimester bleeding
Maternal diabetes mellitus
Multiple gestation
Maternal use of assisted reproductive technology (ART)
Use of the vasoactive drugs pseudoephedrine, aspirin, or ibuprofen during pregnancy has been associated with a 1.5- to 2-fold increase in the risk for CFM [
In general, greater concordance in monozygotic (MZ) twins compared to dizygotic (DZ) twins supports the influence of genetic factors. Conversely, the high levels of discordance for CFM in MZ twins argues in favor of the role of environmental factors [
In an epidemiologic study of 239 individuals with CFM and 854 controls, risk factors identified for CFM included the following [
Maternal ingestion of Accutane
Maternal ingestion of the immunosuppressive medication mycophenolate mofetil during pregnancy can also lead to malformations (microtia, cleft lip/palate, micrognathia, cardiac malformations) that overlap with CFM. Additional findings distinct from CFM observed in infants exposed in utero to mycophenolate mofetil include hypoplastic fingers and toenails, diaphragmatic hernia, and tracheoesophageal fistula [
Craniofacial microsomia has been observed in a number of chromosome disorders (
Some associations could have occurred by chance, but the repeated observation of deletion 5p, duplication 14q23.1, and abnormalities of chromosomes 18 and 22 may represent causal associations.
Of note, several families with autosomal dominant inheritance of CFM have shown segregation of chromosome 14q23.1 duplication inclusive of the gene
Chromosome imbalances (duplications and deletions) were detected by oligonucleotide array-CGH in 14% of 86 individuals with CFM using the minimal diagnostic criteria proposed by
Chromosomal Abnormalities Reported in CFM
Approximately 1%-2% of families demonstrate autosomal dominant inheritance and rare families demonstrate autosomal recessive inheritance of CFM or isolated microtia [
Oculo-Auriculo-Vertebral Spectrum Findings in Families with Autosomal Dominant Inheritance vs Findings in Simplex Cases
Simplex= a single occurrence in a family
To date, the largest segregation analysis included clinical examination of 311 members of the families of 74 probands with CFM. The study provided evidence for genetic transmission, and more specifically, an autosomal dominant mode of inheritance with reduced penetrance [
To the authors' knowledge, two linkage studies have been performed in families with features of CFM [
In one family studied by
Linkage to this region was excluded in two additional families with autosomal dominant pattern of inheritance, providing further evidence of genetic heterogeneity [
Recently, a study reported on a
A missense variant in
As discussed in
Although most cases of CFM appear to be simplex (i.e., a single occurrence in a family), multifactorial inheritance is suggested by the following:
Increased recurrence risk observed in families with an affected relative. The recurrence rate in first-degree relatives of affected individuals is estimated at 2%-3%. This may be an underestimate due to the difficulty of obtaining an accurate family history for some of the subtle features of CFM, such as preauricular tags [
An increased prevalence of twinning [
Increased concordance in MZ twins. In general, greater concordance in MZ twins compared to DZ twins supports the influence of genetic factors. Conversely, the high levels of discordance in MZ twins observed in CFM argues in favor of the role for environmental factors [
Increased relative risk with specific maternal exposures. See
Whereas some individuals have subtle facial asymmetry with a small skin tag in front of an otherwise normal-appearing ear, others have bilateral involvement (typically asymmetric), microtia/anotia with atresia of the ear canals, microphthalmia, and possibly respiratory compromise from severe mandibular hypoplasia.
Possible explanations for those with CFM of unknown cause include:
Mutation of a yet-to-be-identified gene or regulatory region of gene
Pathogenic variants or benign variants in multiple genes involved in craniofacial development (polygenic inheritance)
Effects of both gene and environmental interactions (multifactorial inheritance)
• Maternal use of vasoactive drugs
• Maternal second trimester bleeding
• Maternal diabetes mellitus
• Multiple gestation
• Maternal use of assisted reproductive technology (ART)
• Some associations could have occurred by chance, but the repeated observation of deletion 5p, duplication 14q23.1, and abnormalities of chromosomes 18 and 22 may represent causal associations.
• Of note, several families with autosomal dominant inheritance of CFM have shown segregation of chromosome 14q23.1 duplication inclusive of the gene
• Chromosome imbalances (duplications and deletions) were detected by oligonucleotide array-CGH in 14% of 86 individuals with CFM using the minimal diagnostic criteria proposed by
• In one family studied by
• Linkage to this region was excluded in two additional families with autosomal dominant pattern of inheritance, providing further evidence of genetic heterogeneity [
• Increased recurrence risk observed in families with an affected relative. The recurrence rate in first-degree relatives of affected individuals is estimated at 2%-3%. This may be an underestimate due to the difficulty of obtaining an accurate family history for some of the subtle features of CFM, such as preauricular tags [
• An increased prevalence of twinning [
• Increased concordance in MZ twins. In general, greater concordance in MZ twins compared to DZ twins supports the influence of genetic factors. Conversely, the high levels of discordance in MZ twins observed in CFM argues in favor of the role for environmental factors [
• Increased relative risk with specific maternal exposures. See
• Mutation of a yet-to-be-identified gene or regulatory region of gene
• Pathogenic variants or benign variants in multiple genes involved in craniofacial development (polygenic inheritance)
• Effects of both gene and environmental interactions (multifactorial inheritance)
## Environmental (Acquired) Causes
Several studies have assessed the maternal environmental risk factors that may be associated with CFM in offspring. Because each study used different inclusion criteria, the authors have summarized the patient characteristics for each study in
Minimal Diagnostic Criteria Used in Select Studies Assessing Risk Factors for CFM
Reported risk factors include:
Maternal use of vasoactive drugs
Maternal second trimester bleeding
Maternal diabetes mellitus
Multiple gestation
Maternal use of assisted reproductive technology (ART)
Use of the vasoactive drugs pseudoephedrine, aspirin, or ibuprofen during pregnancy has been associated with a 1.5- to 2-fold increase in the risk for CFM [
In general, greater concordance in monozygotic (MZ) twins compared to dizygotic (DZ) twins supports the influence of genetic factors. Conversely, the high levels of discordance for CFM in MZ twins argues in favor of the role of environmental factors [
In an epidemiologic study of 239 individuals with CFM and 854 controls, risk factors identified for CFM included the following [
Maternal ingestion of Accutane
Maternal ingestion of the immunosuppressive medication mycophenolate mofetil during pregnancy can also lead to malformations (microtia, cleft lip/palate, micrognathia, cardiac malformations) that overlap with CFM. Additional findings distinct from CFM observed in infants exposed in utero to mycophenolate mofetil include hypoplastic fingers and toenails, diaphragmatic hernia, and tracheoesophageal fistula [
• Maternal use of vasoactive drugs
• Maternal second trimester bleeding
• Maternal diabetes mellitus
• Multiple gestation
• Maternal use of assisted reproductive technology (ART)
## Heritable Causes
Craniofacial microsomia has been observed in a number of chromosome disorders (
Some associations could have occurred by chance, but the repeated observation of deletion 5p, duplication 14q23.1, and abnormalities of chromosomes 18 and 22 may represent causal associations.
Of note, several families with autosomal dominant inheritance of CFM have shown segregation of chromosome 14q23.1 duplication inclusive of the gene
Chromosome imbalances (duplications and deletions) were detected by oligonucleotide array-CGH in 14% of 86 individuals with CFM using the minimal diagnostic criteria proposed by
Chromosomal Abnormalities Reported in CFM
Approximately 1%-2% of families demonstrate autosomal dominant inheritance and rare families demonstrate autosomal recessive inheritance of CFM or isolated microtia [
Oculo-Auriculo-Vertebral Spectrum Findings in Families with Autosomal Dominant Inheritance vs Findings in Simplex Cases
Simplex= a single occurrence in a family
To date, the largest segregation analysis included clinical examination of 311 members of the families of 74 probands with CFM. The study provided evidence for genetic transmission, and more specifically, an autosomal dominant mode of inheritance with reduced penetrance [
To the authors' knowledge, two linkage studies have been performed in families with features of CFM [
In one family studied by
Linkage to this region was excluded in two additional families with autosomal dominant pattern of inheritance, providing further evidence of genetic heterogeneity [
Recently, a study reported on a
A missense variant in
As discussed in
Although most cases of CFM appear to be simplex (i.e., a single occurrence in a family), multifactorial inheritance is suggested by the following:
Increased recurrence risk observed in families with an affected relative. The recurrence rate in first-degree relatives of affected individuals is estimated at 2%-3%. This may be an underestimate due to the difficulty of obtaining an accurate family history for some of the subtle features of CFM, such as preauricular tags [
An increased prevalence of twinning [
Increased concordance in MZ twins. In general, greater concordance in MZ twins compared to DZ twins supports the influence of genetic factors. Conversely, the high levels of discordance in MZ twins observed in CFM argues in favor of the role for environmental factors [
Increased relative risk with specific maternal exposures. See
• Some associations could have occurred by chance, but the repeated observation of deletion 5p, duplication 14q23.1, and abnormalities of chromosomes 18 and 22 may represent causal associations.
• Of note, several families with autosomal dominant inheritance of CFM have shown segregation of chromosome 14q23.1 duplication inclusive of the gene
• Chromosome imbalances (duplications and deletions) were detected by oligonucleotide array-CGH in 14% of 86 individuals with CFM using the minimal diagnostic criteria proposed by
• In one family studied by
• Linkage to this region was excluded in two additional families with autosomal dominant pattern of inheritance, providing further evidence of genetic heterogeneity [
• Increased recurrence risk observed in families with an affected relative. The recurrence rate in first-degree relatives of affected individuals is estimated at 2%-3%. This may be an underestimate due to the difficulty of obtaining an accurate family history for some of the subtle features of CFM, such as preauricular tags [
• An increased prevalence of twinning [
• Increased concordance in MZ twins. In general, greater concordance in MZ twins compared to DZ twins supports the influence of genetic factors. Conversely, the high levels of discordance in MZ twins observed in CFM argues in favor of the role for environmental factors [
• Increased relative risk with specific maternal exposures. See
## Chromosomal Causes
Craniofacial microsomia has been observed in a number of chromosome disorders (
Some associations could have occurred by chance, but the repeated observation of deletion 5p, duplication 14q23.1, and abnormalities of chromosomes 18 and 22 may represent causal associations.
Of note, several families with autosomal dominant inheritance of CFM have shown segregation of chromosome 14q23.1 duplication inclusive of the gene
Chromosome imbalances (duplications and deletions) were detected by oligonucleotide array-CGH in 14% of 86 individuals with CFM using the minimal diagnostic criteria proposed by
Chromosomal Abnormalities Reported in CFM
• Some associations could have occurred by chance, but the repeated observation of deletion 5p, duplication 14q23.1, and abnormalities of chromosomes 18 and 22 may represent causal associations.
• Of note, several families with autosomal dominant inheritance of CFM have shown segregation of chromosome 14q23.1 duplication inclusive of the gene
• Chromosome imbalances (duplications and deletions) were detected by oligonucleotide array-CGH in 14% of 86 individuals with CFM using the minimal diagnostic criteria proposed by
## Single-Gene Causes
Approximately 1%-2% of families demonstrate autosomal dominant inheritance and rare families demonstrate autosomal recessive inheritance of CFM or isolated microtia [
Oculo-Auriculo-Vertebral Spectrum Findings in Families with Autosomal Dominant Inheritance vs Findings in Simplex Cases
Simplex= a single occurrence in a family
To date, the largest segregation analysis included clinical examination of 311 members of the families of 74 probands with CFM. The study provided evidence for genetic transmission, and more specifically, an autosomal dominant mode of inheritance with reduced penetrance [
To the authors' knowledge, two linkage studies have been performed in families with features of CFM [
In one family studied by
Linkage to this region was excluded in two additional families with autosomal dominant pattern of inheritance, providing further evidence of genetic heterogeneity [
Recently, a study reported on a
A missense variant in
As discussed in
• In one family studied by
• Linkage to this region was excluded in two additional families with autosomal dominant pattern of inheritance, providing further evidence of genetic heterogeneity [
## Multifactorial Inheritance
Although most cases of CFM appear to be simplex (i.e., a single occurrence in a family), multifactorial inheritance is suggested by the following:
Increased recurrence risk observed in families with an affected relative. The recurrence rate in first-degree relatives of affected individuals is estimated at 2%-3%. This may be an underestimate due to the difficulty of obtaining an accurate family history for some of the subtle features of CFM, such as preauricular tags [
An increased prevalence of twinning [
Increased concordance in MZ twins. In general, greater concordance in MZ twins compared to DZ twins supports the influence of genetic factors. Conversely, the high levels of discordance in MZ twins observed in CFM argues in favor of the role for environmental factors [
Increased relative risk with specific maternal exposures. See
• Increased recurrence risk observed in families with an affected relative. The recurrence rate in first-degree relatives of affected individuals is estimated at 2%-3%. This may be an underestimate due to the difficulty of obtaining an accurate family history for some of the subtle features of CFM, such as preauricular tags [
• An increased prevalence of twinning [
• Increased concordance in MZ twins. In general, greater concordance in MZ twins compared to DZ twins supports the influence of genetic factors. Conversely, the high levels of discordance in MZ twins observed in CFM argues in favor of the role for environmental factors [
• Increased relative risk with specific maternal exposures. See
## Unknown Cause
Whereas some individuals have subtle facial asymmetry with a small skin tag in front of an otherwise normal-appearing ear, others have bilateral involvement (typically asymmetric), microtia/anotia with atresia of the ear canals, microphthalmia, and possibly respiratory compromise from severe mandibular hypoplasia.
Possible explanations for those with CFM of unknown cause include:
Mutation of a yet-to-be-identified gene or regulatory region of gene
Pathogenic variants or benign variants in multiple genes involved in craniofacial development (polygenic inheritance)
Effects of both gene and environmental interactions (multifactorial inheritance)
• Mutation of a yet-to-be-identified gene or regulatory region of gene
• Pathogenic variants or benign variants in multiple genes involved in craniofacial development (polygenic inheritance)
• Effects of both gene and environmental interactions (multifactorial inheritance)
## Evaluation Strategy
A diagnosis of CFM should be considered in individuals with variable combinations of facial asymmetry, mandibular hypoplasia, preauricular tags, microtia, epibulbar dermoids, and/or upper-eyelid coloboma.
Once a diagnosis of CFM has been considered, the following approach can be used to exclude other conditions and to assist with discussions of prognosis and recurrence risk counseling.
The following information should be obtained from pregnancy and family history, physical examination, hearing and ophthalmologic evaluation, imaging studies, and genetic testing.
Facial asymmetry should be noted as well as severity of mandibular hypoplasia.
Ear findings should be noted, including presence of ear pits and/or tags and patency of the external auditory canal.
Eyes should be examined for upper- and lower-eyelid colobomata and epibulbar dermoids. Ophthalmologic consultant should evaluate for chorioretinal colobomas (seen in
The neck should be inspected for branchial sinuses or cysts and torticollis or impaired mobility.
The heart; spine, and limbs should be evaluated.
Audiologic diagnostic testing (ear-specific and frequency-specific) in all individuals
Additional imaging studies. X-rays of the cervical spine, echocardiogram, and renal ultrasound examination
CT scan of the temporal bone (commonly after age five years). Those with significant hearing impairment, aural atresia, and/or features of CHARGE syndrome. If temporal bone CT findings are consistent with CHARGE syndrome, testing for CHD7 is recommended.
Consideration of array comparative genomic hybridization, particularly if there are atypical extracranial malformations, delays in development, or possible autosomal dominant inheritance (which can be caused by chromosome 14q23.1 duplication).
One approach is
Alternative approaches include:
Use of a
For an introduction to multigene panels click
• Facial asymmetry should be noted as well as severity of mandibular hypoplasia.
• Ear findings should be noted, including presence of ear pits and/or tags and patency of the external auditory canal.
• Eyes should be examined for upper- and lower-eyelid colobomata and epibulbar dermoids. Ophthalmologic consultant should evaluate for chorioretinal colobomas (seen in
• The neck should be inspected for branchial sinuses or cysts and torticollis or impaired mobility.
• The heart; spine, and limbs should be evaluated.
• Audiologic diagnostic testing (ear-specific and frequency-specific) in all individuals
• Additional imaging studies. X-rays of the cervical spine, echocardiogram, and renal ultrasound examination
• CT scan of the temporal bone (commonly after age five years). Those with significant hearing impairment, aural atresia, and/or features of CHARGE syndrome. If temporal bone CT findings are consistent with CHARGE syndrome, testing for CHD7 is recommended.
• Consideration of array comparative genomic hybridization, particularly if there are atypical extracranial malformations, delays in development, or possible autosomal dominant inheritance (which can be caused by chromosome 14q23.1 duplication).
• Use of a
• For an introduction to multigene panels click
## Genetic Counseling
Craniofacial microsomia (CFM) most frequently occurs as a simplex case (i.e., occurrence in a single individual in a family) with unknown etiology; recurrence risks are empiric.
If an individual with CFM has an inherited or
Occasional autosomal dominant or autosomal recessive inheritance is observed.
The optimal time for determination of genetic risk is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
Prenatal diagnosis of simplex cases has been reported rarely, and typically in those with severe (unilateral microphthalmia) or multiple malformations [
• The optimal time for determination of genetic risk is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Mode of Inheritance
Craniofacial microsomia (CFM) most frequently occurs as a simplex case (i.e., occurrence in a single individual in a family) with unknown etiology; recurrence risks are empiric.
If an individual with CFM has an inherited or
Occasional autosomal dominant or autosomal recessive inheritance is observed.
## Empiric Risks to Family Members
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• The optimal time for determination of genetic risk is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Prenatal Testing
Prenatal diagnosis of simplex cases has been reported rarely, and typically in those with severe (unilateral microphthalmia) or multiple malformations [
## Resources
258 Harvard Street
#367
Brookline MA 02446-2904
800 Florida Avenue Northeast
Suite 2047
Washington DC 20002-3695
PO Box 751112
Las Vegas NV 89136
13140 Coit Road
Suite 517
Dallas TX 75240
United Kingdom
PO Box 11082
Chattanooga TN 37401
8630 Fenton Street
Suite 820
Silver Spring MD 20910
•
• 258 Harvard Street
• #367
• Brookline MA 02446-2904
•
•
• 800 Florida Avenue Northeast
• Suite 2047
• Washington DC 20002-3695
•
•
• PO Box 751112
• Las Vegas NV 89136
•
•
• 13140 Coit Road
• Suite 517
• Dallas TX 75240
•
•
• United Kingdom
•
•
• PO Box 11082
• Chattanooga TN 37401
•
•
• 8630 Fenton Street
• Suite 820
• Silver Spring MD 20910
•
## Management
To establish the extent of involvement in an individual diagnosed with craniofacial microsomia (CFM), the authors recommend the following evaluations.
Children with findings of upper-airway obstruction should be referred to a craniofacial center and/or otolaryngologist.
For those without obvious findings of upper-airway obstruction, a sleep history should be obtained from caretakers to screen for airway obstruction during sleep, and a sleep study and/or sleep medicine consultation should be pursued in those with concerning reports.
If the child demonstrates both normal parameters for age and normal rate of growth, no further studies are needed.
If the child's rate of growth and/or current measurements is below the fifth percentile, consultation with a clinical dietitian/nutritionist should be considered. Caretakers should be queried regarding feeding history with particular attention to inadequate suction with breast/bottle feeding, nasal regurgitation, coughing or choking during meals, or recurrent pneumonia. If any of these findings are reported, evaluation by a clinical feeding specialist (often occupational therapist or speech pathologist) and/or videofluoroscopic swallowing study is indicated.
Children should be screened for scoliosis at diagnosis and yearly thereafter with annual physical examination. Radiographs should be obtained for children with evidence of scoliosis.
For optimal outcome children with CFM require timely and coordinated assessments and interventions. Ideally, children should be managed by an experienced multidisciplinary craniofacial team that includes the following (in alphabetical order):
Audiologist
Dietitian
Clinical geneticist and genetic counselor
Nurse coordinator
Ophthalmologist
Oral and maxillofacial surgeon
Orthodontist
Orthopedist
Otolaryngologist
Pediatric dentist
Pediatrician
Plastic and reconstructive surgeon
Psychosocial professionals (psychologist, social worker)
Speech pathologist
The goals of treatment for CFM are to assure adequate respiratory support and nutritional status, maximize hearing and communication, optimize development, improve facial symmetry, and treat dental malocclusion. Treatment is age dependent, with time-sensitive interventions at appropriate stages of craniofacial growth and development. Treatment plans should be individually tailored to ensure the best results.
The phenotype in CFM is quite variable (see
Infants with severe mandibular hypoplasia may have significant upper-airway compromise and require tracheostomy placement and/or early mandibular advancement. Referral to a craniofacial center or otolaryngologist is recommended.
Those children with moderate mandibular hypoplasia may develop obstructive sleep apnea and require either medical (CPAP) or surgical (tonsillectomy and adenoidectomy or mandibular surgery) intervention.
Good oral hygiene is especially important for children with CFM. Children should have consistent primary preventative dental care.
Orthodontic evaluations are important to assess for missing teeth, dental crowding, jaw growth, and dental malocclusion. Some children may need one or more dental appliances or braces to optimize facial growth, dental appearance, and function.
Children with mandibular hypoplasia may require a bone graft and/or mandibular distraction osteogenesis to lengthen the mandible and/or create a functional TMJ. In a child without airway compromise, these options may be considered when the child is between ages five and seven years.
The use of functional dental appliances to try and influence facial growth, vertical alveolar growth, and dental eruption in the younger patient may be considered, depending on the patient. When facial and jaw growth is nearly complete (age 13 to 16 years), most children with CFM require orthodontics, and many benefit from a final orthognathic surgery to create skeletal symmetry.
All infants with CFM should have a diagnostic hearing evaluation (brain stem auditory evoked response [BAER]) within the first six months of life (regardless of whether the child passed the newborn hearing screen). Timing and type of additional testing depend on results from this initial evaluation and the child's medical history. Early referral to an otolaryngologist is recommended. Early intervention for infants with hearing loss is important to optimize speech and language outcome.
Children with hearing impairment should receive guidance regarding recommendations for hearing aids, appropriate academic accommodations, and avoidance of ototoxic medications to prevent further hearing loss.
Conductive hearing loss, related to aural atresia in which the ossicles may be poorly formed or absent, may be treated with hearing aids. Children with unilateral conductive hearing loss and normal hearing in the contralateral ear are frequently not treated with amplification; however, their speech and language should be monitored closely.
Prior to planning external ear surgery, the authors recommend obtaining a CT scan to assess the middle- and inner-ear structures to help determine if atresia repair is likely to improve hearing. This surgery typically occurs after age five years. The CT may also reveal cholesteatomas, which occur in a small proportion of children with aural atresia.
Children with unilateral aural atresia should have serial screening (with hearing evaluations and tympanoscopy) to ensure maximal hearing of the unaffected ear.
Individuals with eustachian tube dysfunction should continue to have hearing and otologic status monitored, with a low threshold for placing tympanostomy tube(s).
No action
Prosthetic management, either adhesive or implant-retained
Staged surgical reconstruction, using autogenous rib or a synthetic framework
Because adult ear height is achieved by age six to eight years, surgical reconstruction or prosthetic management is often considered after age six years. Ear reconstruction should be coordinated with jaw surgeries for optimal long-term outcomes.
Children should undergo screening with four-view cervical spine radiographs (i.e., AP, lateral, flexion, and extension) at age three years when the bones are ossified. Those with anomalies should be referred to an orthopedic surgeon.
Children should be screened for scoliosis at diagnosis with annual physical examination. The authors recommend obtaining radiographs for children with evidence of scoliosis.
Click
Avoid vasoactive medications (pseudoephedrine, phenylpropanolamine, ibuprofen, and aspirin);
Manage diabetes mellitus to maintain good control and avoid hyperglycemia.
See
Search
• Audiologist
• Dietitian
• Clinical geneticist and genetic counselor
• Nurse coordinator
• Ophthalmologist
• Oral and maxillofacial surgeon
• Orthodontist
• Orthopedist
• Otolaryngologist
• Pediatric dentist
• Pediatrician
• Plastic and reconstructive surgeon
• Psychosocial professionals (psychologist, social worker)
• Speech pathologist
• Infants with severe mandibular hypoplasia may have significant upper-airway compromise and require tracheostomy placement and/or early mandibular advancement. Referral to a craniofacial center or otolaryngologist is recommended.
• Those children with moderate mandibular hypoplasia may develop obstructive sleep apnea and require either medical (CPAP) or surgical (tonsillectomy and adenoidectomy or mandibular surgery) intervention.
• Good oral hygiene is especially important for children with CFM. Children should have consistent primary preventative dental care.
• Orthodontic evaluations are important to assess for missing teeth, dental crowding, jaw growth, and dental malocclusion. Some children may need one or more dental appliances or braces to optimize facial growth, dental appearance, and function.
• Children with mandibular hypoplasia may require a bone graft and/or mandibular distraction osteogenesis to lengthen the mandible and/or create a functional TMJ. In a child without airway compromise, these options may be considered when the child is between ages five and seven years.
• The use of functional dental appliances to try and influence facial growth, vertical alveolar growth, and dental eruption in the younger patient may be considered, depending on the patient. When facial and jaw growth is nearly complete (age 13 to 16 years), most children with CFM require orthodontics, and many benefit from a final orthognathic surgery to create skeletal symmetry.
• All infants with CFM should have a diagnostic hearing evaluation (brain stem auditory evoked response [BAER]) within the first six months of life (regardless of whether the child passed the newborn hearing screen). Timing and type of additional testing depend on results from this initial evaluation and the child's medical history. Early referral to an otolaryngologist is recommended. Early intervention for infants with hearing loss is important to optimize speech and language outcome.
• Children with hearing impairment should receive guidance regarding recommendations for hearing aids, appropriate academic accommodations, and avoidance of ototoxic medications to prevent further hearing loss.
• Conductive hearing loss, related to aural atresia in which the ossicles may be poorly formed or absent, may be treated with hearing aids. Children with unilateral conductive hearing loss and normal hearing in the contralateral ear are frequently not treated with amplification; however, their speech and language should be monitored closely.
• Prior to planning external ear surgery, the authors recommend obtaining a CT scan to assess the middle- and inner-ear structures to help determine if atresia repair is likely to improve hearing. This surgery typically occurs after age five years. The CT may also reveal cholesteatomas, which occur in a small proportion of children with aural atresia.
• Children with unilateral aural atresia should have serial screening (with hearing evaluations and tympanoscopy) to ensure maximal hearing of the unaffected ear.
• Individuals with eustachian tube dysfunction should continue to have hearing and otologic status monitored, with a low threshold for placing tympanostomy tube(s).
• No action
• Prosthetic management, either adhesive or implant-retained
• Staged surgical reconstruction, using autogenous rib or a synthetic framework
• Children should undergo screening with four-view cervical spine radiographs (i.e., AP, lateral, flexion, and extension) at age three years when the bones are ossified. Those with anomalies should be referred to an orthopedic surgeon.
• Children should be screened for scoliosis at diagnosis with annual physical examination. The authors recommend obtaining radiographs for children with evidence of scoliosis.
• Avoid vasoactive medications (pseudoephedrine, phenylpropanolamine, ibuprofen, and aspirin);
• Manage diabetes mellitus to maintain good control and avoid hyperglycemia.
## Evaluations Following Initial Diagnosis
To establish the extent of involvement in an individual diagnosed with craniofacial microsomia (CFM), the authors recommend the following evaluations.
Children with findings of upper-airway obstruction should be referred to a craniofacial center and/or otolaryngologist.
For those without obvious findings of upper-airway obstruction, a sleep history should be obtained from caretakers to screen for airway obstruction during sleep, and a sleep study and/or sleep medicine consultation should be pursued in those with concerning reports.
If the child demonstrates both normal parameters for age and normal rate of growth, no further studies are needed.
If the child's rate of growth and/or current measurements is below the fifth percentile, consultation with a clinical dietitian/nutritionist should be considered. Caretakers should be queried regarding feeding history with particular attention to inadequate suction with breast/bottle feeding, nasal regurgitation, coughing or choking during meals, or recurrent pneumonia. If any of these findings are reported, evaluation by a clinical feeding specialist (often occupational therapist or speech pathologist) and/or videofluoroscopic swallowing study is indicated.
Children should be screened for scoliosis at diagnosis and yearly thereafter with annual physical examination. Radiographs should be obtained for children with evidence of scoliosis.
## Treatment of Manifestations
For optimal outcome children with CFM require timely and coordinated assessments and interventions. Ideally, children should be managed by an experienced multidisciplinary craniofacial team that includes the following (in alphabetical order):
Audiologist
Dietitian
Clinical geneticist and genetic counselor
Nurse coordinator
Ophthalmologist
Oral and maxillofacial surgeon
Orthodontist
Orthopedist
Otolaryngologist
Pediatric dentist
Pediatrician
Plastic and reconstructive surgeon
Psychosocial professionals (psychologist, social worker)
Speech pathologist
The goals of treatment for CFM are to assure adequate respiratory support and nutritional status, maximize hearing and communication, optimize development, improve facial symmetry, and treat dental malocclusion. Treatment is age dependent, with time-sensitive interventions at appropriate stages of craniofacial growth and development. Treatment plans should be individually tailored to ensure the best results.
The phenotype in CFM is quite variable (see
Infants with severe mandibular hypoplasia may have significant upper-airway compromise and require tracheostomy placement and/or early mandibular advancement. Referral to a craniofacial center or otolaryngologist is recommended.
Those children with moderate mandibular hypoplasia may develop obstructive sleep apnea and require either medical (CPAP) or surgical (tonsillectomy and adenoidectomy or mandibular surgery) intervention.
Good oral hygiene is especially important for children with CFM. Children should have consistent primary preventative dental care.
Orthodontic evaluations are important to assess for missing teeth, dental crowding, jaw growth, and dental malocclusion. Some children may need one or more dental appliances or braces to optimize facial growth, dental appearance, and function.
Children with mandibular hypoplasia may require a bone graft and/or mandibular distraction osteogenesis to lengthen the mandible and/or create a functional TMJ. In a child without airway compromise, these options may be considered when the child is between ages five and seven years.
The use of functional dental appliances to try and influence facial growth, vertical alveolar growth, and dental eruption in the younger patient may be considered, depending on the patient. When facial and jaw growth is nearly complete (age 13 to 16 years), most children with CFM require orthodontics, and many benefit from a final orthognathic surgery to create skeletal symmetry.
All infants with CFM should have a diagnostic hearing evaluation (brain stem auditory evoked response [BAER]) within the first six months of life (regardless of whether the child passed the newborn hearing screen). Timing and type of additional testing depend on results from this initial evaluation and the child's medical history. Early referral to an otolaryngologist is recommended. Early intervention for infants with hearing loss is important to optimize speech and language outcome.
Children with hearing impairment should receive guidance regarding recommendations for hearing aids, appropriate academic accommodations, and avoidance of ototoxic medications to prevent further hearing loss.
Conductive hearing loss, related to aural atresia in which the ossicles may be poorly formed or absent, may be treated with hearing aids. Children with unilateral conductive hearing loss and normal hearing in the contralateral ear are frequently not treated with amplification; however, their speech and language should be monitored closely.
Prior to planning external ear surgery, the authors recommend obtaining a CT scan to assess the middle- and inner-ear structures to help determine if atresia repair is likely to improve hearing. This surgery typically occurs after age five years. The CT may also reveal cholesteatomas, which occur in a small proportion of children with aural atresia.
Children with unilateral aural atresia should have serial screening (with hearing evaluations and tympanoscopy) to ensure maximal hearing of the unaffected ear.
Individuals with eustachian tube dysfunction should continue to have hearing and otologic status monitored, with a low threshold for placing tympanostomy tube(s).
No action
Prosthetic management, either adhesive or implant-retained
Staged surgical reconstruction, using autogenous rib or a synthetic framework
Because adult ear height is achieved by age six to eight years, surgical reconstruction or prosthetic management is often considered after age six years. Ear reconstruction should be coordinated with jaw surgeries for optimal long-term outcomes.
Children should undergo screening with four-view cervical spine radiographs (i.e., AP, lateral, flexion, and extension) at age three years when the bones are ossified. Those with anomalies should be referred to an orthopedic surgeon.
Children should be screened for scoliosis at diagnosis with annual physical examination. The authors recommend obtaining radiographs for children with evidence of scoliosis.
• Audiologist
• Dietitian
• Clinical geneticist and genetic counselor
• Nurse coordinator
• Ophthalmologist
• Oral and maxillofacial surgeon
• Orthodontist
• Orthopedist
• Otolaryngologist
• Pediatric dentist
• Pediatrician
• Plastic and reconstructive surgeon
• Psychosocial professionals (psychologist, social worker)
• Speech pathologist
• Infants with severe mandibular hypoplasia may have significant upper-airway compromise and require tracheostomy placement and/or early mandibular advancement. Referral to a craniofacial center or otolaryngologist is recommended.
• Those children with moderate mandibular hypoplasia may develop obstructive sleep apnea and require either medical (CPAP) or surgical (tonsillectomy and adenoidectomy or mandibular surgery) intervention.
• Good oral hygiene is especially important for children with CFM. Children should have consistent primary preventative dental care.
• Orthodontic evaluations are important to assess for missing teeth, dental crowding, jaw growth, and dental malocclusion. Some children may need one or more dental appliances or braces to optimize facial growth, dental appearance, and function.
• Children with mandibular hypoplasia may require a bone graft and/or mandibular distraction osteogenesis to lengthen the mandible and/or create a functional TMJ. In a child without airway compromise, these options may be considered when the child is between ages five and seven years.
• The use of functional dental appliances to try and influence facial growth, vertical alveolar growth, and dental eruption in the younger patient may be considered, depending on the patient. When facial and jaw growth is nearly complete (age 13 to 16 years), most children with CFM require orthodontics, and many benefit from a final orthognathic surgery to create skeletal symmetry.
• All infants with CFM should have a diagnostic hearing evaluation (brain stem auditory evoked response [BAER]) within the first six months of life (regardless of whether the child passed the newborn hearing screen). Timing and type of additional testing depend on results from this initial evaluation and the child's medical history. Early referral to an otolaryngologist is recommended. Early intervention for infants with hearing loss is important to optimize speech and language outcome.
• Children with hearing impairment should receive guidance regarding recommendations for hearing aids, appropriate academic accommodations, and avoidance of ototoxic medications to prevent further hearing loss.
• Conductive hearing loss, related to aural atresia in which the ossicles may be poorly formed or absent, may be treated with hearing aids. Children with unilateral conductive hearing loss and normal hearing in the contralateral ear are frequently not treated with amplification; however, their speech and language should be monitored closely.
• Prior to planning external ear surgery, the authors recommend obtaining a CT scan to assess the middle- and inner-ear structures to help determine if atresia repair is likely to improve hearing. This surgery typically occurs after age five years. The CT may also reveal cholesteatomas, which occur in a small proportion of children with aural atresia.
• Children with unilateral aural atresia should have serial screening (with hearing evaluations and tympanoscopy) to ensure maximal hearing of the unaffected ear.
• Individuals with eustachian tube dysfunction should continue to have hearing and otologic status monitored, with a low threshold for placing tympanostomy tube(s).
• No action
• Prosthetic management, either adhesive or implant-retained
• Staged surgical reconstruction, using autogenous rib or a synthetic framework
• Children should undergo screening with four-view cervical spine radiographs (i.e., AP, lateral, flexion, and extension) at age three years when the bones are ossified. Those with anomalies should be referred to an orthopedic surgeon.
• Children should be screened for scoliosis at diagnosis with annual physical examination. The authors recommend obtaining radiographs for children with evidence of scoliosis.
## Surveillance
Click
## Agents/Circumstances to Avoid
Avoid vasoactive medications (pseudoephedrine, phenylpropanolamine, ibuprofen, and aspirin);
Manage diabetes mellitus to maintain good control and avoid hyperglycemia.
• Avoid vasoactive medications (pseudoephedrine, phenylpropanolamine, ibuprofen, and aspirin);
• Manage diabetes mellitus to maintain good control and avoid hyperglycemia.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## References
## Literature Cited
## Chapter Notes
Web:
We thank the following Seattle Children's Craniofacial Center members for their valuable contributions to this article: Dr Michael Cunningham, Dr Kathleen Sie, Dr Craig Birgfeld, Dr Mark Egbert, Dr Jacqueline Starr, Marsha Ose, and Cassandra Aspinall.
2 April 2020 (ma) Chapter retired: rarely genetic
9 October 2014 (me) Comprehensive update posted live
19 March 2009 (cg) Review posted live
29 August 2008 (clh) Original submission
• 2 April 2020 (ma) Chapter retired: rarely genetic
• 9 October 2014 (me) Comprehensive update posted live
• 19 March 2009 (cg) Review posted live
• 29 August 2008 (clh) Original submission
## Author Notes
Web:
## Acknowledgments
We thank the following Seattle Children's Craniofacial Center members for their valuable contributions to this article: Dr Michael Cunningham, Dr Kathleen Sie, Dr Craig Birgfeld, Dr Mark Egbert, Dr Jacqueline Starr, Marsha Ose, and Cassandra Aspinall.
## Revision History
2 April 2020 (ma) Chapter retired: rarely genetic
9 October 2014 (me) Comprehensive update posted live
19 March 2009 (cg) Review posted live
29 August 2008 (clh) Original submission
• 2 April 2020 (ma) Chapter retired: rarely genetic
• 9 October 2014 (me) Comprehensive update posted live
• 19 March 2009 (cg) Review posted live
• 29 August 2008 (clh) Original submission
Examples of the variability of the skeletal malformations associated with craniofacial microsomia
Grades of auricular malformations described by
(A) Frontal and (B) lateral views of a boy with right-sided microtia, preauricular tag, macrostomia, and mandibular hypoplasia with soft tissue deficiency. Illustrations by Bridget Rafferty.
A. Lateral view of the six embryonic pharyngeal arches (I-VI)
B. Coronal view through the first pharyngeal arch showing the migration of cells from the neural tube to the neural crest where they will develop into the head, neck, and body
Adapted from
Origin of the external ear structures from the first and second pharyngeal arches
Adapted from
Bones (A) and muscles (B) derived from the first pharyngeal arch
Adapted from
Bones (A) and muscles (B) derived from the second pharyngeal arch
Adapted from
|
[
"S Ala-Mello, L Siggberg, S Knuutila, H von Koskull, M Taskinen, M Peippo. Further evidence for a relationship between the 5p15 chromosome region and the oculoauriculovertebral anomaly.. Am J Med Genet A. 2008;146A:2490-4",
"F Alasti, A Sadeghi, MH Sanati, M Farhadi, E Stollar, T Somers, G Van Camp. A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family.. Am J Hum Genet. 2008;82:982-91",
"J Amiel, L Faivre, R Marianowskl, D Bonnet, G Couly, Y Manach, M Le Merrer, V Cormier-Daire, A Munnich, S. Lyonnet. Hypertelorism-Microtia-Clefting syndrome (Bixler syndrome): report of two unrelated cases.. Clin Dysmorph. 2001;10:15-8",
"M Aouchiche, R Boyer, A Nouar. Caryotype results in Goldenhar's syndrome.. Bull Mem Soc Fr Ophtalmol 1972;85:57-69",
"MR Araneta, CA Moore, RS Olney, LD Edmonds, JA Karcher, C McDonough, KM Hiliopoulos, KM Schlangen, GC Gray. Goldenhar syndrome among infants born in military hospitals to Gulf War veterans.. Teratology 1997;56:244-51",
"MJ Ballesta-Martínez, V López-González, LA Dulcet, B Rodríguez-Santiago, S Garcia-Miñaúr, E Guillen-Navarro. Autosomal dominant oculoauriculovertebral spectrum and 14q23.1 microduplication.. Am J Med Genet A. 2013;161A:2030-5",
"I Barisic, L Odak, M Loane, E Garne, D Wellesley, E Calzolari, H Dolk, MC Addor, L Arriola, J Bergman, S Bianca, B Doray, B Khoshnood, K Klungsoyr, B McDonnell, A Pierini, J Rankin, A Rissmann, C Rounding, A Queisser-Luft, G Scarano, D Tucker. Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe.. Eur J Hum Genet. 2014;22:1026-33",
"RD Bennun, JB Mulliken, LB Kaban, JE Murray. Microtia: a microform of hemifacial microsomia.. Plast Reconstr Surg 1985;76:859-65",
"C Bergmann, K Zerres, T Peschgens, J Senderek, H Hörnchen, S. Rudnik-Schöneborn. Overlap between VACTERL and hemifacial microsomia illustrating a spectrum of malformations seen in axial mesodermal dysplasia complex (AMDC).. Am J Med Genet 2003;121A:151-5",
"FP Bernier, O Caluseriu, S Ng, J Schwartzentruber, KJ Buckingham, AM Innes, EW Jabs, JW Innis, JL Schuette, JL Gorski, PH Byers, G Andelfinger, V Siu, J Lauzon, BA Fernandez, M McMillin, RH Scott, H Racher. Majewski J, Nickerson DA, Shendure J, Bamshad MJ, Parboosingh JS. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome.. Am J Hum Genet. 2012;90:925-33",
"ET Bersu, JL Ramirez-Castro. Anatomical analysis of the developmental effects of aneuploidy in man--the 18-trisomy syndrome: I. Anomalies of the head and neck.. Am J Med Genet 1977;1:173-93",
"U Bestelmeyer, H Weerda, R Siegert, M Greiwe, E Schwinger. Familial occurrence of oculoauricolovertebral dysplasia and Franceschetti syndrome.. HNO 1996;44:452-5",
"CB Birgfeld, C Heike. Craniofacial microsomia.. Semin Plast Surg. 2012;26:91-104",
"DT Bonthron, DF Macgregor, DG Barr. Nager acrofacial dysostosis: minor familial manifestations supporting dominant inheritance.. Clin Genet 1993;43:127-31",
"KK Brown, LM Viana, CC Helwig, MA Artunduaga, L Quintanilla-Dieck, P Jarrin, G Osorno, B McDonough, SR DePalma, RD Eavey, JG Seidman, CE Seidman. HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss.. Hum Mutat. 2013;34:1347-51",
"L Buffoni, A Tarateta, G Aicardi, MG Vianello, E Bonioli. Pituitary dwarfism and \"Goldenhar type\" multiple deformities in a patient with deletion of the short arm of chromosome 18.. Minerva Pediatr 1976;28:716-29",
"U Burck. Genetic aspects of hemifacial microsomia.. Hum Genet 1983;64:291-6",
"M Castori, F Brancati, R Rinaldi, L Adami, R Mingarelli, P Grammatico, B Dallapiccola. Antenatal presentation of the oculo-auriculo-vertebral spectrum (OAVS).. Am J Med Genet A 2006;140:1573-9",
"YF Choong, P Watts, E Little, L Beck. Goldenhar and cri-du-chat syndromes: a contiguous gene deletion syndrome?. J AAPOS 2003;7:226-7",
"K Chrzanowska, JP Fryns. Miller postaxial acrofacial dysostosis syndrome. Follow-up data of a family and confirmation of autosomal recessive inheritance.. Clin Genet 1993;43:270",
"SK Clarren, DJ Salk. Chromosome studies in hemifacial microsomia with radial ray defect.. Am J Med Genet 1983;15:169-70",
"MM Cohen, BR Rollnick, CI Kaye. Oculoauriculovertebral spectrum: an updated critique.. Cleft Palate J 1989;26:276-86",
"RR Cousley. A comparison of two classification systems for hemifacial microsomia.. Br J Oral Maxillofac Surg 1993;31:78-82",
"RR Cousley, ML Calvert. Current concepts in the understanding and management of hemifacial microsomia.. Br J Plast Surg 1997;50:536-51",
"RR Cousley, DJ Wilson. Hemifacial microsomia: developmental consequence of perturbation of the auriculofacial cartilage model?. Am J Med Genet 1992;42:461-6",
"JP Curran, FL al-Salihi, PW Allderdice. Partial deletion of the long arm of Chromosome E-18.. Pediatrics 1970;46:721-9",
"JC Czeschik, C Voigt, Y Alanay, B Albrecht, S Avci, D Fitzpatrick, DR Goudie, U Hehr, AJ Hoogeboom, H Kayserili, PO Simsek-Kiper, L Klein-Hitpass, A Kuechler, V López-González, M Martin, S Rahmann, B Schweiger, M Splitt, B Wollnik, HJ Lüdecke, M Zeschnigk, D Wieczorek. Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome.. Hum Genet. 2013;132:885-98",
"DJ David, C Mahatumarat, RD Cooter. Hemifacial microsomia: a multisystem classification.. Plast Reconstr Surg 1987;80:525-35",
"M Derbent, Z Yilmaz, V Baltaci, A Saygili, B Varan, K Tokel. Chromosome 22q11.2 deletion and phenotypic features in 30 patients with conotruncal heart defects.. Am J Med Genet A 2003;116A:129-35",
"MC Digilio, DM McDonald-McGinn, C Heike, C Catania, B Dallapiccola, B Marino, EH Zackai. Three patients with oculo-auriculo-vertebral spectrum and microdeletion 22q11.2.. Am J Med Genet A. 2009;149A:2860-4",
"HV Dyggve, M Mikkelsen. Partial deletion of the short arms of chormosome of the 4-5 group (Denver).. Arch Dis Child 1965;40:82-5",
"KN Evans, JS Gruss, PC Khanna, ML Cunningham, TC Cox, AV Hing. Oculoauriculofrontonasal syndrome: case series revealing new bony nasal anomalies in an old syndrome.. Am J Med Genet A. 2013;161A:1345-53",
"J El-Kehdy, O Abbas, N. Rubeiz. A review of Parry-Romberg syndrome.. J Am Acad Dermatol. 2012;67:769-84",
"C Farra, K Yunis, N Yazbeck, M Majdalani, L Charafeddine, R Wakim, J. Awwad. A Lebanese family with autosomal recessive oculo-auriculo-vertebral (OAV) spectrum and review of the literature: is OAV a genetically heterogeneous disorder?. Appl Clin Genet. 2011;4:93-7",
"MT Gabbett, SP Robertson, R Broadbent, S Aftimos, R Sachdev, MM Nezarati. Characterizing the oculoauriculofrontonasal syndrome.. Clin Dysmorphol. 2008;17:79-85",
"L Garavelli, R Virdis, A Donadio, M Sigorini, G Banchini, P Balestrazzi, JP Fryns. Oculo-auriculo-vertebral spectrum in Klinefelter syndrome.. Genet Couns 1999;10:321-4",
"SJ Gaunt, M Blum, EM De Robertis. Expression of the mouse goosecoid gene during mid-embryogenesis may mark mesenchymal cell lineages in the developing head, limbs and body wall.. Development 1993;117:769-78",
"CT Gordon, F Petit, PM Kroisel, L Jakobsen, RM Zechi-Ceide, M Oufadem, C Bole-Feysot, S Pruvost, C Masson, F Tores, T Hieu, P Nitschké, P Lindholm, P Pellerin, ML Guion-Almeida, NM Kokitsu-Nakata, S Vendramini-Pittoli, A Munnich, S Lyonnet, M Holder-Espinasse, J Amiel. Mutations in endothelin 1 cause recessive auriculocondylar syndrome and dominant isolated question-mark ears.. Am J Hum Genet. 2013;93:1118-25",
"AJ Gougoutas, DJ Singh, DW Low, SP Bartlett. Hemifacial microsomia: clinical features and pictographic representations of the OMENS classification system.. Plast Reconstr Surg 2007;120:112e-20e",
"WC Grabb. The first and second branchial arch syndrome.. Plast Reconstr Surg 1965;36:485-508",
"C Grippaudo, R Deli, FR Grippaudo, T Di Cuia, M Paradisi. Management of craniofacial development in the Parry-Romberg syndrome: report of two patients.. Cleft Palate Craniofac J 2004;41:95-104",
"J Harris, B Källén, E Robert. The epidemiology of anotia and microtia.. J Med Genet 1996;33:809-13",
"JK Hartsfield. Review of the etiologic heterogeneity of the oculo-auriculo-vertebral spectrum (hemifacial microsomia).. Orthod Craniofac Res 2007;10:121-8",
"EH Hathout, E Elmendorf, J Bartley. Hemifacial microsomia and abnormal chromosome 22.. Am J Med Genet 1998;76:71-3",
"Y Hattori, M Tanaka, T Matsumoto, K Uehara, K Ueno, K Miwegishi, H Ishimoto, K Miyakoshi, Y Yoshimura. Prenatal diagnosis of hemifacial microsomia by magnetic resonance imaging.. J Perinat Med 2005;33:69-71",
"JT Hecht, LL Immken, LF Harris, S Malini, CI Scott. The Nager syndrome.. Am J Med Genet 1987;27:965-9",
"GE Herman, F Greenberg, DH Ledbetter. Multiple congenital anomaly/mental retardation (MCA/MR) syndrome with Goldenhar complex due to a terminal del(22q).. Am J Med Genet 1988;29:909-15",
"ME Hodes, S Gleiser, GP DeRosa, HY Yune, DA Girod, DD Weaver, CG Palmer. Trisomy 7 mosaicism and manifestations of Goldenhar syndrome with unilateral radial hypoplasia.. J Craniofac Genet Dev Biol 1981;1:49-55",
"JJ Hoo, R Lorenz, A Fischer, W Fuhrmann. Tiny interstitial duplication of proximal 7q in association with a maternal paracentric inversion.. Hum Genet 1982;62:113-6",
"XS Huang, X Li, C Tan, L Xiao, HO Jiang, SF Zhang, DM Wang, JX Zhang. Genome-wide scanning reveals complex etiology of oculo-auriculo-vertebral spectrum.. Tohoku J Exp Med. 2010a;222:311-8",
"XS Huang, L Xiao, X Li, Y Xie, HO Jiang, C Tan, L Wang, JX Zhang. Two neighboring microdeletions of 5q13.2 in a child with oculo-auriculo-vertebral spectrum.. Eur J Med Genet. 2010b;53:153-8",
"DJ Josifova, MA Patton, K Marks. Oculoauriculovertebral spectrum phenotype caused by an unbalanced t(5;8)(p15.31;p23.1) rearrangement.. Clin Dysmorphol 2004;13:151-3",
"CI Kaye, AO Martin, BR Rollnick, K Nagatoshi, J Israel, M Hermanoff, B Tropea, JT Richtsmeier, NE Morton. Oculoauriculovertebral anomaly: segregation analysis.. Am J Med Genet 1992;43:913-7",
"CE Keegan, JB Mulliken, BL Wu, BR Korf. Townes-Brocks syndrome versus expanded spectrum hemifacial microsomia: review of eight patients and further evidence of a \"hot spot\" for mutation in the SALL1 gene.. Genet Med 2001;3:310-3",
"D Kelberman, J Tyson, DC Chandler, AM McInerney, J Slee, D Albert, A Aymat, M Botma, M Calvert, J Goldblatt, EA Haan, NG Laing, J Lim, S Malcolm, SL Singer, RM Winter, M Bitner-Glindzicz. Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome.. Hum Genet. 2001;109:638-45",
"G. Koren. Mycophenolate mofetil: emerging as a potential human teratogen.. Can Fam Physician. 2008;54:1112-3",
"IJ Keogh, MJ Troulis, AA Monroy, RD Eavey, LB Kaban. Isolated microtia as a marker for unsuspected hemifacial microsomia.. Arch Otolaryngol Head Neck Surg 2007;133:997-1001",
"L Kobrynski, D Chitayat, L Zahed, D McGregor, L Rochon, S Brownstein, M Vekemans, DL Albert. Trisomy 22 and facioauriculovertebral (Goldenhar) sequence.. Am J Med Genet 1993;46:68-71",
"J Kohlhase, PE Taschner, P Burfeind, B Pasche, B Newman, C Blanck, MH Breuning, LP ten Kate, P Maaswinkel-Mooy, B Mitulla, J Seidel, SJ Kirkpatrick, RM Pauli, DS Wargowski, K Devriendt, W Proesmans, O Gabrielli, GV Coppa, E Wesby-van Swaay, RC Trembath, AA Schinzel, W Reardon, E Seemanova, W Engel. Molecular analysis of SALL1 mutations in Townes-Brocks syndrome.. Am J Hum Genet 1999;64:435-45",
"R Kosaki, R Fujimaru, H Samejima, H Yamada, K Izumi, K Iijima, K Kosaki. Wide phenotypic variations within a family with SALL1 mutations: Isolated external ear abnormalities to Goldenhar syndrome.. Am J Med Genet A 2007;143A:1087-90",
"T Kushnick, M Colondrillo. 49, XXXXY patient with hemifacial microsomia.. Clin Genet 1975;7:442-8",
"S Ladekarl. Combination of Goldenhar syndrome with cri-dre-chat syndrome.. Acta Ophthalmol (Copenh) 1968;46:605-10",
"E Lammer. Preliminary observations on isotretinoin-induced ear malformations and pattern formation of the external ear.. J Craniofac Genet Dev Biol 1991;11:292-5",
"K Lawson, N Waterhouse, DT Gault, ML Calvert, M Botma, R Ng. Is hemifacial microsomia linked to multiple maternities?. Br J Plast Surg 2002;55:474-8",
"D Lehalle, CT Gordon, M Oufadem, G Goudefroye, L Boutaud, JL Alessandri, N Baena, G Baujat, C Baumann, O Boute-Benejean, R Caumes, C Decaestecker, D Gaillard, A Goldenberg, M Gonzales, M Holder-Espinasse, ML Jacquemont, D Lacombe, S Manouvrier-Hanu, S Marlin, M Mathieu-Dramard, G Morin, L Pasquier, F Petit, M Rio, R Smigiel, C Thauvin-Robinet, A Vasiljevic, A Verloes, V Malan, A Munnich, L de Pontual, M Vekemans, S Lyonnet, T Attié-Bitach, J Amiel. Delineation of EFTUD2 haploinsufficiency-related phenotypes through a series of 36 patients.. Hum Mutat. 2014;35:478-85",
"MA Lines, L Huang, J Schwartzentruber, SL Douglas, DC Lynch, C Beaulieu, ML Guion-Almeida, RM Zechi-Ceide, B Gener, G Gillessen-Kaesbach, C Nava, G Baujat, D Horn, U Kini, A Caliebe, Y Alanay, GE Utine, D Lev, J Kohlhase, AW Grix, DR Lohmann, U Hehr, D Böhm. Majewski J, Bulman DE, Wieczorek D, Boycott KM. Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly.. Am J Hum Genet. 2012;90:369-77",
"I Llano-Rivas, A González-del Angel, V del Castillo, R Reyes, A Carnevale. Microtia: a clinical and genetic study at the National Institute of Pediatrics in Mexico City.. Arch Med Res 1999;30:120-4",
"JS Lopez-Camelo, IM Orioli. Heterogeneous rates for birth defects in Latin America: hints on causality.. Genet Epidemiol 1996;13:469-81",
"DV Luquetti, AV Hing, MJ Rieder, DA Nickerson, EH Turner, J Smith, S Park, ML Cunningham. \"Mandibulofacial dysostosis with microcephaly\" caused by EFTUD2 mutations: expanding the phenotype.. Am J Med Genet A. 2013;161A:108-13",
"CL Maris, MC Endriga, ML Omnell, ML Speltz. Psychosocial adjustment in twin pairs with and without hemifacial microsomia.. Cleft Palate Craniofac J 1999;36:43-50",
"P Martinelli, GM Maruotti, A Agangi, LL Mazzarelli, G Bifulco, D Paladini. Prenatal diagnosis of hemifacial microsomia and ipsilateral cerebellar hypoplasia in a fetus with oculoauriculovertebral spectrum.. Ultrasound Obstet Gynecol 2004;24:199-201",
"M Melnick, NC Myrianthopoulos, NW Paul. External ear malformations: epidemiology, genetics, and natural history.. Birth Defects Orig Artic Ser. 1979;15:i-ix,1-140",
"KW Neu, JM Friedman, PN Howard-Peebles. Hemifacial microsomia in cri du chat (5p-) syndrome.. J Craniofac Genet Dev Biol 1982;2:295-8",
"JK Northup, D Matalon, JC Hawkins, R Matalon, GV Velagaleti. Pericentric inversion, inv(14)(p11.2q22.3), in a 9-month old with features of Goldenhar syndrome.. Clin Dysmorphol. 2010;19:185-9",
"JM Opitz. The developmental field concept.. Am J Med Genet 1985;21:1-11",
"JM Opitz, SO Lewin. The developmental field concept in pediatric pathology--especially with respect to fibular a/hypoplasia and the DiGeorge anomaly.. Birth Defects Orig Artic Ser 1987;23:277-92",
"MA Parisi, H Zayed, AM Slavotinek, JC Rutledge. Congenital diaphragmatic hernia and microtia in a newborn with mycophenolate mofetil (MMF) exposure: phenocopy for Fryns syndrome or broad spectrum of teratogenic effects?. Am J Med Genet A. 2009;149A:1237-40",
"DF Pereira-Perdomo, J Vélez-Forero, R Prada-Madrid. Hemifacial myohyperplasia sequence.. Am J Med Genet A. 2010;152A:1770-3",
"F Petit, F Escande, AS Jourdain, N Porchet, J Amiel, B Doray, MA Delrue, E Flori, CA Kim, S Marlin, SP Robertson, S Manouvrier-Hanu, M Holder-Espinasse. Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause.. Clin Genet. 2014;86:246-51",
"HH Poonawalla, CI Kaye, IM Rosenthal, S Pruzansky. Hemifacial microsomia in a patient with Klinefelter syndrome.. Cleft Palate J 1980;17:194-6",
"F Quintero-Rivera, JA Martinez-Agosto. Hemifacial microsomia in cat-eye syndrome: 22q11.1-q11.21 as candidate loci for facial symmetry.. Am J Med Genet A. 2013;161A:1985-91",
"MJ Rieder, GE Green, SS Park, BD Stamper, CT Gordon, JM Johnson, CM Cunniff, JD Smith, SB Emery, S Lyonnet, J Amiel, M Holder, AA Heggie, MJ Bamshad, DA Nickerson, TC Cox, AV Hing, JA Horst, ML Cunningham. A human homeotic transformation resulting from mutations in PLCB4 and GNAI3 causes auriculocondylar syndrome.. Am J Hum Genet. 2012;90:907-14",
"JA Rivera-Pérez, M Mallo, M Gendron-Maguire, T Gridley, RR Behringer. Goosecoid is not an essential component of the mouse gastrula organizer but is required for craniofacial and rib development.. Development 1995;121:3005-12",
"BR Rollnick. Oculoauriculovertebral anomaly: variability and causal heterogeneity.. Am J Med Genet Suppl 1988;4:41-53",
"BR Rollnick, CI Kaye. Hemifacial microsomia and variants: pedigree data.. Am J Med Genet 1983;15:233-53",
"BR Rollnick, CI Kaye, K Nagatoshi, W Hauck, AO Martin. Oculoauriculovertebral dysplasia and variants: phenotypic characteristics of 294 patients.. Am J Med Genet 1987;26:361-75",
"C Rooryck, N Souakri, D Cailley, J Bouron, C Goizet, MA Delrue, S Marlin, FD Lacombe, B Arveiler. Array-CGH analysis of a cohort of 86 patients with oculoauriculovertebral spectrum.. Am J Med Genet A. 2010;152A:1984-9",
"D Rotten, JM Levaillant, H Martinez, H Ducou le Pointe, E Vicaut. The fetal mandible: a 2D and 3D sonographic approach to the diagnosis of retrognathia and micrognathia.. Ultrasound Obstet Gynecol 2002;19:122-30",
"E Schaefer, C Collet, D Genevieve, M Vincent, DR Lohmann, E Sanchez, C Bolender, MM Eliot, G Nürnberg, MR Passos-Bueno, D Wieczorek, L van Maldergem, B Doray. Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome.. Genet Med. 2014;16:720-4",
"M Schmid, M Schröder, U Langenbeck. Familial microtia, meatal atresia, and conductive deafness in three siblings.. Am J Med Genet 1985;22:327-32",
"C Schroeter, K Jährig, I Weinke. Helv Paediatr Acta 1980;35:233-41",
"GM Shaw, SL Carmichael, Z Kaidarova, JA Harris. Epidemiologic characteristics of anotia and microtia in California, 1989-1997.. Birth Defects Res A Clin Mol Teratol 2004;70:472-5",
"BD Solomon. VACTERL/VATER association.. Orphanet J Rare Dis. 2011;6:56",
"A Splendore, MR Passos-Bueno, EW Jabs, L Van Maldergem, EA Wulfsberg. TCOF1 mutations excluded from a role in other first and second branchial arch-related disorders.. Am J Med Genet 2002;111:324-7",
"M Stanojević, F Stipoljev, B Koprcina, A Kurjak. Oculo-auriculo-vertebral (Goldenhar) spectrum associated with pericentric inversion 9: coincidental findings or etiologic factor?. J Craniofac Genet Dev Biol 2000;20:150-4",
"PH Su, JS Yu, JY Chen, SJ Chen, SY Li, HN Chen. Mutations and new polymorphic changes in the TCOF1 gene of patients with oculo-auriculo-vertebral spectrum and Treacher-Collins syndrome.. Clin Dysmorphol 2007;16:261-7",
"E Sujansky, A Smith. Recombinant chromosome 18 in two male sibs with first and second branchial arch syndrome.. Am J Hum Genet 1981;33:92A",
"RW Sze, AM Paladin, S Lee, ML Cunningham. Hemifacial microsomia in pediatric patients: asymmetric abnormal development of the first and second branchial arches.. AJR Am J Roentgenol 2002;178:1523-30",
"TY Tan, A Collins, PA James, G McGillivray, Z Stark, CT Gordon, RJ Leventer, K Pope, R Forbes, JA Crolla, D Ganesamoorthy, T Burgess, DL Bruno, HR Slater, PG Farlie, DJ Amor. Phenotypic variability of distal 22q11.2 copy number abnormalities.. Am J Med Genet A. 2011;155A:1623-33",
"RC Tanzer. Microtia.. Clin Plast Surg. 1978;5:317-36",
"C Tasse, S Böhringer, S Fischer, HJ Lüdecke, B Albrecht, D Horn, A Janecke, R Kling, R König, B Lorenz, F Majewski, E Maeyens, P Meinecke, B Mitulla, C Mohr, M Preischl, H Umstadt, J Kohlhase, G Gillessen-Kaesbach, D Wieczorek. Oculo-auriculo-vertebral spectrum (OAVS): clinical evaluation and severity scoring of 53 patients and proposal for a new classification.. Eur J Med Genet 2005;48:397-411",
"C Tasse, F Majewski, S Böhringer, S Fischer, HJ Lüdecke, G Gillessen-Kaesbach, D Wieczorek. A family with autosomal dominant oculo-auriculo-vertebral spectrum.. Clin Dysmorphol 2007;16:1-7",
"K Taysi, JL Marsh, DM Wise. Familial hemifacial microsomia.. Cleft Palate J 1983;20:47-53",
"EE Torti, SR Braddock, K Bernreuter, JR Batanian. Oculo-auriculo-vertebral spectrum, cat eye, and distal 22q11 microdeletion syndromes: a unique double rearrangement.. Am J Med Genet A. 2013;161A:1992-8",
"S Vendramini-Pittoli, NM Kokitsu-Nakata. Oculoauriculovertebral spectrum: report of nine familial cases with evidence of autosomal dominant inheritance and review of the literature.. Clin Dysmorphol. 2009;18:67-77",
"AR Vento, RA LaBrie, JB Mulliken. The O.M.E.N.S. classification of hemifacial microsomia.. Cleft Palate Craniofac J 1991;28:68-76",
"A Verloes, N Seret, V Bernier, M Gonzales, C Herens, L Koulischer. Branchial arch anomalies in trisomy 18.. Ann Genet 1991;34:22-4",
"J Vigneron, M Stricker, P Vert, JM Rousselot, M Levy. Postaxial acrofacial dystosis (Miller) syndrome: a new case.. J Med Genet. 1991;28:636-8",
"C Voigt, A Mégarbané, K Neveling, JC Czeschik, B Albrecht, B Callewaert, F von Deimling, A Hehr, M Falkenberg Smeland, R König, A Kuechler, C Marcelis, M Puiu, W Reardon, HM Riise Stensland, B Schweiger, M Steehouwer, C Teller, M Martin, S Rahmann, U Hehr, HG Brunner, HJ Lüdecke, D Wieczorek. Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations.. Orphanet J Rare Dis. 2013;8:110",
"CM Van Bennekom, AA Mitchell, CA Moore, MM Werler. Vasoactive exposures during pregnancy and risk of microtia.. Birth Defects Res A Clin Mol Teratol. 2013;97:53-9",
"R Wang, ML Martínez-Frías, JM Graham. Infants of diabetic mothers are at increased risk for the oculo-auriculo-vertebral sequence: A case-based and case-control approach.. J Pediatr 2002;141:611-7",
"MM Werler, JE Sheehan, C Hayes, AA Mitchell, JB Mulliken. Vasoactive exposures, vascular events, and hemifacial microsomia.. Birth Defects Res A Clin Mol Teratol 2004a;70:389-95",
"MM Werler, JE Sheehan, C Hayes, BL Padwa, AA Mitchell, JB Mulliken. Demographic and Reproductive Factors Associated With Hemifacial Microsomia.. Cleft Palate Craniofac J 2004b;41:494-50",
"D Wieczorek, M Ludwig, S Boehringer, PH Jongbloet, G Gillessen-Kaesbach, B Horsthemke. Reproduction abnormalities and twin pregnancies in parents of sporadic patients with oculo-auriculo-vertebral spectrum/Goldenhar syndrome.. Hum Genet 2007;121:369-76",
"GN Wilson, M Barr. Trisomy 9 mosaicism: another etiology for the manifestations of Goldenhar syndrome.. J Craniofac Genet Dev Biol 1983;3:313-6",
"G Yamada, A Mansouri, M Torres, ET Stuart, M Blum, M Schultz, EM De Robertis, P Gruss. Targeted mutation of the murine goosecoid gene results in craniofacial defects and neonatal death.. Development 1995;121:2917-22",
"D Zielinski, B Markus, M Sheikh, M Gymrek, C Chu, M Zaks, B Srinivasan, JD Hoffman, D Aizenbud, Y Erlich. OTX2 duplication is implicated in hemifacial microsomia.. PLoS One. 2014;9"
] |
19/3/2009
|
9/10/2014
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
m-sulfatase-def
|
m-sulfatase-def
|
[
"Formylglycine-generating enzyme",
"SUMF1",
"Multiple Sulfatase Deficiency"
] |
Multiple Sulfatase Deficiency
|
Lars Schlotawa, Laura Adang, Mauricio De Castro, Rebecca Ahrens-Nicklas
|
Summary Initial symptoms of multiple sulfatase deficiency (MSD) can develop from infancy through early childhood, and presentation is widely variable. Some individuals display the multisystemic features characteristic of mucopolysaccharidosis disorders (e.g., developmental regression, organomegaly, skeletal deformities) while other individuals present primarily with neurologic regression (associated with leukodystrophy). Based on age of onset, rate of progression, and disease severity, several different clinical subtypes of MSD have been described: Neonatal MSD is the most severe with presentation in the prenatal period or at birth with rapid progression and death occurring within the first two years of life. Infantile MSD is the most common variant and may be characterized as attenuated (slower clinical course with cognitive disability and neurodegeneration identified in the 2nd year of life) or severe (loss of the majority of developmental milestones by age 5 years). Juvenile MSD is the rarest subtype with later onset of symptoms and subacute clinical presentation. Many of the features found in MSD are progressive, including neurologic deterioration, heart disease, hearing loss, and airway compromise. The diagnosis of multiple sulfatase deficiency is established in a proband with low activity levels in at least two sulfatase enzymes and/or biallelic pathogenic variants in Multiple sulfatase deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% change of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible using molecular genetic techniques if the pathogenic variants in the family are known.
|
## Diagnosis
Formal clinical diagnostic criteria for multiple sulfatase deficiency have not been established.
Multiple sulfatase deficiency
Developmental delay with subsequent neurologic regression and psychomotor retardation
Macrocephaly with or without hydrocephalus
Epilepsy
Poor growth with a progressive decrease in growth rate
Coarse facial features
Recurrent otitis media and/or upper respiratory tract infections
Progressive hearing loss
Hepatosplenomegaly
Skeletal changes including kyphosis, gibbus deformity, hip dislocation, genu valgum
Cardiac hypertrophy or thickening of cardiac valves
Ichthyosis
Decreased activity of at least two sulfatase enzymes on lysosomal enzyme testing analysis
Note: Individual enzyme activities may be higher than those seen in individuals with single enzyme deficiencies and some may be within normal ranges.
Elevated urinary glycosaminoglycan levels
Elevated urinary sulfatides
Abnormal brain MRI showing progressive demyelination, prominence of the perivascular spaces, cerebral volume loss, and/or hydrocephalus
Skeletal radiographs demonstrating features of dysostosis multiplex including anomalies of the vertebrae, hands, feet, long bones, and skull
The diagnosis of multiple sulfatase deficiency
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of multiple sulfatase deficiency is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of multiple sulfatase deficiency, molecular genetic testing approaches can include
Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
For an introduction to multigene panels click
When the diagnosis of multiple sulfatase deficiency is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multiple Sulfatase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Review of all available cases in the literature revealed three large deletions and no duplications out of 201 alleles [Author observation, in preparation for publication].
• Developmental delay with subsequent neurologic regression and psychomotor retardation
• Macrocephaly with or without hydrocephalus
• Epilepsy
• Poor growth with a progressive decrease in growth rate
• Coarse facial features
• Recurrent otitis media and/or upper respiratory tract infections
• Progressive hearing loss
• Hepatosplenomegaly
• Skeletal changes including kyphosis, gibbus deformity, hip dislocation, genu valgum
• Cardiac hypertrophy or thickening of cardiac valves
• Ichthyosis
• Decreased activity of at least two sulfatase enzymes on lysosomal enzyme testing analysis
• Note: Individual enzyme activities may be higher than those seen in individuals with single enzyme deficiencies and some may be within normal ranges.
• Elevated urinary glycosaminoglycan levels
• Elevated urinary sulfatides
• Abnormal brain MRI showing progressive demyelination, prominence of the perivascular spaces, cerebral volume loss, and/or hydrocephalus
• Skeletal radiographs demonstrating features of dysostosis multiplex including anomalies of the vertebrae, hands, feet, long bones, and skull
• Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• For an introduction to multigene panels click
## Suggestive Findings
Multiple sulfatase deficiency
Developmental delay with subsequent neurologic regression and psychomotor retardation
Macrocephaly with or without hydrocephalus
Epilepsy
Poor growth with a progressive decrease in growth rate
Coarse facial features
Recurrent otitis media and/or upper respiratory tract infections
Progressive hearing loss
Hepatosplenomegaly
Skeletal changes including kyphosis, gibbus deformity, hip dislocation, genu valgum
Cardiac hypertrophy or thickening of cardiac valves
Ichthyosis
Decreased activity of at least two sulfatase enzymes on lysosomal enzyme testing analysis
Note: Individual enzyme activities may be higher than those seen in individuals with single enzyme deficiencies and some may be within normal ranges.
Elevated urinary glycosaminoglycan levels
Elevated urinary sulfatides
Abnormal brain MRI showing progressive demyelination, prominence of the perivascular spaces, cerebral volume loss, and/or hydrocephalus
Skeletal radiographs demonstrating features of dysostosis multiplex including anomalies of the vertebrae, hands, feet, long bones, and skull
• Developmental delay with subsequent neurologic regression and psychomotor retardation
• Macrocephaly with or without hydrocephalus
• Epilepsy
• Poor growth with a progressive decrease in growth rate
• Coarse facial features
• Recurrent otitis media and/or upper respiratory tract infections
• Progressive hearing loss
• Hepatosplenomegaly
• Skeletal changes including kyphosis, gibbus deformity, hip dislocation, genu valgum
• Cardiac hypertrophy or thickening of cardiac valves
• Ichthyosis
• Decreased activity of at least two sulfatase enzymes on lysosomal enzyme testing analysis
• Note: Individual enzyme activities may be higher than those seen in individuals with single enzyme deficiencies and some may be within normal ranges.
• Elevated urinary glycosaminoglycan levels
• Elevated urinary sulfatides
• Abnormal brain MRI showing progressive demyelination, prominence of the perivascular spaces, cerebral volume loss, and/or hydrocephalus
• Skeletal radiographs demonstrating features of dysostosis multiplex including anomalies of the vertebrae, hands, feet, long bones, and skull
## Establishing the Diagnosis
The diagnosis of multiple sulfatase deficiency
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of multiple sulfatase deficiency is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of multiple sulfatase deficiency, molecular genetic testing approaches can include
Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
For an introduction to multigene panels click
When the diagnosis of multiple sulfatase deficiency is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multiple Sulfatase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Review of all available cases in the literature revealed three large deletions and no duplications out of 201 alleles [Author observation, in preparation for publication].
• Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of multiple sulfatase deficiency, molecular genetic testing approaches can include
Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
For an introduction to multigene panels click
• Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• For an introduction to multigene panels click
## Option 2
When the diagnosis of multiple sulfatase deficiency is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multiple Sulfatase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Review of all available cases in the literature revealed three large deletions and no duplications out of 201 alleles [Author observation, in preparation for publication].
## Clinical Characteristics
Multiple sulfatase deficiency (MSD) is a multisystem lysosomal storage disorder with variable age of onset and wide variability in clinical presentation and rate of progression. Initial symptoms can present from infancy through early childhood [
Based on age of onset, rate of progression and disease severity, several different subtypes of MSD have been described [
The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
Dysmorphic features, if present, are subtle but may become more prominent with age.
Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
Dysmorphic features, skeletal changes, and organomegaly are common [
Life span is significantly shortened, and many die within the first decade of life.
Age of onset is between three and seven years with an insidious clinical presentation and neurologic decline.
Presenting symptoms can include generalized tremor, hypotonia, and mild-moderate developmental delays [
Affected individuals can also develop ichthyosis, visual loss (although corneal clouding is rare), and behavioral abnormalities, and may have minor dysmorphic features (broad thumbs and index fingers) that frequently become more prominent with age [
The oldest known person with the condition survived until the fourth decade of life [Author, personal communication].
Individuals with juvenile MSD can retain the ability to walk into their teenage years.
Many of the features found in MSD can be progressive, including the neurologic deterioration, heart disease, hearing loss, and airway compromise. The progressive nature of the disease is at least in part due to the accumulation of glycosaminoglycans (GAGs) and other substrates, including sulfatides.
Developmental delay and progressive neurologic deterioration, including long track signs (spasticity)
Ataxia
Autistic features
Epilepsy [
Microcephaly [
Short stature
Irregular ribs (typically paddle-shaped with widening anteriorly and tapering posteriorly) associated with dysostosis multiplex
Scoliosis and/or kyphosis
Vertebral abnormalities, including odontoid dysplasia, atlanto-axial instability, cervical spinal canal stenosis, and vertebral body abnormalities (wedge-shaped vertebral bodies, anterior beaking with posterior scalloping, and platyspondyly)
Vertebral instability and risk of spinal cord compression, which can be dangerous with neck hyperextension (such as occurs during intubation)
Short metacarpals
Joint stiffness and contractures, which may pose a prominent issue that can impede mobility [
Broad thumbs and toes [
Glaucoma
Strabismus
Retinal degeneration
Corneal clouding
Cataracts
Retinitis pigmentosa [
Myopia
Cerebral atrophy and/or cerebellar atrophy
Abnormalities of the corpus callosum
Dilatation of the ventricular system
Prominence of the sulci
Enlarged perivascular spaces
Cervical cord compression
Delayed myelination
The wide clinical spectrum seen in MSD is largely a function of the unique pathophysiology of this condition, as multiple pathways are affected by a common enzymatic defect. All known 17 human sulfatases may be affected; thus, the clinical presentation is a composite of the effects of each individual sulfatase deficiency [
Sulfatase-modifying-factor-1 (SUMF1) protein stability and residual formylglycine-generating enzyme (FGE) activity influence the clinical presentation in individuals with pathogenic changes in
For a small subset of pathogenic missense variants, experimental evidence for residual SUMF1 activity and FGE stability has been published and specific genotype-phenotype correlations exist.
Homozygosity for the p.Gly263Val or p.Ala279Val
Homozygosity for the p.Ser155Pro, p.Gly247Arg, or p.Arg349Trp
Non-experimental prediction methods attempting to correlate a particular
Other terms used to describe MSD are Austin disease (named after Dr James Austin, who first described the condition [
The estimated prevalence of MSD is one in 1.4 million individuals. There have been approximately 75-100 cases reported to date [
• The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
• Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
• Dysmorphic features, if present, are subtle but may become more prominent with age.
• Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
• The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
• Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
• Dysmorphic features, if present, are subtle but may become more prominent with age.
• Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
• Dysmorphic features, skeletal changes, and organomegaly are common [
• Life span is significantly shortened, and many die within the first decade of life.
• Dysmorphic features, skeletal changes, and organomegaly are common [
• Life span is significantly shortened, and many die within the first decade of life.
• The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
• Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
• Dysmorphic features, if present, are subtle but may become more prominent with age.
• Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
• Dysmorphic features, skeletal changes, and organomegaly are common [
• Life span is significantly shortened, and many die within the first decade of life.
• Age of onset is between three and seven years with an insidious clinical presentation and neurologic decline.
• Presenting symptoms can include generalized tremor, hypotonia, and mild-moderate developmental delays [
• Affected individuals can also develop ichthyosis, visual loss (although corneal clouding is rare), and behavioral abnormalities, and may have minor dysmorphic features (broad thumbs and index fingers) that frequently become more prominent with age [
• The oldest known person with the condition survived until the fourth decade of life [Author, personal communication].
• Individuals with juvenile MSD can retain the ability to walk into their teenage years.
• Developmental delay and progressive neurologic deterioration, including long track signs (spasticity)
• Ataxia
• Autistic features
• Epilepsy [
• Microcephaly [
• Short stature
• Irregular ribs (typically paddle-shaped with widening anteriorly and tapering posteriorly) associated with dysostosis multiplex
• Scoliosis and/or kyphosis
• Vertebral abnormalities, including odontoid dysplasia, atlanto-axial instability, cervical spinal canal stenosis, and vertebral body abnormalities (wedge-shaped vertebral bodies, anterior beaking with posterior scalloping, and platyspondyly)
• Vertebral instability and risk of spinal cord compression, which can be dangerous with neck hyperextension (such as occurs during intubation)
• Short metacarpals
• Joint stiffness and contractures, which may pose a prominent issue that can impede mobility [
• Broad thumbs and toes [
• Glaucoma
• Strabismus
• Retinal degeneration
• Corneal clouding
• Cataracts
• Retinitis pigmentosa [
• Myopia
• Cerebral atrophy and/or cerebellar atrophy
• Abnormalities of the corpus callosum
• Dilatation of the ventricular system
• Prominence of the sulci
• Enlarged perivascular spaces
• Cervical cord compression
• Delayed myelination
• Homozygosity for the p.Gly263Val or p.Ala279Val
• Homozygosity for the p.Ser155Pro, p.Gly247Arg, or p.Arg349Trp
## Clinical Description
Multiple sulfatase deficiency (MSD) is a multisystem lysosomal storage disorder with variable age of onset and wide variability in clinical presentation and rate of progression. Initial symptoms can present from infancy through early childhood [
Based on age of onset, rate of progression and disease severity, several different subtypes of MSD have been described [
The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
Dysmorphic features, if present, are subtle but may become more prominent with age.
Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
Dysmorphic features, skeletal changes, and organomegaly are common [
Life span is significantly shortened, and many die within the first decade of life.
Age of onset is between three and seven years with an insidious clinical presentation and neurologic decline.
Presenting symptoms can include generalized tremor, hypotonia, and mild-moderate developmental delays [
Affected individuals can also develop ichthyosis, visual loss (although corneal clouding is rare), and behavioral abnormalities, and may have minor dysmorphic features (broad thumbs and index fingers) that frequently become more prominent with age [
The oldest known person with the condition survived until the fourth decade of life [Author, personal communication].
Individuals with juvenile MSD can retain the ability to walk into their teenage years.
Many of the features found in MSD can be progressive, including the neurologic deterioration, heart disease, hearing loss, and airway compromise. The progressive nature of the disease is at least in part due to the accumulation of glycosaminoglycans (GAGs) and other substrates, including sulfatides.
Developmental delay and progressive neurologic deterioration, including long track signs (spasticity)
Ataxia
Autistic features
Epilepsy [
Microcephaly [
Short stature
Irregular ribs (typically paddle-shaped with widening anteriorly and tapering posteriorly) associated with dysostosis multiplex
Scoliosis and/or kyphosis
Vertebral abnormalities, including odontoid dysplasia, atlanto-axial instability, cervical spinal canal stenosis, and vertebral body abnormalities (wedge-shaped vertebral bodies, anterior beaking with posterior scalloping, and platyspondyly)
Vertebral instability and risk of spinal cord compression, which can be dangerous with neck hyperextension (such as occurs during intubation)
Short metacarpals
Joint stiffness and contractures, which may pose a prominent issue that can impede mobility [
Broad thumbs and toes [
Glaucoma
Strabismus
Retinal degeneration
Corneal clouding
Cataracts
Retinitis pigmentosa [
Myopia
Cerebral atrophy and/or cerebellar atrophy
Abnormalities of the corpus callosum
Dilatation of the ventricular system
Prominence of the sulci
Enlarged perivascular spaces
Cervical cord compression
Delayed myelination
• The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
• Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
• Dysmorphic features, if present, are subtle but may become more prominent with age.
• Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
• The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
• Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
• Dysmorphic features, if present, are subtle but may become more prominent with age.
• Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
• Dysmorphic features, skeletal changes, and organomegaly are common [
• Life span is significantly shortened, and many die within the first decade of life.
• Dysmorphic features, skeletal changes, and organomegaly are common [
• Life span is significantly shortened, and many die within the first decade of life.
• The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
• Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
• Dysmorphic features, if present, are subtle but may become more prominent with age.
• Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
• Dysmorphic features, skeletal changes, and organomegaly are common [
• Life span is significantly shortened, and many die within the first decade of life.
• Age of onset is between three and seven years with an insidious clinical presentation and neurologic decline.
• Presenting symptoms can include generalized tremor, hypotonia, and mild-moderate developmental delays [
• Affected individuals can also develop ichthyosis, visual loss (although corneal clouding is rare), and behavioral abnormalities, and may have minor dysmorphic features (broad thumbs and index fingers) that frequently become more prominent with age [
• The oldest known person with the condition survived until the fourth decade of life [Author, personal communication].
• Individuals with juvenile MSD can retain the ability to walk into their teenage years.
• Developmental delay and progressive neurologic deterioration, including long track signs (spasticity)
• Ataxia
• Autistic features
• Epilepsy [
• Microcephaly [
• Short stature
• Irregular ribs (typically paddle-shaped with widening anteriorly and tapering posteriorly) associated with dysostosis multiplex
• Scoliosis and/or kyphosis
• Vertebral abnormalities, including odontoid dysplasia, atlanto-axial instability, cervical spinal canal stenosis, and vertebral body abnormalities (wedge-shaped vertebral bodies, anterior beaking with posterior scalloping, and platyspondyly)
• Vertebral instability and risk of spinal cord compression, which can be dangerous with neck hyperextension (such as occurs during intubation)
• Short metacarpals
• Joint stiffness and contractures, which may pose a prominent issue that can impede mobility [
• Broad thumbs and toes [
• Glaucoma
• Strabismus
• Retinal degeneration
• Corneal clouding
• Cataracts
• Retinitis pigmentosa [
• Myopia
• Cerebral atrophy and/or cerebellar atrophy
• Abnormalities of the corpus callosum
• Dilatation of the ventricular system
• Prominence of the sulci
• Enlarged perivascular spaces
• Cervical cord compression
• Delayed myelination
## Natural History
Based on age of onset, rate of progression and disease severity, several different subtypes of MSD have been described [
The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
Dysmorphic features, if present, are subtle but may become more prominent with age.
Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
Dysmorphic features, skeletal changes, and organomegaly are common [
Life span is significantly shortened, and many die within the first decade of life.
Age of onset is between three and seven years with an insidious clinical presentation and neurologic decline.
Presenting symptoms can include generalized tremor, hypotonia, and mild-moderate developmental delays [
Affected individuals can also develop ichthyosis, visual loss (although corneal clouding is rare), and behavioral abnormalities, and may have minor dysmorphic features (broad thumbs and index fingers) that frequently become more prominent with age [
The oldest known person with the condition survived until the fourth decade of life [Author, personal communication].
Individuals with juvenile MSD can retain the ability to walk into their teenage years.
• The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
• Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
• Dysmorphic features, if present, are subtle but may become more prominent with age.
• Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
• The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
• Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
• Dysmorphic features, if present, are subtle but may become more prominent with age.
• Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
• Dysmorphic features, skeletal changes, and organomegaly are common [
• Life span is significantly shortened, and many die within the first decade of life.
• Dysmorphic features, skeletal changes, and organomegaly are common [
• Life span is significantly shortened, and many die within the first decade of life.
• The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
• Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [
• Dysmorphic features, if present, are subtle but may become more prominent with age.
• Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [
• Dysmorphic features, skeletal changes, and organomegaly are common [
• Life span is significantly shortened, and many die within the first decade of life.
• Age of onset is between three and seven years with an insidious clinical presentation and neurologic decline.
• Presenting symptoms can include generalized tremor, hypotonia, and mild-moderate developmental delays [
• Affected individuals can also develop ichthyosis, visual loss (although corneal clouding is rare), and behavioral abnormalities, and may have minor dysmorphic features (broad thumbs and index fingers) that frequently become more prominent with age [
• The oldest known person with the condition survived until the fourth decade of life [Author, personal communication].
• Individuals with juvenile MSD can retain the ability to walk into their teenage years.
## Clinical Features Common To All Subtypes
Many of the features found in MSD can be progressive, including the neurologic deterioration, heart disease, hearing loss, and airway compromise. The progressive nature of the disease is at least in part due to the accumulation of glycosaminoglycans (GAGs) and other substrates, including sulfatides.
Developmental delay and progressive neurologic deterioration, including long track signs (spasticity)
Ataxia
Autistic features
Epilepsy [
Microcephaly [
Short stature
Irregular ribs (typically paddle-shaped with widening anteriorly and tapering posteriorly) associated with dysostosis multiplex
Scoliosis and/or kyphosis
Vertebral abnormalities, including odontoid dysplasia, atlanto-axial instability, cervical spinal canal stenosis, and vertebral body abnormalities (wedge-shaped vertebral bodies, anterior beaking with posterior scalloping, and platyspondyly)
Vertebral instability and risk of spinal cord compression, which can be dangerous with neck hyperextension (such as occurs during intubation)
Short metacarpals
Joint stiffness and contractures, which may pose a prominent issue that can impede mobility [
Broad thumbs and toes [
Glaucoma
Strabismus
Retinal degeneration
Corneal clouding
Cataracts
Retinitis pigmentosa [
Myopia
Cerebral atrophy and/or cerebellar atrophy
Abnormalities of the corpus callosum
Dilatation of the ventricular system
Prominence of the sulci
Enlarged perivascular spaces
Cervical cord compression
Delayed myelination
• Developmental delay and progressive neurologic deterioration, including long track signs (spasticity)
• Ataxia
• Autistic features
• Epilepsy [
• Microcephaly [
• Short stature
• Irregular ribs (typically paddle-shaped with widening anteriorly and tapering posteriorly) associated with dysostosis multiplex
• Scoliosis and/or kyphosis
• Vertebral abnormalities, including odontoid dysplasia, atlanto-axial instability, cervical spinal canal stenosis, and vertebral body abnormalities (wedge-shaped vertebral bodies, anterior beaking with posterior scalloping, and platyspondyly)
• Vertebral instability and risk of spinal cord compression, which can be dangerous with neck hyperextension (such as occurs during intubation)
• Short metacarpals
• Joint stiffness and contractures, which may pose a prominent issue that can impede mobility [
• Broad thumbs and toes [
• Glaucoma
• Strabismus
• Retinal degeneration
• Corneal clouding
• Cataracts
• Retinitis pigmentosa [
• Myopia
• Cerebral atrophy and/or cerebellar atrophy
• Abnormalities of the corpus callosum
• Dilatation of the ventricular system
• Prominence of the sulci
• Enlarged perivascular spaces
• Cervical cord compression
• Delayed myelination
## Pathophysiology
The wide clinical spectrum seen in MSD is largely a function of the unique pathophysiology of this condition, as multiple pathways are affected by a common enzymatic defect. All known 17 human sulfatases may be affected; thus, the clinical presentation is a composite of the effects of each individual sulfatase deficiency [
## Genotype-Phenotype Correlations
Sulfatase-modifying-factor-1 (SUMF1) protein stability and residual formylglycine-generating enzyme (FGE) activity influence the clinical presentation in individuals with pathogenic changes in
For a small subset of pathogenic missense variants, experimental evidence for residual SUMF1 activity and FGE stability has been published and specific genotype-phenotype correlations exist.
Homozygosity for the p.Gly263Val or p.Ala279Val
Homozygosity for the p.Ser155Pro, p.Gly247Arg, or p.Arg349Trp
Non-experimental prediction methods attempting to correlate a particular
• Homozygosity for the p.Gly263Val or p.Ala279Val
• Homozygosity for the p.Ser155Pro, p.Gly247Arg, or p.Arg349Trp
## Nomenclature
Other terms used to describe MSD are Austin disease (named after Dr James Austin, who first described the condition [
## Prevalence
The estimated prevalence of MSD is one in 1.4 million individuals. There have been approximately 75-100 cases reported to date [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of Multiple Sulfatase Deficiency (MSD)
AD = autosomal dominant, AR = autosomal recessive, MOI = mode of inheritance: XL = X-linked; DD = developmental delay; ID = intellectual disability; MPS = mucopolysaccharidosis
Severe or attenuated MPS I; Note: while individuals with MPS I have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap; thus, affected individuals are best described as having either severe or attenuated MPS I.
Cherry red spot of the fovea is not a typical finding in MSD.
Cherry red spot and increased startle response are not typical findings in MSD.
## Management
To establish the extent of disease and needs in an individual diagnosed with multiple sulfatase deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Multiple Sulfatase Deficiency
To assess for hydrocephalus w/↑ intracranial pressure
Consider urgent head imaging for any rapid neurologic changes.
To assess for spine instability or stenosis leading to cord compression
Consultation w/neurosurgeon as indicated
DXA = dual-energy x-ray absorptiometry; GAGs = glycosaminoglycans
Measurement of serum AST, ALT, and GGT
A detailed clinical management guide was recently published delineating a symptomatic management strategy [
While there are no targeted therapeutic options to date, many complications are amenable to symptomatic management [
Treatment of Manifestations in Individuals with Multiple Sulfatase Deficiency
G = gastrostomy; NG = nasogastric; PFTs = pulmonary function tests
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
See
No definitive surveillance guidelines have been established, although particular attention to and monitoring of the cardiac, respiratory, ophthalmologic, neurologic, skeletal, and gastroenterologic systems is indicated [
Surveillance to Consider for Individuals with Multiple Sulfatase Deficiency
PFT = pulmonary function test
To screen for progressive hydrocephalus and/or cord compression
To monitor bone health
To monitor for cardiac hypertrophy, progressive valvular abnormalities, arrhythmia, and hypertension
With special attention to the liver, gallbladder, and spleen
Individuals should avoid neck hyperextension, including hyperextension used for intubation, because of the risk of spinal cord compression. Foods that are choking hazards should also be avoided.
See
A multi-institutional natural history study is underway through the Myelin Disorders Biorepository Project (Clinical Trials Identifier:
Search
• To assess for hydrocephalus w/↑ intracranial pressure
• Consider urgent head imaging for any rapid neurologic changes.
• To assess for spine instability or stenosis leading to cord compression
• Consultation w/neurosurgeon as indicated
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with multiple sulfatase deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Multiple Sulfatase Deficiency
To assess for hydrocephalus w/↑ intracranial pressure
Consider urgent head imaging for any rapid neurologic changes.
To assess for spine instability or stenosis leading to cord compression
Consultation w/neurosurgeon as indicated
DXA = dual-energy x-ray absorptiometry; GAGs = glycosaminoglycans
Measurement of serum AST, ALT, and GGT
• To assess for hydrocephalus w/↑ intracranial pressure
• Consider urgent head imaging for any rapid neurologic changes.
• To assess for spine instability or stenosis leading to cord compression
• Consultation w/neurosurgeon as indicated
## Treatment of Manifestations
A detailed clinical management guide was recently published delineating a symptomatic management strategy [
While there are no targeted therapeutic options to date, many complications are amenable to symptomatic management [
Treatment of Manifestations in Individuals with Multiple Sulfatase Deficiency
G = gastrostomy; NG = nasogastric; PFTs = pulmonary function tests
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
See
## Surveillance
No definitive surveillance guidelines have been established, although particular attention to and monitoring of the cardiac, respiratory, ophthalmologic, neurologic, skeletal, and gastroenterologic systems is indicated [
Surveillance to Consider for Individuals with Multiple Sulfatase Deficiency
PFT = pulmonary function test
To screen for progressive hydrocephalus and/or cord compression
To monitor bone health
To monitor for cardiac hypertrophy, progressive valvular abnormalities, arrhythmia, and hypertension
With special attention to the liver, gallbladder, and spleen
## Agents/Circumstances to Avoid
Individuals should avoid neck hyperextension, including hyperextension used for intubation, because of the risk of spinal cord compression. Foods that are choking hazards should also be avoided.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
A multi-institutional natural history study is underway through the Myelin Disorders Biorepository Project (Clinical Trials Identifier:
Search
## Genetic Counseling
Multiple sulfatase deficiency is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
Multiple sulfatase deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier (Heterozygote) Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Grattan Lodge
Dublin
Ireland
United Kingdom
United Kingdom
•
• Grattan Lodge
• Dublin
• Ireland
•
•
•
•
• United Kingdom
•
•
• United Kingdom
•
## Molecular Genetics
Multiple Sulfatase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Multiple Sulfatase Deficiency (
Multiple sulfatase deficiency (MSD) is the result of a defect of the post-translational modification of cellular sulfatases. Sulfatases are a group of enzymes necessary for the breakdown of sulfate residues on macromolecules in cells (e.g., sulfatides, glycosaminoglycans, transcription factors). All newly synthesized sulfatases require activation by formylglycine-generating enzyme (FGE), encoded by
See
Variants listed in the table have been provided by the authors.
FGE recognizes newly synthesized sulfatases via an amino acid motif (CXPSR) that is present in all sulfatases. FGE oxidizes the cysteine to an aldehyde, C-alpha-formylglycine,which is indispensable for sulfatase catalytic function [
A minority of FGE protein pathogenic variants alter regulation by the ER quality-control process, protein-disulfide-isomerase (PDI). These variants result in an abnormal arrangement of intramolecular stabilizing disulfide bridges; PDI recognizes the misfolded FGE and induces early degradation [
Both the
## Molecular Pathogenesis
Multiple sulfatase deficiency (MSD) is the result of a defect of the post-translational modification of cellular sulfatases. Sulfatases are a group of enzymes necessary for the breakdown of sulfate residues on macromolecules in cells (e.g., sulfatides, glycosaminoglycans, transcription factors). All newly synthesized sulfatases require activation by formylglycine-generating enzyme (FGE), encoded by
See
Variants listed in the table have been provided by the authors.
FGE recognizes newly synthesized sulfatases via an amino acid motif (CXPSR) that is present in all sulfatases. FGE oxidizes the cysteine to an aldehyde, C-alpha-formylglycine,which is indispensable for sulfatase catalytic function [
A minority of FGE protein pathogenic variants alter regulation by the ER quality-control process, protein-disulfide-isomerase (PDI). These variants result in an abnormal arrangement of intramolecular stabilizing disulfide bridges; PDI recognizes the misfolded FGE and induces early degradation [
Both the
## Chapter Notes
21 March 2019 (ma) Review posted live
27 August 2018 (ran) Original submission
• 21 March 2019 (ma) Review posted live
• 27 August 2018 (ran) Original submission
## Revision History
21 March 2019 (ma) Review posted live
27 August 2018 (ran) Original submission
• 21 March 2019 (ma) Review posted live
• 27 August 2018 (ran) Original submission
## References
## Literature Cited
|
[
"LA Adang, O Sherbini, L Ball, M Bloom, A Darbari, H Amartino, D DiVito, F Eichler, M Escolar, SH Evans, A Fatemi, J Fraser, L Hollowell, N Jaffe, C Joseph, M Karpinski, S Keller, R Maddock, E Mancilla, B McClary, J Mertz, K Morgart, T Langan, R Leventer, S Parikh, A Pizzino, E Prange, DL Renaud, W Rizzo, J Shapiro, D Suhr, T Suhr, D Tonduti, J Waggoner, A Waldman, NI Wolf, A Zerem, JL Bonkowsky, G Bernard, K van Haren, A Vanderver. Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies.. Mol Genet Metab. 2017;122:18-32",
"R Ahrens-Nicklas, L Schlotawa, A Ballabio, N Brunetti-Pierri, M De Castro, T Dierks, F Eichler, C Ficicioglu, A Finglas, J Gaertner, B Kirmse, J Klepper, M Lee, A Olsen, G Parenti, A Vossough, A Vanderver, LA Adang. Complex care of individuals with multiple sulfatase deficiency: Clinical cases and consensus statement.. Mol Genet Metab. 2018;123:337-46",
"OA Artigalás, LR da Silva, M Burin, GM Pastores, B Zeng, N Macedo, IV Schwartz. Multiple sulfatase deficiency: clinical report and description of two novel mutations in a Brazilian patient.. Metab Brain Dis. 2009;24:493-500",
"J Austin, D McAfee, D Armstrong, M O'Rourke, L Shearer, B Bachhawat. Abnormal sulphatase activities in two human diseases (metachromatic leucodystrophy and gargoylism).. Biochem J. 1964;93:15C-17C",
"ME Blanco-Aguirre, SH Kofman-Alfaro, MR Rivera-Vega, C Medina, M Valdes-Flores, WB Rizzo, SA Cuevas-Covarrubias. Unusual clinical presentation in two cases of multiple sulfatase deficiency.. Pediatr Dermatol. 2001;18:388-92",
"EA Braunlin, PR Harmatz, M Scarpa, B Furlanetto, C Kampmann, JP Loehr, KP Ponder, WC Roberts, HM Rosenfeld, R Giugliani. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management.. J Inherit Metab Dis. 2011;34:1183-97",
"M Burch, AH Fensom, M Jackson, T Pitts-Tucker, PJ Congdon. Multiple sulphatase deficiency presenting at birth.. Clinical Genet. 1986;30:409-15",
"RD Burk, D Valle, GH Thomas, C Miller, A Moser, H Moser, KN Rosenbaum. Early manifestations of multiple sulfatase deficiency.. J Pediatr. 1984;104:574-8",
"A Busche, JB Hennermann, F Bürger, H Proquitté, T Dierks, A von Arnim-Baas, D Horn. Neonatal manifestation of multiple sulfatase deficiency.. Eur J Pediatr. 2009;168:969-73",
"H Church, K Brammeier, J Petty, C Egerton, J Righart, L Heptinstall, S Jones, KL Tylee. How many sulphatase deficiencies become multiple: An unusual presentation of multiple sulphatase deficiency.. Lysosome. 2018;123:S32",
"MP Cosma, S Pepe, G Parenti, C Settembre, I Annunziata, R Wade-Martins, C Di Domenico, P Di Natale, A Mankad, B Cox, G Uziel, GM Mancini, E Zammarchi, MA Donati, WJ Kleijer, M Filocamo, R Carrozzo, M Carella, A Ballabio. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency.. Hum Mutat. 2004;23:576-81",
"T Dierks, A Dickmanns, A Preusser-Kunze, B Schmidt, M Mariappan, K von Figura, R Ficner, MG Rudolph. Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme.. Cell. 2005;121:541-52",
"T Dierks, L Schlotawa, MA Frese, K Radhakrishnan, K von Figura, B Schmidt. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann–Pick C1 disease — Lysosomal storage disorders caused by defects of non-lysosomal proteins.. Biochim Biophys Acta. 2009;1793:710-25",
"T Dierks, B Schmidt, LV Borissenko, J Peng, A Preusser, M Mariappan, K von Figura. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme.. Cell. 2003;113:435-44",
"Y Eto, I Gomibuchi, F Umezawa, T Tsuda. Pathochemistry, pathogenesis and enzyme replacement in multiple-sulfatase deficiency.. Enzyme. 1987;38:273-9",
"A Fraldi, E Zito, F Annunziata, A Lombardi, M Cozzolino, M Monti, C Spampanato, A Ballabio, P Pucci, R Sitia, MP Cosma. Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44.. Hum Mol Genet. 2008;17:2610-21",
"L Garavelli, L Santoro, A Iori, G Gargano, S Braibanti, S Pedori, N Melli, D Frattini, L Zampini, T Galeazzi, L Padella, S Pepe, A Wischmeijer, S Rosato, I Ivanovski, L Iughetti, C Gelmini, S Bernasconi, A Superti-Furga, A Ballabio, O. Gabrielli. Multiple sulfatase deficiency with neonatal manifestation.. Ital J Pediatr. 2014;40:86",
"WF Guerra, MA Verity, AL Fluharty, HT Nguyen, M Philippart. Multiple sulfatase deficiency: clinical, neuropathological, ultrastructural and biochemical studies.. J Neuropathol Exp Neurol. 1990;49:406-23",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"F Incecik, OM Herguner. Hydrocephalus as a rare clinical symptom in a child with multiple sulfatase deficiency.. Acta Neurol Belg. 2017;117:779-80",
"F Incecik, MN Ozbek, S Gungor, S Pepe, OM Herguner, NO Mungan, S Gungor, S Altunbasak. Multiple sulfatase deficiency: A case series of four children.. Annals of Indian Academy of Neurology. 2013;16:720-2",
"I Jaszczuk, L Schlotawa, T Dierks, A Ohlenbusch, D Koppenhöfer, M Babicz, M Lejman, K Radhakrishnan, A Ługowska. Expanding the genetic cause of multiple sulfatase deficiency: A novel SUMF1 variant in a patient displaying a severe late infantile form of the disease.. Mol Genet Metab. 2017;121:252-8",
"S Khateb, B Kowalewski, N Bedoni, M Damme, N Pollack, A Saada, A Obolensky, T Ben-Yosef, M Gross, T Dierks, E Banin, C Rivolta, D. Sharon. A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans.. Genet Med. 2018;20:1004-12",
"J Landgrebe, T Dierks, B Schmidt, K. von Figura. The human SUMF1 gene, required for posttranslational sulfatase modification, defines a new gene family which is conserved from pro- to eukaryotes.. Gene. 2003;316:47-56",
"L Lorioli, MP Cicalese, P Silvani, A Assanelli, I Salvo, A Mandelli, F Fumagalli, R Fiori, F Ciceri, A Aiuti, M Sessa, MG Roncarolo, C Lanzani, A Biffi. Abnormalities of acid-base balance and predisposition to metabolic acidosis in metachromatic leukodystrophy patients.. Mol Genet Metab. 2015;115:48-52",
"M Mariappan, SL Gande, K Radhakrishnan, B Schmidt, T Dierks, K von Figura. The non-catalytic N-terminal extension of formylglycine-generating enzyme is required for its biological activity and retention in the endoplasmic reticulum.. J Biol Chem. 2008a;283:11556-64",
"M Mariappan, K Radhakrishnan, T Dierks, B Schmidt, K. von Figura. ERp44 mediates a thiol-independent retention of formylglycine-generating enzyme in the endoplasmic reticulum.. J Biol Chem. 2008b;283:6375-83",
"Y Meng, WM Zhang, HP Shi, FX Yao, ZQ Qiu, T Yang, SM Zhao, SZ Huang. Clinical characterization and mutation identification for multiple sulfatase deficiency patients in China.. Zhonghua Er Ke Za Zhi 2013;51:836-41",
"D Meshach Paul, T Chadah, B Senthilkumar, R Sethumadhavan, R. Rajasekaran. Structural distortions due to missense mutations in human formylglycine-generating enzyme leading to multiple sulfatase deficiency.. J Biomol Struct Dyn. 2018;36:3575-85",
"C Miskin, JJ Melvin, A Legido, DA Wenger, SM Harasink, DS Khurana. A patient with atypical multiple sulfatase deficiency.. Pediatr Neurol. 2016;57:98-100",
"C Prasad, CA Rupar, C Campbell, M Napier, D Ramsay, KY Tay, S Sharan, AN Prasad. Case of multiple sulfatase deficiency and ocular albinism: a diagnostic odyssey.. Can J Neurol Sci. 2014;41:626-31",
"A Preusser-Kunze, M Mariappan, B Schmidt, SL Gande, K Mutenda, D Wenzel, K von Figura, T Dierks. Molecular characterization of the human Cα-formylglycine-generating enzyme.. J Biol Chem. 2005;280:14900-10",
"F Sabourdy, L Mourey, E Le Trionnaire, N Bednarek, C Caillaud, Y Chaix, MA Delrue, A Dusser, R Froissart, R Garnotel, N Guffon, A Megarbane, H Ogier de Baulny, JM Pédespan, S Pichard, V Valayannopoulos, A Verloes, T Levade. Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency.. Orphanet J Rare Dis. 2015;10:31",
"RP Santos, JJ Hoo. Difficulty in recognizing multiple sulfatase deficiency in an infant.. Pediatrics. 2006;117:955-8",
"M Sardiello, I Annunziata, G Roma, A Ballabio. Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship.. Hum Mol Genet. 2005;14:3203-17",
"L Schlotawa, EC Ennemann, K Radhakrishnan, B Schmidt, A Chakrapani, HJ Christen, H Moser, B Steinmann, T Dierks, J Gärtner. SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency.. Eur J Hum Genet. 2011;19:253-61",
"L Schlotawa, R Steinfeld, K von Figura, T Dierks, J. Gärtner. Molecular analysis of SUMF1 mutations: stability and residual activity of mutant formylglycine-generating enzyme determine disease severity in multiple sulfatase deficiency.. Hum Mutat. 2008;29:205",
"L Schlotawa, M Wachs, O Bernhard, FJ Mayer, T Dierks, B Schmidt, K Radhakrishnan. Recognition and ER quality control of misfolded formylglycine-generating enzyme by protein disulfide isomerase.. Cell Rep. 2018;24:27-37.e4",
"C Settembre, A Fraldi, L Jahreiss, C Spampanato, C Venturi, D Medina, R de Pablo, C Tacchetti, DC Rubinsztein, A Ballabio. A block of autophagy in lysosomal storage disorders.. Hum Mol Genet. 2008;17:119-29",
"U Zilberman, H Bibi. The effect of multiple sulfatase deficiency (MSD) on dental development: can we use the teeth as an early diagnostic tool?. JIMD Rep. 2016;30:95-101"
] |
21/3/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
madd
|
madd
|
[
"Electron Transfer Flavoprotein Dehydrogenase Deficiency",
"Glutaric Acidemia II",
"Glutaric Aciduria II",
"MADD",
"MADD",
"Glutaric Acidemia II",
"Glutaric Aciduria II",
"Electron Transfer Flavoprotein Dehydrogenase Deficiency",
"Electron transfer flavoprotein subunit alpha, mitochondrial",
"Electron transfer flavoprotein subunit beta",
"Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial",
"ETFA",
"ETFB",
"ETFDH",
"Multiple Acyl-CoA Dehydrogenase Deficiency"
] |
Multiple Acyl-CoA Dehydrogenase Deficiency
|
Pankaj Prasun
|
Summary Multiple acyl-CoA dehydrogenase deficiency (MADD) represents a clinical spectrum in which presentations can be divided into type I (neonatal onset with congenital anomalies), type II (neonatal onset without congenital anomalies), and type III (late onset). Individuals with type I or II MADD typically become symptomatic in the neonatal period with severe metabolic acidosis, which may be accompanied by profound hypoglycemia and hyperammonemia. Many affected individuals die in the newborn period despite metabolic treatment. In those who survive the neonatal period, recurrent metabolic decompensation resembling Reye syndrome and the development of hypertrophic cardiomyopathy can occur. Congenital anomalies may include dysmorphic facial features, large cystic kidneys, hypospadias and chordee in males, and neuronal migration defects (heterotopias) on brain MRI. Individuals with type III MADD, the most common presentation, can present from infancy to adulthood. The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain, although metabolic decompensation with episodes of rhabdomyolysis can also be seen. Rarely, individuals with late-onset MADD (type III) may develop severe sensory neuropathy in addition to proximal myopathy. The diagnosis of MADD is established in a proband with elevation of several acylcarnitine species in blood in combination with increased excretion of multiple organic acids in urine and/or by identification of biallelic pathogenic variants in MADD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% change of being affected, a 50% chance of being unaffected and a carrier, and a 25% change of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.
|
## Diagnosis
Formal clinical diagnostic criteria for multiple acyl-CoA dehydrogenase deficiency (MADD) have not been established.
NBS for MADD is primarily based on quantification of the analytes C4, C5, and C8 with or without other higher acylcarnitine species on dried blood spots.
Multiple acylcarnitine species (C4, C5, C8, and other higher acylcarnitine) values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, including plasma acylcarnitine and urine organic acid profiles (see
If follow-up biochemical testing supports the likelihood of MADD, additional testing is required to establish the diagnosis (see
Medical interventions (see
Note: The most severe neonatal-onset form of MADD presents in the newborn period despite initiation of treatment. A newborn may become symptomatic before NBS is sent or resulted.
Supportive – but often nonspecific –
Encephalopathy
Tachypnea
Hepatomegaly
Hypotonia
Neonatal-onset form can present with or without congenital anomalies. When present, the main congenital anomalies are:
Dysmorphic facial features (See
Dysplastic kidneys
Rocker-bottom feet
Hypospadias with or without chordee in males
Episodic vomiting with hypoglycemia and metabolic acidosis
Muscle weakness and/or exercise intolerance
Reye syndrome-like illness
Rhabdomyolysis
Acute respiratory failure
Hypoglycemia (nonketotic or hypoketotic) with blood glucose often less than 45 mg/dL
Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia
Metabolic acidosis
Hyperammonemia; blood ammonia level may be more than 200 µmol/L in newborns and more than 100 µmol/L after the neonatal period.
Elevated liver transaminases (AST, ALT)
Elevated creatine kinase (CK), particularly in the late-onset myopathic form
A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
Lactic acid
Glutaric acid
2-hydroxyglutaric acid
2-hydroxybutyric acid
2-hydroxyisocaproic acid
3-hydroxyisovaleric acid
5-hydroxyhexanoic acid
Ethylmalonic acid
Adipic acid
Suberic acid
Sebacic acid
Other dicarboxylic acids
Isobutyrylglycine
Isovalerylglycine
Hexanoylglycine
Suberylglycine
Note: Because elevations of these metabolites individually are not entirely specific to MADD and can be intermittent, follow-up testing is required to establish the diagnosis of MADD (see
MRI of affected muscle group typically shows fatty infiltration and edema [
Muscle biopsy outside an episode of rhabdomyolysis, in the late-onset form with myopathic presentation, shows extramitochondrial lipid accumulation characteristic of lipid storage myopathy, which may be accompanied by coenzyme Q
Diminished activity of mitochondrial respiratory chain complexes has also been reported [
Note: Muscle imaging, biopsy, and enzymology are not required to establish the diagnosis of MADD.
The diagnosis of MADD
Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Perform sequence analysis of
Perform sequence analysis of
Lastly, perform sequence analysis of the remaining gene
For an introduction to multigene panels click
For a symptomatic individual who has findings associated with late-onset MADD OR neonatal-onset MADD that has not been treated (because symptoms occurred before NBS results were returned, NBS was not performed, or NBS yielded a false negative result), molecular genetic testing approaches can include
When the diagnosis of MADD has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multiple Acyl-CoA Dehydrogenase Deficiency
Genes are listed in alphabetic order.
See
See
Of note, many studies of
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Although sequence analysis is sensitive in detecting the pathogenic variants mentioned here, it is important to remember that often only one pathogenic variant is detected, suggesting deep intronic or promoter region variants. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The proportion of pathogenic variants listed here are specific for late-onset variant MADD (type III) (see also
A deletion of exon 11 has been reported [
A 312-bp deletion and two multiexon deletions have been reported [
Sometimes no pathogenic variant is found after sequencing all three genes, which may indicate other unidentified genetic etiologies for MADD.
• Encephalopathy
• Tachypnea
• Hepatomegaly
• Hypotonia
• Dysmorphic facial features (See
• Dysplastic kidneys
• Rocker-bottom feet
• Hypospadias with or without chordee in males
• Episodic vomiting with hypoglycemia and metabolic acidosis
• Muscle weakness and/or exercise intolerance
• Reye syndrome-like illness
• Rhabdomyolysis
• Acute respiratory failure
• Hypoglycemia (nonketotic or hypoketotic) with blood glucose often less than 45 mg/dL
• Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia
• Metabolic acidosis
• Hyperammonemia; blood ammonia level may be more than 200 µmol/L in newborns and more than 100 µmol/L after the neonatal period.
• Elevated liver transaminases (AST, ALT)
• Elevated creatine kinase (CK), particularly in the late-onset myopathic form
• A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
• A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
• A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
• A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
• A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
• A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
• Lactic acid
• Glutaric acid
• 2-hydroxyglutaric acid
• 2-hydroxybutyric acid
• 2-hydroxyisocaproic acid
• 3-hydroxyisovaleric acid
• 5-hydroxyhexanoic acid
• Ethylmalonic acid
• Adipic acid
• Suberic acid
• Sebacic acid
• Other dicarboxylic acids
• Lactic acid
• Glutaric acid
• 2-hydroxyglutaric acid
• 2-hydroxybutyric acid
• 2-hydroxyisocaproic acid
• 3-hydroxyisovaleric acid
• 5-hydroxyhexanoic acid
• Ethylmalonic acid
• Adipic acid
• Suberic acid
• Sebacic acid
• Other dicarboxylic acids
• Isobutyrylglycine
• Isovalerylglycine
• Hexanoylglycine
• Suberylglycine
• Isobutyrylglycine
• Isovalerylglycine
• Hexanoylglycine
• Suberylglycine
• Lactic acid
• Glutaric acid
• 2-hydroxyglutaric acid
• 2-hydroxybutyric acid
• 2-hydroxyisocaproic acid
• 3-hydroxyisovaleric acid
• 5-hydroxyhexanoic acid
• Ethylmalonic acid
• Adipic acid
• Suberic acid
• Sebacic acid
• Other dicarboxylic acids
• Isobutyrylglycine
• Isovalerylglycine
• Hexanoylglycine
• Suberylglycine
• MRI of affected muscle group typically shows fatty infiltration and edema [
• Muscle biopsy outside an episode of rhabdomyolysis, in the late-onset form with myopathic presentation, shows extramitochondrial lipid accumulation characteristic of lipid storage myopathy, which may be accompanied by coenzyme Q
• Diminished activity of mitochondrial respiratory chain complexes has also been reported [
• Perform sequence analysis of
• Perform sequence analysis of
• Lastly, perform sequence analysis of the remaining gene
• Perform sequence analysis of
• Perform sequence analysis of
• Lastly, perform sequence analysis of the remaining gene
• For an introduction to multigene panels click
• Perform sequence analysis of
• Perform sequence analysis of
• Lastly, perform sequence analysis of the remaining gene
• For a symptomatic individual who has findings associated with late-onset MADD OR neonatal-onset MADD that has not been treated (because symptoms occurred before NBS results were returned, NBS was not performed, or NBS yielded a false negative result), molecular genetic testing approaches can include
• When the diagnosis of MADD has not been considered,
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
NBS for MADD is primarily based on quantification of the analytes C4, C5, and C8 with or without other higher acylcarnitine species on dried blood spots.
Multiple acylcarnitine species (C4, C5, C8, and other higher acylcarnitine) values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, including plasma acylcarnitine and urine organic acid profiles (see
If follow-up biochemical testing supports the likelihood of MADD, additional testing is required to establish the diagnosis (see
Medical interventions (see
Note: The most severe neonatal-onset form of MADD presents in the newborn period despite initiation of treatment. A newborn may become symptomatic before NBS is sent or resulted.
Supportive – but often nonspecific –
Encephalopathy
Tachypnea
Hepatomegaly
Hypotonia
Neonatal-onset form can present with or without congenital anomalies. When present, the main congenital anomalies are:
Dysmorphic facial features (See
Dysplastic kidneys
Rocker-bottom feet
Hypospadias with or without chordee in males
Episodic vomiting with hypoglycemia and metabolic acidosis
Muscle weakness and/or exercise intolerance
Reye syndrome-like illness
Rhabdomyolysis
Acute respiratory failure
Hypoglycemia (nonketotic or hypoketotic) with blood glucose often less than 45 mg/dL
Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia
Metabolic acidosis
Hyperammonemia; blood ammonia level may be more than 200 µmol/L in newborns and more than 100 µmol/L after the neonatal period.
Elevated liver transaminases (AST, ALT)
Elevated creatine kinase (CK), particularly in the late-onset myopathic form
A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
Lactic acid
Glutaric acid
2-hydroxyglutaric acid
2-hydroxybutyric acid
2-hydroxyisocaproic acid
3-hydroxyisovaleric acid
5-hydroxyhexanoic acid
Ethylmalonic acid
Adipic acid
Suberic acid
Sebacic acid
Other dicarboxylic acids
Isobutyrylglycine
Isovalerylglycine
Hexanoylglycine
Suberylglycine
Note: Because elevations of these metabolites individually are not entirely specific to MADD and can be intermittent, follow-up testing is required to establish the diagnosis of MADD (see
MRI of affected muscle group typically shows fatty infiltration and edema [
Muscle biopsy outside an episode of rhabdomyolysis, in the late-onset form with myopathic presentation, shows extramitochondrial lipid accumulation characteristic of lipid storage myopathy, which may be accompanied by coenzyme Q
Diminished activity of mitochondrial respiratory chain complexes has also been reported [
Note: Muscle imaging, biopsy, and enzymology are not required to establish the diagnosis of MADD.
• Encephalopathy
• Tachypnea
• Hepatomegaly
• Hypotonia
• Dysmorphic facial features (See
• Dysplastic kidneys
• Rocker-bottom feet
• Hypospadias with or without chordee in males
• Episodic vomiting with hypoglycemia and metabolic acidosis
• Muscle weakness and/or exercise intolerance
• Reye syndrome-like illness
• Rhabdomyolysis
• Acute respiratory failure
• Hypoglycemia (nonketotic or hypoketotic) with blood glucose often less than 45 mg/dL
• Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia
• Metabolic acidosis
• Hyperammonemia; blood ammonia level may be more than 200 µmol/L in newborns and more than 100 µmol/L after the neonatal period.
• Elevated liver transaminases (AST, ALT)
• Elevated creatine kinase (CK), particularly in the late-onset myopathic form
• A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
• A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
• A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
• A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
• A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
• A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
• Lactic acid
• Glutaric acid
• 2-hydroxyglutaric acid
• 2-hydroxybutyric acid
• 2-hydroxyisocaproic acid
• 3-hydroxyisovaleric acid
• 5-hydroxyhexanoic acid
• Ethylmalonic acid
• Adipic acid
• Suberic acid
• Sebacic acid
• Other dicarboxylic acids
• Lactic acid
• Glutaric acid
• 2-hydroxyglutaric acid
• 2-hydroxybutyric acid
• 2-hydroxyisocaproic acid
• 3-hydroxyisovaleric acid
• 5-hydroxyhexanoic acid
• Ethylmalonic acid
• Adipic acid
• Suberic acid
• Sebacic acid
• Other dicarboxylic acids
• Isobutyrylglycine
• Isovalerylglycine
• Hexanoylglycine
• Suberylglycine
• Isobutyrylglycine
• Isovalerylglycine
• Hexanoylglycine
• Suberylglycine
• Lactic acid
• Glutaric acid
• 2-hydroxyglutaric acid
• 2-hydroxybutyric acid
• 2-hydroxyisocaproic acid
• 3-hydroxyisovaleric acid
• 5-hydroxyhexanoic acid
• Ethylmalonic acid
• Adipic acid
• Suberic acid
• Sebacic acid
• Other dicarboxylic acids
• Isobutyrylglycine
• Isovalerylglycine
• Hexanoylglycine
• Suberylglycine
• MRI of affected muscle group typically shows fatty infiltration and edema [
• Muscle biopsy outside an episode of rhabdomyolysis, in the late-onset form with myopathic presentation, shows extramitochondrial lipid accumulation characteristic of lipid storage myopathy, which may be accompanied by coenzyme Q
• Diminished activity of mitochondrial respiratory chain complexes has also been reported [
## Scenario 1. Abnormal Newborn Screening (NBS) Result
NBS for MADD is primarily based on quantification of the analytes C4, C5, and C8 with or without other higher acylcarnitine species on dried blood spots.
Multiple acylcarnitine species (C4, C5, C8, and other higher acylcarnitine) values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, including plasma acylcarnitine and urine organic acid profiles (see
If follow-up biochemical testing supports the likelihood of MADD, additional testing is required to establish the diagnosis (see
Medical interventions (see
Note: The most severe neonatal-onset form of MADD presents in the newborn period despite initiation of treatment. A newborn may become symptomatic before NBS is sent or resulted.
## Scenario 2. Symptomatic Individual
Supportive – but often nonspecific –
## Clinical Findings
Encephalopathy
Tachypnea
Hepatomegaly
Hypotonia
Neonatal-onset form can present with or without congenital anomalies. When present, the main congenital anomalies are:
Dysmorphic facial features (See
Dysplastic kidneys
Rocker-bottom feet
Hypospadias with or without chordee in males
Episodic vomiting with hypoglycemia and metabolic acidosis
Muscle weakness and/or exercise intolerance
Reye syndrome-like illness
Rhabdomyolysis
Acute respiratory failure
• Encephalopathy
• Tachypnea
• Hepatomegaly
• Hypotonia
• Dysmorphic facial features (See
• Dysplastic kidneys
• Rocker-bottom feet
• Hypospadias with or without chordee in males
• Episodic vomiting with hypoglycemia and metabolic acidosis
• Muscle weakness and/or exercise intolerance
• Reye syndrome-like illness
• Rhabdomyolysis
• Acute respiratory failure
## Supportive Laboratory Findings
Hypoglycemia (nonketotic or hypoketotic) with blood glucose often less than 45 mg/dL
Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia
Metabolic acidosis
Hyperammonemia; blood ammonia level may be more than 200 µmol/L in newborns and more than 100 µmol/L after the neonatal period.
Elevated liver transaminases (AST, ALT)
Elevated creatine kinase (CK), particularly in the late-onset myopathic form
A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
Lactic acid
Glutaric acid
2-hydroxyglutaric acid
2-hydroxybutyric acid
2-hydroxyisocaproic acid
3-hydroxyisovaleric acid
5-hydroxyhexanoic acid
Ethylmalonic acid
Adipic acid
Suberic acid
Sebacic acid
Other dicarboxylic acids
Isobutyrylglycine
Isovalerylglycine
Hexanoylglycine
Suberylglycine
Note: Because elevations of these metabolites individually are not entirely specific to MADD and can be intermittent, follow-up testing is required to establish the diagnosis of MADD (see
• Hypoglycemia (nonketotic or hypoketotic) with blood glucose often less than 45 mg/dL
• Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia
• Metabolic acidosis
• Hyperammonemia; blood ammonia level may be more than 200 µmol/L in newborns and more than 100 µmol/L after the neonatal period.
• Elevated liver transaminases (AST, ALT)
• Elevated creatine kinase (CK), particularly in the late-onset myopathic form
• A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
• A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
• A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
• A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
• A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
• A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [
• Lactic acid
• Glutaric acid
• 2-hydroxyglutaric acid
• 2-hydroxybutyric acid
• 2-hydroxyisocaproic acid
• 3-hydroxyisovaleric acid
• 5-hydroxyhexanoic acid
• Ethylmalonic acid
• Adipic acid
• Suberic acid
• Sebacic acid
• Other dicarboxylic acids
• Lactic acid
• Glutaric acid
• 2-hydroxyglutaric acid
• 2-hydroxybutyric acid
• 2-hydroxyisocaproic acid
• 3-hydroxyisovaleric acid
• 5-hydroxyhexanoic acid
• Ethylmalonic acid
• Adipic acid
• Suberic acid
• Sebacic acid
• Other dicarboxylic acids
• Isobutyrylglycine
• Isovalerylglycine
• Hexanoylglycine
• Suberylglycine
• Isobutyrylglycine
• Isovalerylglycine
• Hexanoylglycine
• Suberylglycine
• Lactic acid
• Glutaric acid
• 2-hydroxyglutaric acid
• 2-hydroxybutyric acid
• 2-hydroxyisocaproic acid
• 3-hydroxyisovaleric acid
• 5-hydroxyhexanoic acid
• Ethylmalonic acid
• Adipic acid
• Suberic acid
• Sebacic acid
• Other dicarboxylic acids
• Isobutyrylglycine
• Isovalerylglycine
• Hexanoylglycine
• Suberylglycine
## Other Studies
MRI of affected muscle group typically shows fatty infiltration and edema [
Muscle biopsy outside an episode of rhabdomyolysis, in the late-onset form with myopathic presentation, shows extramitochondrial lipid accumulation characteristic of lipid storage myopathy, which may be accompanied by coenzyme Q
Diminished activity of mitochondrial respiratory chain complexes has also been reported [
Note: Muscle imaging, biopsy, and enzymology are not required to establish the diagnosis of MADD.
• MRI of affected muscle group typically shows fatty infiltration and edema [
• Muscle biopsy outside an episode of rhabdomyolysis, in the late-onset form with myopathic presentation, shows extramitochondrial lipid accumulation characteristic of lipid storage myopathy, which may be accompanied by coenzyme Q
• Diminished activity of mitochondrial respiratory chain complexes has also been reported [
## Establishing the Diagnosis
The diagnosis of MADD
Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Perform sequence analysis of
Perform sequence analysis of
Lastly, perform sequence analysis of the remaining gene
For an introduction to multigene panels click
For a symptomatic individual who has findings associated with late-onset MADD OR neonatal-onset MADD that has not been treated (because symptoms occurred before NBS results were returned, NBS was not performed, or NBS yielded a false negative result), molecular genetic testing approaches can include
When the diagnosis of MADD has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multiple Acyl-CoA Dehydrogenase Deficiency
Genes are listed in alphabetic order.
See
See
Of note, many studies of
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Although sequence analysis is sensitive in detecting the pathogenic variants mentioned here, it is important to remember that often only one pathogenic variant is detected, suggesting deep intronic or promoter region variants. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The proportion of pathogenic variants listed here are specific for late-onset variant MADD (type III) (see also
A deletion of exon 11 has been reported [
A 312-bp deletion and two multiexon deletions have been reported [
Sometimes no pathogenic variant is found after sequencing all three genes, which may indicate other unidentified genetic etiologies for MADD.
• Perform sequence analysis of
• Perform sequence analysis of
• Lastly, perform sequence analysis of the remaining gene
• Perform sequence analysis of
• Perform sequence analysis of
• Lastly, perform sequence analysis of the remaining gene
• For an introduction to multigene panels click
• Perform sequence analysis of
• Perform sequence analysis of
• Lastly, perform sequence analysis of the remaining gene
• For a symptomatic individual who has findings associated with late-onset MADD OR neonatal-onset MADD that has not been treated (because symptoms occurred before NBS results were returned, NBS was not performed, or NBS yielded a false negative result), molecular genetic testing approaches can include
• When the diagnosis of MADD has not been considered,
• For an introduction to comprehensive genomic testing click
## Molecular Genetic Testing Approaches
Perform sequence analysis of
Perform sequence analysis of
Lastly, perform sequence analysis of the remaining gene
For an introduction to multigene panels click
For a symptomatic individual who has findings associated with late-onset MADD OR neonatal-onset MADD that has not been treated (because symptoms occurred before NBS results were returned, NBS was not performed, or NBS yielded a false negative result), molecular genetic testing approaches can include
When the diagnosis of MADD has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multiple Acyl-CoA Dehydrogenase Deficiency
Genes are listed in alphabetic order.
See
See
Of note, many studies of
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Although sequence analysis is sensitive in detecting the pathogenic variants mentioned here, it is important to remember that often only one pathogenic variant is detected, suggesting deep intronic or promoter region variants. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The proportion of pathogenic variants listed here are specific for late-onset variant MADD (type III) (see also
A deletion of exon 11 has been reported [
A 312-bp deletion and two multiexon deletions have been reported [
Sometimes no pathogenic variant is found after sequencing all three genes, which may indicate other unidentified genetic etiologies for MADD.
• Perform sequence analysis of
• Perform sequence analysis of
• Lastly, perform sequence analysis of the remaining gene
• Perform sequence analysis of
• Perform sequence analysis of
• Lastly, perform sequence analysis of the remaining gene
• For an introduction to multigene panels click
• Perform sequence analysis of
• Perform sequence analysis of
• Lastly, perform sequence analysis of the remaining gene
• For a symptomatic individual who has findings associated with late-onset MADD OR neonatal-onset MADD that has not been treated (because symptoms occurred before NBS results were returned, NBS was not performed, or NBS yielded a false negative result), molecular genetic testing approaches can include
• When the diagnosis of MADD has not been considered,
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Multiple acyl-CoA dehydrogenase deficiency (MADD) represents a clinical spectrum in which individuals at the most severe end present with severe decompensation in the neonatal period either with or without congenital anomalies. Those on the milder end may present anytime beyond the neonatal period. They may present with metabolic decompensations when challenged by metabolic stressors, or with chronic symptoms of myopathy and exercise intolerance. Newborn screening (NBS) has enabled identification of asymptomatic newborns with late-onset forms. Early diagnosis and treatment may prevent complications in such cases. The clinical presentation can be divided into three categories according to severity – from most to least severe:
This group represents the most severe spectrum of MADD.
High anterior hairline
Wide nasal bridge
Short nose with anteverted nares and long philtrum
Tented upper lip
Midface retrusion
Low-set ears
Newborns usually present within a few days after birth with metabolic decompensation as described
This is the most common presentation. Signs and symptoms of late-onset MADD may become apparent any time from infancy to adulthood. In a cohort of 350 individuals with late-onset MADD, the mean age at diagnosis was 17.6 years with a range of 0.13 years to 69 years [
The most common myopathic presentation is progressive or fluctuating proximal myopathy. Weakness of neck muscles and masseter is also commonly seen [
Progressive weakness may involve respiratory muscles leading to acute or subacute respiratory failure [
Rapidly progressive proximal myopathy and respiratory failure may mimic Guillain-Barre syndrome (GBS) [
Electrophysiologic studies such as electromyography and nerve conduction velocity (NCV) are helpful in differentiating MADD from GBS, as these studies typically show evidence of peripheral nerve demyelination in GBS. However, further differentiation by plasma acylcarnitine profile and urine organic acid assay should be done promptly.
Individuals with MADD are at risk of developing rhabdomyolysis, which may manifest during the acute episode of metabolic decompensation [
Bent spine syndrome characterized by progressive forward flexion of the trunk caused by selective involvement of paravertebral muscles has also been reported [
Elevations of several acylcarnitine species in blood in combination with increased exertion of multiple organic acids in urine are highly suggestive of MADD, as summarized in
Genotype-phenotype correlation is seen in the three known genes that lead to MADD (
Biallelic pathogenic null variants or pathogenic variants that severely affect mRNA expression or stability and result in total lack of protein cause the most severe form of MADD (i.e., neonatal onset with congenital malformations [type I]).
Pathogenic variants that affect the active site and/or pathogenic splice site variants giving rise to very low residual enzyme activity more often lead to neonatal presentation without congenital anomalies (type II).
Affected individuals who have at least one pathogenic missense variant that does not affect the active site, mRNA expression, or mRNA stability typically have relatively high residual enzyme activity with resulting late onset and milder disease (type III).
MADD was first described in 1976 in an infant with nonketotic hypoglycemia, metabolic acidosis, and strong "sweaty feet" odor [
MADD is very rare. Exact prevalence is not known. Incidence at birth is estimated at 1:250,000 [
• High anterior hairline
• Wide nasal bridge
• Short nose with anteverted nares and long philtrum
• Tented upper lip
• Midface retrusion
• Low-set ears
• The most common myopathic presentation is progressive or fluctuating proximal myopathy. Weakness of neck muscles and masseter is also commonly seen [
• Progressive weakness may involve respiratory muscles leading to acute or subacute respiratory failure [
• Rapidly progressive proximal myopathy and respiratory failure may mimic Guillain-Barre syndrome (GBS) [
• Electrophysiologic studies such as electromyography and nerve conduction velocity (NCV) are helpful in differentiating MADD from GBS, as these studies typically show evidence of peripheral nerve demyelination in GBS. However, further differentiation by plasma acylcarnitine profile and urine organic acid assay should be done promptly.
• Individuals with MADD are at risk of developing rhabdomyolysis, which may manifest during the acute episode of metabolic decompensation [
• Bent spine syndrome characterized by progressive forward flexion of the trunk caused by selective involvement of paravertebral muscles has also been reported [
• Biallelic pathogenic null variants or pathogenic variants that severely affect mRNA expression or stability and result in total lack of protein cause the most severe form of MADD (i.e., neonatal onset with congenital malformations [type I]).
• Pathogenic variants that affect the active site and/or pathogenic splice site variants giving rise to very low residual enzyme activity more often lead to neonatal presentation without congenital anomalies (type II).
• Affected individuals who have at least one pathogenic missense variant that does not affect the active site, mRNA expression, or mRNA stability typically have relatively high residual enzyme activity with resulting late onset and milder disease (type III).
## Clinical Description
Multiple acyl-CoA dehydrogenase deficiency (MADD) represents a clinical spectrum in which individuals at the most severe end present with severe decompensation in the neonatal period either with or without congenital anomalies. Those on the milder end may present anytime beyond the neonatal period. They may present with metabolic decompensations when challenged by metabolic stressors, or with chronic symptoms of myopathy and exercise intolerance. Newborn screening (NBS) has enabled identification of asymptomatic newborns with late-onset forms. Early diagnosis and treatment may prevent complications in such cases. The clinical presentation can be divided into three categories according to severity – from most to least severe:
This group represents the most severe spectrum of MADD.
High anterior hairline
Wide nasal bridge
Short nose with anteverted nares and long philtrum
Tented upper lip
Midface retrusion
Low-set ears
Newborns usually present within a few days after birth with metabolic decompensation as described
This is the most common presentation. Signs and symptoms of late-onset MADD may become apparent any time from infancy to adulthood. In a cohort of 350 individuals with late-onset MADD, the mean age at diagnosis was 17.6 years with a range of 0.13 years to 69 years [
The most common myopathic presentation is progressive or fluctuating proximal myopathy. Weakness of neck muscles and masseter is also commonly seen [
Progressive weakness may involve respiratory muscles leading to acute or subacute respiratory failure [
Rapidly progressive proximal myopathy and respiratory failure may mimic Guillain-Barre syndrome (GBS) [
Electrophysiologic studies such as electromyography and nerve conduction velocity (NCV) are helpful in differentiating MADD from GBS, as these studies typically show evidence of peripheral nerve demyelination in GBS. However, further differentiation by plasma acylcarnitine profile and urine organic acid assay should be done promptly.
Individuals with MADD are at risk of developing rhabdomyolysis, which may manifest during the acute episode of metabolic decompensation [
Bent spine syndrome characterized by progressive forward flexion of the trunk caused by selective involvement of paravertebral muscles has also been reported [
Elevations of several acylcarnitine species in blood in combination with increased exertion of multiple organic acids in urine are highly suggestive of MADD, as summarized in
• High anterior hairline
• Wide nasal bridge
• Short nose with anteverted nares and long philtrum
• Tented upper lip
• Midface retrusion
• Low-set ears
• The most common myopathic presentation is progressive or fluctuating proximal myopathy. Weakness of neck muscles and masseter is also commonly seen [
• Progressive weakness may involve respiratory muscles leading to acute or subacute respiratory failure [
• Rapidly progressive proximal myopathy and respiratory failure may mimic Guillain-Barre syndrome (GBS) [
• Electrophysiologic studies such as electromyography and nerve conduction velocity (NCV) are helpful in differentiating MADD from GBS, as these studies typically show evidence of peripheral nerve demyelination in GBS. However, further differentiation by plasma acylcarnitine profile and urine organic acid assay should be done promptly.
• Individuals with MADD are at risk of developing rhabdomyolysis, which may manifest during the acute episode of metabolic decompensation [
• Bent spine syndrome characterized by progressive forward flexion of the trunk caused by selective involvement of paravertebral muscles has also been reported [
## Neonatal Onset with Congenital Anomalies (Type I)
This group represents the most severe spectrum of MADD.
High anterior hairline
Wide nasal bridge
Short nose with anteverted nares and long philtrum
Tented upper lip
Midface retrusion
Low-set ears
• High anterior hairline
• Wide nasal bridge
• Short nose with anteverted nares and long philtrum
• Tented upper lip
• Midface retrusion
• Low-set ears
## Neonatal Onset Without Congenital Anomalies (Type II)
Newborns usually present within a few days after birth with metabolic decompensation as described
## Late Onset (Type III)
This is the most common presentation. Signs and symptoms of late-onset MADD may become apparent any time from infancy to adulthood. In a cohort of 350 individuals with late-onset MADD, the mean age at diagnosis was 17.6 years with a range of 0.13 years to 69 years [
The most common myopathic presentation is progressive or fluctuating proximal myopathy. Weakness of neck muscles and masseter is also commonly seen [
Progressive weakness may involve respiratory muscles leading to acute or subacute respiratory failure [
Rapidly progressive proximal myopathy and respiratory failure may mimic Guillain-Barre syndrome (GBS) [
Electrophysiologic studies such as electromyography and nerve conduction velocity (NCV) are helpful in differentiating MADD from GBS, as these studies typically show evidence of peripheral nerve demyelination in GBS. However, further differentiation by plasma acylcarnitine profile and urine organic acid assay should be done promptly.
Individuals with MADD are at risk of developing rhabdomyolysis, which may manifest during the acute episode of metabolic decompensation [
Bent spine syndrome characterized by progressive forward flexion of the trunk caused by selective involvement of paravertebral muscles has also been reported [
• The most common myopathic presentation is progressive or fluctuating proximal myopathy. Weakness of neck muscles and masseter is also commonly seen [
• Progressive weakness may involve respiratory muscles leading to acute or subacute respiratory failure [
• Rapidly progressive proximal myopathy and respiratory failure may mimic Guillain-Barre syndrome (GBS) [
• Electrophysiologic studies such as electromyography and nerve conduction velocity (NCV) are helpful in differentiating MADD from GBS, as these studies typically show evidence of peripheral nerve demyelination in GBS. However, further differentiation by plasma acylcarnitine profile and urine organic acid assay should be done promptly.
• Individuals with MADD are at risk of developing rhabdomyolysis, which may manifest during the acute episode of metabolic decompensation [
• Bent spine syndrome characterized by progressive forward flexion of the trunk caused by selective involvement of paravertebral muscles has also been reported [
## Biochemical Features
Elevations of several acylcarnitine species in blood in combination with increased exertion of multiple organic acids in urine are highly suggestive of MADD, as summarized in
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
Genotype-phenotype correlation is seen in the three known genes that lead to MADD (
Biallelic pathogenic null variants or pathogenic variants that severely affect mRNA expression or stability and result in total lack of protein cause the most severe form of MADD (i.e., neonatal onset with congenital malformations [type I]).
Pathogenic variants that affect the active site and/or pathogenic splice site variants giving rise to very low residual enzyme activity more often lead to neonatal presentation without congenital anomalies (type II).
Affected individuals who have at least one pathogenic missense variant that does not affect the active site, mRNA expression, or mRNA stability typically have relatively high residual enzyme activity with resulting late onset and milder disease (type III).
• Biallelic pathogenic null variants or pathogenic variants that severely affect mRNA expression or stability and result in total lack of protein cause the most severe form of MADD (i.e., neonatal onset with congenital malformations [type I]).
• Pathogenic variants that affect the active site and/or pathogenic splice site variants giving rise to very low residual enzyme activity more often lead to neonatal presentation without congenital anomalies (type II).
• Affected individuals who have at least one pathogenic missense variant that does not affect the active site, mRNA expression, or mRNA stability typically have relatively high residual enzyme activity with resulting late onset and milder disease (type III).
## Nomenclature
MADD was first described in 1976 in an infant with nonketotic hypoglycemia, metabolic acidosis, and strong "sweaty feet" odor [
## Prevalence
MADD is very rare. Exact prevalence is not known. Incidence at birth is estimated at 1:250,000 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders of riboflavin metabolism can mimic multiple acyl-CoA dehydrogenase deficiency (MADD) (both biochemically and clinically) or have overlapping phenotypic features with MADD and should be considered as the primary differential diagnoses. With frequent use of exome sequencing, it is postulated that many individuals diagnosed with MADD of unknown genetic etiology will be identified as having a genetic alteration associated with a disorder of riboflavin metabolism.
Cellular uptake of riboflavin is mediated by the transmembrane proteins hRFVT1, hRFVT2, and hRFVT3 (encoded by
FAD is a cofactor for electron transfer by the ETF/ETFDH complex from oxidations of fatty acids and some amino acids to the electron transport chain in the inner mitochondrial membrane [
Riboflavin Metabolism Disorders to Consider in the Differential Diagnosis of MADD
Assoc swallowing & speech difficulties usually seen
Respiratory difficulties → respiratory arrest is the usual outcome.
Neonatal presentation w/poor feeding, lethargy, hypotonia, hypoglycemia, & hyperammonemia similar to neonatal-onset MADD
Biochemical profile similar to MADD
Transient presentation & dramatic improvement w/riboflavin supplementation
May be secondary to maternal heterozygous pathogenic variant → maternal riboflavin deficiency & secondary neonatal riboflavin deficiency
Can present in infancy w/progressive neurologic deterioration, hypotonia, respiratory insufficiency, & early death, or later in life w/deafness & cranial nerve palsies
Riboflavin supplementation may improve symptoms.
AD = autosomal dominant; AR = autosomal recessive; MADD = multiple acyl-CoA dehydrogenase deficiency; MOI = mode of inheritance
Note: Many other inborn errors of metabolism (in additional to disorders of riboflavin metabolism) can have a very similar clinical presentation to MADD and should be considered in the differential diagnosis.
Inborn errors of metabolism with neonatal onset and clinical similarities with MADD are summarized in
Disorders with Neonatal Onset to Consider in the Differential Diagnosis of Multiple Acyl-CoA Dehydrogenase Deficiency
Lethal neonatal form: hypoglycemia, hyperammonemia, & congenital anomalies (cystic kidney dysplasia & neuronal migration defects)
Severe infantile hepatocardiomuscular form: profound nonketotic hypoglycemia mimicking other FAO defects; not assoc w/congenital anomalies
AR = autosomal recessive; FAO = fatty acid oxidation; MADD = multiple acyl-CoA dehydrogenase deficiency; MOI = mode of inheritance; XL = X-linked
Acylcarnitine profile and urine organic acid profile are helpful in differentiating systemic primary carnitine deficiency and MADD; these tests are more useful during acute episodes and after carnitine supplementation.
Inborn errors of metabolism with late onset and clinical similarities with MADD are summarized in
Disorders with Late Onset to Consider in the Differential Diagnosis of MADD
All disorders in
GSD = glycogen storage disease
Usually precipitated by infection or fasting
With recurrent rhabdomyolysis
Acylcarnitine profile and urine organic acid profile are helpful in differentiating systemic primary carnitine deficiency and MADD; these tests are more useful during acute episodes and after carnitine supplementation.
Lipid Storage Myopathies to Consider in the Differential Diagnosis of MADD
AR = autosomal recessive; ID = intellectual disability; MADD = multiple acyl-CoA dehydrogenase deficiency; MOI = mode of inheritance
• Assoc swallowing & speech difficulties usually seen
• Respiratory difficulties → respiratory arrest is the usual outcome.
• Neonatal presentation w/poor feeding, lethargy, hypotonia, hypoglycemia, & hyperammonemia similar to neonatal-onset MADD
• Biochemical profile similar to MADD
• Transient presentation & dramatic improvement w/riboflavin supplementation
• May be secondary to maternal heterozygous pathogenic variant → maternal riboflavin deficiency & secondary neonatal riboflavin deficiency
• Can present in infancy w/progressive neurologic deterioration, hypotonia, respiratory insufficiency, & early death, or later in life w/deafness & cranial nerve palsies
• Riboflavin supplementation may improve symptoms.
• Lethal neonatal form: hypoglycemia, hyperammonemia, & congenital anomalies (cystic kidney dysplasia & neuronal migration defects)
• Severe infantile hepatocardiomuscular form: profound nonketotic hypoglycemia mimicking other FAO defects; not assoc w/congenital anomalies
## Disorders of Riboflavin Metabolism
Disorders of riboflavin metabolism can mimic multiple acyl-CoA dehydrogenase deficiency (MADD) (both biochemically and clinically) or have overlapping phenotypic features with MADD and should be considered as the primary differential diagnoses. With frequent use of exome sequencing, it is postulated that many individuals diagnosed with MADD of unknown genetic etiology will be identified as having a genetic alteration associated with a disorder of riboflavin metabolism.
Cellular uptake of riboflavin is mediated by the transmembrane proteins hRFVT1, hRFVT2, and hRFVT3 (encoded by
FAD is a cofactor for electron transfer by the ETF/ETFDH complex from oxidations of fatty acids and some amino acids to the electron transport chain in the inner mitochondrial membrane [
Riboflavin Metabolism Disorders to Consider in the Differential Diagnosis of MADD
Assoc swallowing & speech difficulties usually seen
Respiratory difficulties → respiratory arrest is the usual outcome.
Neonatal presentation w/poor feeding, lethargy, hypotonia, hypoglycemia, & hyperammonemia similar to neonatal-onset MADD
Biochemical profile similar to MADD
Transient presentation & dramatic improvement w/riboflavin supplementation
May be secondary to maternal heterozygous pathogenic variant → maternal riboflavin deficiency & secondary neonatal riboflavin deficiency
Can present in infancy w/progressive neurologic deterioration, hypotonia, respiratory insufficiency, & early death, or later in life w/deafness & cranial nerve palsies
Riboflavin supplementation may improve symptoms.
AD = autosomal dominant; AR = autosomal recessive; MADD = multiple acyl-CoA dehydrogenase deficiency; MOI = mode of inheritance
Note: Many other inborn errors of metabolism (in additional to disorders of riboflavin metabolism) can have a very similar clinical presentation to MADD and should be considered in the differential diagnosis.
• Assoc swallowing & speech difficulties usually seen
• Respiratory difficulties → respiratory arrest is the usual outcome.
• Neonatal presentation w/poor feeding, lethargy, hypotonia, hypoglycemia, & hyperammonemia similar to neonatal-onset MADD
• Biochemical profile similar to MADD
• Transient presentation & dramatic improvement w/riboflavin supplementation
• May be secondary to maternal heterozygous pathogenic variant → maternal riboflavin deficiency & secondary neonatal riboflavin deficiency
• Can present in infancy w/progressive neurologic deterioration, hypotonia, respiratory insufficiency, & early death, or later in life w/deafness & cranial nerve palsies
• Riboflavin supplementation may improve symptoms.
## Neonatal-Onset MADD
Inborn errors of metabolism with neonatal onset and clinical similarities with MADD are summarized in
Disorders with Neonatal Onset to Consider in the Differential Diagnosis of Multiple Acyl-CoA Dehydrogenase Deficiency
Lethal neonatal form: hypoglycemia, hyperammonemia, & congenital anomalies (cystic kidney dysplasia & neuronal migration defects)
Severe infantile hepatocardiomuscular form: profound nonketotic hypoglycemia mimicking other FAO defects; not assoc w/congenital anomalies
AR = autosomal recessive; FAO = fatty acid oxidation; MADD = multiple acyl-CoA dehydrogenase deficiency; MOI = mode of inheritance; XL = X-linked
Acylcarnitine profile and urine organic acid profile are helpful in differentiating systemic primary carnitine deficiency and MADD; these tests are more useful during acute episodes and after carnitine supplementation.
• Lethal neonatal form: hypoglycemia, hyperammonemia, & congenital anomalies (cystic kidney dysplasia & neuronal migration defects)
• Severe infantile hepatocardiomuscular form: profound nonketotic hypoglycemia mimicking other FAO defects; not assoc w/congenital anomalies
## Late-Onset MADD
Inborn errors of metabolism with late onset and clinical similarities with MADD are summarized in
Disorders with Late Onset to Consider in the Differential Diagnosis of MADD
All disorders in
GSD = glycogen storage disease
Usually precipitated by infection or fasting
With recurrent rhabdomyolysis
Acylcarnitine profile and urine organic acid profile are helpful in differentiating systemic primary carnitine deficiency and MADD; these tests are more useful during acute episodes and after carnitine supplementation.
Lipid Storage Myopathies to Consider in the Differential Diagnosis of MADD
AR = autosomal recessive; ID = intellectual disability; MADD = multiple acyl-CoA dehydrogenase deficiency; MOI = mode of inheritance
## Other
## Management
When multiple acyl-CoA dehydrogenase deficiency (MADD) is suspected during the diagnostic evaluation (i.e., due to abnormal acylcarnitine profile and urine organic acids profile following a positive newborn screening, or evaluation of exercise intolerance and/or muscle weakness in adults), treatment should be initiated immediately.
Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.
To establish the extent of disease and needs in an individual diagnosed with MADD, the evaluations in
Recommended Evaluations Following Initial Diagnosis of MADD in a Neonate
STAT blood gas (arterial or venous), ammonia & lactic acid
Glucose, liver transaminases (AST, ALT)
Electrolytes w/bicarbonate, BUN, creatinine
CK
CBC w/differential & additional eval if infection suspected
BUN = blood urea nitrogen; CBC = complete blood counts; CK = creatine kinase
After a new diagnosis of MADD in an infant, the closest hospital and local pediatrician should also be informed.
Recommended Evaluations Following Initial Diagnosis of MADD in an Older Child, Adolescent, or Adult with Later-Onset Disease
STAT blood gas (arterial or venous), ammonia & lactic acid
Glucose, liver transaminases (AST, ALT)
Electrolytes w/bicarbonate, BUN, creatinine
CK
CBC w/differential & additional eval when infection is suspected.
Motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
BUN = blood urea nitrogen; CBC = complete blood counts; CK = creatine kinase
Routine Daily Treatment in Individuals with MADD
Diet should be started in consultation w/metabolic dietitian to ensure adequate metabolic control & appropriate growth in infants, children, & adolescents.
Late-onset MADD w/milder presentation may not require specialized diet.
Between ages 1 & 2 yrs: fasting up to 10 hrs may be attempted.
After 2 yrs: fasting up to 12 hrs may be attempted.
If hypoglycemia remains an issue, overnight feedings or 2 g/kg of uncooked cornstarch
Decrease feeding interval by 50% during periods of illness (see
Riboflavin supplementation should be tried in all persons w/MADD irrespective of the molecular genetic cause.
~98% of persons w/late-onset MADD respond to riboflavin.
Coenzyme Q is the electron acceptor from ETF/ETFDH complex.
Like riboflavin, coenzyme Q
The antioxidant properties of coenzyme Q
MADD = multiple acyl-CoA dehydrogenase deficiency; OT = occupational therapy; PT = physical therapy
These represent general recommendations; no consensus guidelines on duration of fasting are available.
To ensure sufficient glucose supply overnight
Riboflavin is converted to FAD, which is a cofactor for both ETF and ETFDH. By increasing the FAD level, riboflavin supplementation in late-onset forms stabilizes the ETFDH enzyme and hence enhances its activity.
Secondary coenzyme Q
Emergency Outpatient Treatment in Individuals with MADD
If ↓ PO intake, vomiting, or lethargy: start emergency inpatient treatment (see
There should be low threshold for starting inpatient management for infants & young children.
PO = oral
Parents or local hospitals should immediately inform the designated metabolic center if: (a) temperature rises above 38.5°C; (b) persistent vomiting/diarrhea or other symptoms of intercurrent illness develop; or (c) new neurologic symptoms occur.
Acute manifestations (e.g., lethargy, encephalopathy, intractable vomiting, seizures, or progressive coma) often occur in the setting of intercurrent illness and/or inadequate caloric intake due to poor appetite or prolonged fasting. These should be managed with generous caloric support in a hospital setting. Identification and treatment of any suspected or proven infection should be done simultaneously.
Acute Inpatient Treatment in Individuals with MADD
High-dose glucose needed to avoid catabolism
If hyperglycemia: start insulin infusion rather than ↓ glucose infusion rate.
For severe metabolic acidosis (pH <7.10): initiate bicarbonate therapy.
A common formula for bicarbonate dose is: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate - measured bicarbonate]
Give half of calculated dose as slow bolus & remaining half over 24 hrs.
Metabolic acidosis usually improves w/generous fluid & calorie support.
Bicarbonate therapy is needed for severe metabolic acidosis.
Hyperammonemia improves w/reversal of catabolism.
High-dose glucose infusion w/insulin infusion is helpful.
If severe hyperammonemia & altered mental status persists after above measures, consider extracorporeal toxin removal procedures (e.g., hemodialysis, hemofiltration).
Start IV fluid containing 10% dextrose & electrolytes as necessary at 1.5-2x maintenance to provide adequate hydration & calories, & ensure a urine output of >3 mL/kg/hr to prevent acute renal failure.
If there is acute renal failure at presentation, a nephrologist should be consulted for hemodialysis.
Avoid treating rhabdomyolysis w/glucose-free IV fluid such as 0.45% normal saline, as it will promote catabolism & worsening of rhabdomyolysis.
If hyperglycemia develops due to high dextrose infusion, start insulin infusion.
Note: For late-onset MADD, oral riboflavin should be initiated as soon as possible (see
IV = intravenous; mEq = milliequivalent
Monitor blood glucose levels every 1-2 hours initially.
Intralipid administration is contraindicated; supplemental calories should be provided in the form of carbohydrates.
Note that bicarbonate therapy alone is not sufficient to correct the metabolic acidosis. Correction of metabolic acidosis relies on reversing the catabolic state by providing calorie support from glucose.
Avoidance of fasting and supplementation with riboflavin remains the mainstay of treatment. In addition, L-carnitine supplementation to maintain normal carnitine level and coenzyme Q
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors. Prompt initiation of dextrose-containing intravenous fluids is essential to avoid complications such as liver failure, rhabdomyolysis, encephalopathy, and coma.
Written protocols for emergency treatment (see
Sample Emergency Management Protocol for Individuals with MADD
Start intravenous fluid immediately even if not clinically dehydrated with 10% dextrose and appropriate electrolytes at 1.5 times maintenance rate. It is imperative to prevent or reverse catabolism immediately.
Correct metabolic acidosis by giving sodium bicarbonate if acidosis is severe (pH <7.10 or bicarbonate <10 mEq/L).
Do not wait for results of laboratory evaluation before starting intravenous fluids with glucose.
Monitor blood glucose levels every 1-2 hours initially and maintain glucose levels above 100 mg/dL.
STAT blood gas (arterial or venous), ammonia, and lactic acid
Glucose, liver transaminases (AST, ALT)
Electrolytes with bicarbonate, blood urea nitrogen (BUN), creatinine
Creatine kinase (CK)
Complete blood counts (CBC) with differential and additional evaluation when infection is suspected.
Plasma free and total carnitine, plasma acylcarnitine profile, urine organic acids
Published guidelines for surveillance are not currently available. In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations in
Recommended Surveillance for Individuals with MADD
CK = creatine kinase
In infants and children
Avoid the following:
Fasting, including periods of preparation and recovery from planned surgery or anesthesia
Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
Inadequate calories following vaccination. Vaccination is safe.
Dehydration (risk for rhabdomyolysis and acute renal failure)
High-fat, high-protein diet, including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet
Volatile anesthetics and those that contain high doses of long-chain fatty acids such as propofol and etomidate. However, a combination of low-dose propofol, fentanyl, and nitrous oxide was used successfully in an individual with MADD [
Administration of intravenous intralipids during an acute metabolic crisis
Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of MADD. For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening either test for the familial
Acylcarnitine profile may be normal in the setting of low plasma free carnitine and should be repeated after carnitine supplementation in such cases.
See
Successful pregnancy with a low-fat, high-carbohydrate diet in late-onset MADD has been published [
No evidence suggests that taking supplemental carnitine during pregnancy leads to adverse fetal effects.
Riboflavin is a B vitamin and is considered an essential nutrient. There is limited published information on adverse pregnancy or fetal outcome with excessive riboflavin intake, although
See
There are few experimental therapies for MADD. Only a few case reports are available to support their utility:
Search
• STAT blood gas (arterial or venous), ammonia & lactic acid
• Glucose, liver transaminases (AST, ALT)
• Electrolytes w/bicarbonate, BUN, creatinine
• CK
• CBC w/differential & additional eval if infection suspected
• STAT blood gas (arterial or venous), ammonia & lactic acid
• Glucose, liver transaminases (AST, ALT)
• Electrolytes w/bicarbonate, BUN, creatinine
• CK
• CBC w/differential & additional eval when infection is suspected.
• Motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Diet should be started in consultation w/metabolic dietitian to ensure adequate metabolic control & appropriate growth in infants, children, & adolescents.
• Late-onset MADD w/milder presentation may not require specialized diet.
• Between ages 1 & 2 yrs: fasting up to 10 hrs may be attempted.
• After 2 yrs: fasting up to 12 hrs may be attempted.
• If hypoglycemia remains an issue, overnight feedings or 2 g/kg of uncooked cornstarch
• Decrease feeding interval by 50% during periods of illness (see
• Riboflavin supplementation should be tried in all persons w/MADD irrespective of the molecular genetic cause.
• ~98% of persons w/late-onset MADD respond to riboflavin.
• Coenzyme Q is the electron acceptor from ETF/ETFDH complex.
• Like riboflavin, coenzyme Q
• The antioxidant properties of coenzyme Q
• If ↓ PO intake, vomiting, or lethargy: start emergency inpatient treatment (see
• There should be low threshold for starting inpatient management for infants & young children.
• High-dose glucose needed to avoid catabolism
• If hyperglycemia: start insulin infusion rather than ↓ glucose infusion rate.
• For severe metabolic acidosis (pH <7.10): initiate bicarbonate therapy.
• A common formula for bicarbonate dose is: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate - measured bicarbonate]
• Give half of calculated dose as slow bolus & remaining half over 24 hrs.
• Metabolic acidosis usually improves w/generous fluid & calorie support.
• Bicarbonate therapy is needed for severe metabolic acidosis.
• Hyperammonemia improves w/reversal of catabolism.
• High-dose glucose infusion w/insulin infusion is helpful.
• If severe hyperammonemia & altered mental status persists after above measures, consider extracorporeal toxin removal procedures (e.g., hemodialysis, hemofiltration).
• Start IV fluid containing 10% dextrose & electrolytes as necessary at 1.5-2x maintenance to provide adequate hydration & calories, & ensure a urine output of >3 mL/kg/hr to prevent acute renal failure.
• If there is acute renal failure at presentation, a nephrologist should be consulted for hemodialysis.
• Avoid treating rhabdomyolysis w/glucose-free IV fluid such as 0.45% normal saline, as it will promote catabolism & worsening of rhabdomyolysis.
• If hyperglycemia develops due to high dextrose infusion, start insulin infusion.
• Start intravenous fluid immediately even if not clinically dehydrated with 10% dextrose and appropriate electrolytes at 1.5 times maintenance rate. It is imperative to prevent or reverse catabolism immediately.
• Correct metabolic acidosis by giving sodium bicarbonate if acidosis is severe (pH <7.10 or bicarbonate <10 mEq/L).
• Do not wait for results of laboratory evaluation before starting intravenous fluids with glucose.
• Monitor blood glucose levels every 1-2 hours initially and maintain glucose levels above 100 mg/dL.
• STAT blood gas (arterial or venous), ammonia, and lactic acid
• Glucose, liver transaminases (AST, ALT)
• Electrolytes with bicarbonate, blood urea nitrogen (BUN), creatinine
• Creatine kinase (CK)
• Complete blood counts (CBC) with differential and additional evaluation when infection is suspected.
• Plasma free and total carnitine, plasma acylcarnitine profile, urine organic acids
• Fasting, including periods of preparation and recovery from planned surgery or anesthesia
• Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
• Inadequate calories following vaccination. Vaccination is safe.
• Dehydration (risk for rhabdomyolysis and acute renal failure)
• High-fat, high-protein diet, including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet
• Volatile anesthetics and those that contain high doses of long-chain fatty acids such as propofol and etomidate. However, a combination of low-dose propofol, fentanyl, and nitrous oxide was used successfully in an individual with MADD [
• Administration of intravenous intralipids during an acute metabolic crisis
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MADD, the evaluations in
Recommended Evaluations Following Initial Diagnosis of MADD in a Neonate
STAT blood gas (arterial or venous), ammonia & lactic acid
Glucose, liver transaminases (AST, ALT)
Electrolytes w/bicarbonate, BUN, creatinine
CK
CBC w/differential & additional eval if infection suspected
BUN = blood urea nitrogen; CBC = complete blood counts; CK = creatine kinase
After a new diagnosis of MADD in an infant, the closest hospital and local pediatrician should also be informed.
Recommended Evaluations Following Initial Diagnosis of MADD in an Older Child, Adolescent, or Adult with Later-Onset Disease
STAT blood gas (arterial or venous), ammonia & lactic acid
Glucose, liver transaminases (AST, ALT)
Electrolytes w/bicarbonate, BUN, creatinine
CK
CBC w/differential & additional eval when infection is suspected.
Motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
BUN = blood urea nitrogen; CBC = complete blood counts; CK = creatine kinase
• STAT blood gas (arterial or venous), ammonia & lactic acid
• Glucose, liver transaminases (AST, ALT)
• Electrolytes w/bicarbonate, BUN, creatinine
• CK
• CBC w/differential & additional eval if infection suspected
• STAT blood gas (arterial or venous), ammonia & lactic acid
• Glucose, liver transaminases (AST, ALT)
• Electrolytes w/bicarbonate, BUN, creatinine
• CK
• CBC w/differential & additional eval when infection is suspected.
• Motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
## Treatment of Manifestations
Routine Daily Treatment in Individuals with MADD
Diet should be started in consultation w/metabolic dietitian to ensure adequate metabolic control & appropriate growth in infants, children, & adolescents.
Late-onset MADD w/milder presentation may not require specialized diet.
Between ages 1 & 2 yrs: fasting up to 10 hrs may be attempted.
After 2 yrs: fasting up to 12 hrs may be attempted.
If hypoglycemia remains an issue, overnight feedings or 2 g/kg of uncooked cornstarch
Decrease feeding interval by 50% during periods of illness (see
Riboflavin supplementation should be tried in all persons w/MADD irrespective of the molecular genetic cause.
~98% of persons w/late-onset MADD respond to riboflavin.
Coenzyme Q is the electron acceptor from ETF/ETFDH complex.
Like riboflavin, coenzyme Q
The antioxidant properties of coenzyme Q
MADD = multiple acyl-CoA dehydrogenase deficiency; OT = occupational therapy; PT = physical therapy
These represent general recommendations; no consensus guidelines on duration of fasting are available.
To ensure sufficient glucose supply overnight
Riboflavin is converted to FAD, which is a cofactor for both ETF and ETFDH. By increasing the FAD level, riboflavin supplementation in late-onset forms stabilizes the ETFDH enzyme and hence enhances its activity.
Secondary coenzyme Q
Emergency Outpatient Treatment in Individuals with MADD
If ↓ PO intake, vomiting, or lethargy: start emergency inpatient treatment (see
There should be low threshold for starting inpatient management for infants & young children.
PO = oral
Parents or local hospitals should immediately inform the designated metabolic center if: (a) temperature rises above 38.5°C; (b) persistent vomiting/diarrhea or other symptoms of intercurrent illness develop; or (c) new neurologic symptoms occur.
Acute manifestations (e.g., lethargy, encephalopathy, intractable vomiting, seizures, or progressive coma) often occur in the setting of intercurrent illness and/or inadequate caloric intake due to poor appetite or prolonged fasting. These should be managed with generous caloric support in a hospital setting. Identification and treatment of any suspected or proven infection should be done simultaneously.
Acute Inpatient Treatment in Individuals with MADD
High-dose glucose needed to avoid catabolism
If hyperglycemia: start insulin infusion rather than ↓ glucose infusion rate.
For severe metabolic acidosis (pH <7.10): initiate bicarbonate therapy.
A common formula for bicarbonate dose is: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate - measured bicarbonate]
Give half of calculated dose as slow bolus & remaining half over 24 hrs.
Metabolic acidosis usually improves w/generous fluid & calorie support.
Bicarbonate therapy is needed for severe metabolic acidosis.
Hyperammonemia improves w/reversal of catabolism.
High-dose glucose infusion w/insulin infusion is helpful.
If severe hyperammonemia & altered mental status persists after above measures, consider extracorporeal toxin removal procedures (e.g., hemodialysis, hemofiltration).
Start IV fluid containing 10% dextrose & electrolytes as necessary at 1.5-2x maintenance to provide adequate hydration & calories, & ensure a urine output of >3 mL/kg/hr to prevent acute renal failure.
If there is acute renal failure at presentation, a nephrologist should be consulted for hemodialysis.
Avoid treating rhabdomyolysis w/glucose-free IV fluid such as 0.45% normal saline, as it will promote catabolism & worsening of rhabdomyolysis.
If hyperglycemia develops due to high dextrose infusion, start insulin infusion.
Note: For late-onset MADD, oral riboflavin should be initiated as soon as possible (see
IV = intravenous; mEq = milliequivalent
Monitor blood glucose levels every 1-2 hours initially.
Intralipid administration is contraindicated; supplemental calories should be provided in the form of carbohydrates.
Note that bicarbonate therapy alone is not sufficient to correct the metabolic acidosis. Correction of metabolic acidosis relies on reversing the catabolic state by providing calorie support from glucose.
• Diet should be started in consultation w/metabolic dietitian to ensure adequate metabolic control & appropriate growth in infants, children, & adolescents.
• Late-onset MADD w/milder presentation may not require specialized diet.
• Between ages 1 & 2 yrs: fasting up to 10 hrs may be attempted.
• After 2 yrs: fasting up to 12 hrs may be attempted.
• If hypoglycemia remains an issue, overnight feedings or 2 g/kg of uncooked cornstarch
• Decrease feeding interval by 50% during periods of illness (see
• Riboflavin supplementation should be tried in all persons w/MADD irrespective of the molecular genetic cause.
• ~98% of persons w/late-onset MADD respond to riboflavin.
• Coenzyme Q is the electron acceptor from ETF/ETFDH complex.
• Like riboflavin, coenzyme Q
• The antioxidant properties of coenzyme Q
• If ↓ PO intake, vomiting, or lethargy: start emergency inpatient treatment (see
• There should be low threshold for starting inpatient management for infants & young children.
• High-dose glucose needed to avoid catabolism
• If hyperglycemia: start insulin infusion rather than ↓ glucose infusion rate.
• For severe metabolic acidosis (pH <7.10): initiate bicarbonate therapy.
• A common formula for bicarbonate dose is: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate - measured bicarbonate]
• Give half of calculated dose as slow bolus & remaining half over 24 hrs.
• Metabolic acidosis usually improves w/generous fluid & calorie support.
• Bicarbonate therapy is needed for severe metabolic acidosis.
• Hyperammonemia improves w/reversal of catabolism.
• High-dose glucose infusion w/insulin infusion is helpful.
• If severe hyperammonemia & altered mental status persists after above measures, consider extracorporeal toxin removal procedures (e.g., hemodialysis, hemofiltration).
• Start IV fluid containing 10% dextrose & electrolytes as necessary at 1.5-2x maintenance to provide adequate hydration & calories, & ensure a urine output of >3 mL/kg/hr to prevent acute renal failure.
• If there is acute renal failure at presentation, a nephrologist should be consulted for hemodialysis.
• Avoid treating rhabdomyolysis w/glucose-free IV fluid such as 0.45% normal saline, as it will promote catabolism & worsening of rhabdomyolysis.
• If hyperglycemia develops due to high dextrose infusion, start insulin infusion.
## Prevention of Primary Manifestations
Avoidance of fasting and supplementation with riboflavin remains the mainstay of treatment. In addition, L-carnitine supplementation to maintain normal carnitine level and coenzyme Q
## Prevention of Secondary Complications
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors. Prompt initiation of dextrose-containing intravenous fluids is essential to avoid complications such as liver failure, rhabdomyolysis, encephalopathy, and coma.
Written protocols for emergency treatment (see
Sample Emergency Management Protocol for Individuals with MADD
Start intravenous fluid immediately even if not clinically dehydrated with 10% dextrose and appropriate electrolytes at 1.5 times maintenance rate. It is imperative to prevent or reverse catabolism immediately.
Correct metabolic acidosis by giving sodium bicarbonate if acidosis is severe (pH <7.10 or bicarbonate <10 mEq/L).
Do not wait for results of laboratory evaluation before starting intravenous fluids with glucose.
Monitor blood glucose levels every 1-2 hours initially and maintain glucose levels above 100 mg/dL.
STAT blood gas (arterial or venous), ammonia, and lactic acid
Glucose, liver transaminases (AST, ALT)
Electrolytes with bicarbonate, blood urea nitrogen (BUN), creatinine
Creatine kinase (CK)
Complete blood counts (CBC) with differential and additional evaluation when infection is suspected.
Plasma free and total carnitine, plasma acylcarnitine profile, urine organic acids
• Start intravenous fluid immediately even if not clinically dehydrated with 10% dextrose and appropriate electrolytes at 1.5 times maintenance rate. It is imperative to prevent or reverse catabolism immediately.
• Correct metabolic acidosis by giving sodium bicarbonate if acidosis is severe (pH <7.10 or bicarbonate <10 mEq/L).
• Do not wait for results of laboratory evaluation before starting intravenous fluids with glucose.
• Monitor blood glucose levels every 1-2 hours initially and maintain glucose levels above 100 mg/dL.
• STAT blood gas (arterial or venous), ammonia, and lactic acid
• Glucose, liver transaminases (AST, ALT)
• Electrolytes with bicarbonate, blood urea nitrogen (BUN), creatinine
• Creatine kinase (CK)
• Complete blood counts (CBC) with differential and additional evaluation when infection is suspected.
• Plasma free and total carnitine, plasma acylcarnitine profile, urine organic acids
## Surveillance
Published guidelines for surveillance are not currently available. In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations in
Recommended Surveillance for Individuals with MADD
CK = creatine kinase
In infants and children
## Agents/Circumstances to Avoid
Avoid the following:
Fasting, including periods of preparation and recovery from planned surgery or anesthesia
Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
Inadequate calories following vaccination. Vaccination is safe.
Dehydration (risk for rhabdomyolysis and acute renal failure)
High-fat, high-protein diet, including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet
Volatile anesthetics and those that contain high doses of long-chain fatty acids such as propofol and etomidate. However, a combination of low-dose propofol, fentanyl, and nitrous oxide was used successfully in an individual with MADD [
Administration of intravenous intralipids during an acute metabolic crisis
• Fasting, including periods of preparation and recovery from planned surgery or anesthesia
• Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
• Inadequate calories following vaccination. Vaccination is safe.
• Dehydration (risk for rhabdomyolysis and acute renal failure)
• High-fat, high-protein diet, including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet
• Volatile anesthetics and those that contain high doses of long-chain fatty acids such as propofol and etomidate. However, a combination of low-dose propofol, fentanyl, and nitrous oxide was used successfully in an individual with MADD [
• Administration of intravenous intralipids during an acute metabolic crisis
## Evaluation of Relatives at Risk
Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of MADD. For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening either test for the familial
Acylcarnitine profile may be normal in the setting of low plasma free carnitine and should be repeated after carnitine supplementation in such cases.
See
## Pregnancy Management
Successful pregnancy with a low-fat, high-carbohydrate diet in late-onset MADD has been published [
No evidence suggests that taking supplemental carnitine during pregnancy leads to adverse fetal effects.
Riboflavin is a B vitamin and is considered an essential nutrient. There is limited published information on adverse pregnancy or fetal outcome with excessive riboflavin intake, although
See
## Therapies Under Investigation
There are few experimental therapies for MADD. Only a few case reports are available to support their utility:
Search
## Genetic Counseling
Multiple acyl-CoA dehydrogenase deficiency (MADD) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Multiple acyl-CoA dehydrogenase deficiency (MADD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Health Resources & Services Administration
•
•
•
•
•
• Health Resources & Services Administration
•
•
•
## Molecular Genetics
Multiple Acyl-CoA Dehydrogenase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Multiple Acyl-CoA Dehydrogenase Deficiency (
ETF is a heterodimer protein in the mitochondrial matrix composed of alpha (ETFA) and beta (ETFB) subunits. It accepts electrons from several acyl-coA dehydrogenases involved in fatty acid oxidation and also some dehydrogenases involved in amino acid and choline metabolism pathways. The electrons are then transferred to ETFDH, located in the inner mitochondrial membrane, which then transfers electrons to ubiquinone (coenzyme Q) in the electron transport chain. Hence, impairment of the ETF-ETFDH complex leads to multiple acyl-coA dehydrogenase deficiency (MADD) as well as impairment of the metabolism of several amino acids and choline. Some of the enzymes indirectly affected because of ETF-ETFDH complex impairment:
Fatty acid oxidation
Short-chain acyl-CoA dehydrogenase
Medium-chain acyl-CoA dehydrogenase
Very long-chain acyl-CoA dehydrogenase
Amino acid metabolism
Isovaleryl CoA dehydrogenase (leucine metabolism)
Short-/branched-chain acyl-CoA dehydrogenase (isoleucine metabolism)
Isobutyryl CoA dehydrogenase (valine metabolism)
Alpha ketoadipic acid dehydrogenase, glutaryl CoA dehydrogenase (lysine and tryptophan metabolism)
Choline metabolism
Dimethylglycine dehydrogenase
Sarcosine dehydrogenase
MADD: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the author.
• Fatty acid oxidation
• Short-chain acyl-CoA dehydrogenase
• Medium-chain acyl-CoA dehydrogenase
• Very long-chain acyl-CoA dehydrogenase
• Short-chain acyl-CoA dehydrogenase
• Medium-chain acyl-CoA dehydrogenase
• Very long-chain acyl-CoA dehydrogenase
• Amino acid metabolism
• Isovaleryl CoA dehydrogenase (leucine metabolism)
• Short-/branched-chain acyl-CoA dehydrogenase (isoleucine metabolism)
• Isobutyryl CoA dehydrogenase (valine metabolism)
• Alpha ketoadipic acid dehydrogenase, glutaryl CoA dehydrogenase (lysine and tryptophan metabolism)
• Isovaleryl CoA dehydrogenase (leucine metabolism)
• Short-/branched-chain acyl-CoA dehydrogenase (isoleucine metabolism)
• Isobutyryl CoA dehydrogenase (valine metabolism)
• Alpha ketoadipic acid dehydrogenase, glutaryl CoA dehydrogenase (lysine and tryptophan metabolism)
• Choline metabolism
• Dimethylglycine dehydrogenase
• Sarcosine dehydrogenase
• Dimethylglycine dehydrogenase
• Sarcosine dehydrogenase
• Short-chain acyl-CoA dehydrogenase
• Medium-chain acyl-CoA dehydrogenase
• Very long-chain acyl-CoA dehydrogenase
• Isovaleryl CoA dehydrogenase (leucine metabolism)
• Short-/branched-chain acyl-CoA dehydrogenase (isoleucine metabolism)
• Isobutyryl CoA dehydrogenase (valine metabolism)
• Alpha ketoadipic acid dehydrogenase, glutaryl CoA dehydrogenase (lysine and tryptophan metabolism)
• Dimethylglycine dehydrogenase
• Sarcosine dehydrogenase
## Molecular Pathogenesis
ETF is a heterodimer protein in the mitochondrial matrix composed of alpha (ETFA) and beta (ETFB) subunits. It accepts electrons from several acyl-coA dehydrogenases involved in fatty acid oxidation and also some dehydrogenases involved in amino acid and choline metabolism pathways. The electrons are then transferred to ETFDH, located in the inner mitochondrial membrane, which then transfers electrons to ubiquinone (coenzyme Q) in the electron transport chain. Hence, impairment of the ETF-ETFDH complex leads to multiple acyl-coA dehydrogenase deficiency (MADD) as well as impairment of the metabolism of several amino acids and choline. Some of the enzymes indirectly affected because of ETF-ETFDH complex impairment:
Fatty acid oxidation
Short-chain acyl-CoA dehydrogenase
Medium-chain acyl-CoA dehydrogenase
Very long-chain acyl-CoA dehydrogenase
Amino acid metabolism
Isovaleryl CoA dehydrogenase (leucine metabolism)
Short-/branched-chain acyl-CoA dehydrogenase (isoleucine metabolism)
Isobutyryl CoA dehydrogenase (valine metabolism)
Alpha ketoadipic acid dehydrogenase, glutaryl CoA dehydrogenase (lysine and tryptophan metabolism)
Choline metabolism
Dimethylglycine dehydrogenase
Sarcosine dehydrogenase
MADD: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the author.
• Fatty acid oxidation
• Short-chain acyl-CoA dehydrogenase
• Medium-chain acyl-CoA dehydrogenase
• Very long-chain acyl-CoA dehydrogenase
• Short-chain acyl-CoA dehydrogenase
• Medium-chain acyl-CoA dehydrogenase
• Very long-chain acyl-CoA dehydrogenase
• Amino acid metabolism
• Isovaleryl CoA dehydrogenase (leucine metabolism)
• Short-/branched-chain acyl-CoA dehydrogenase (isoleucine metabolism)
• Isobutyryl CoA dehydrogenase (valine metabolism)
• Alpha ketoadipic acid dehydrogenase, glutaryl CoA dehydrogenase (lysine and tryptophan metabolism)
• Isovaleryl CoA dehydrogenase (leucine metabolism)
• Short-/branched-chain acyl-CoA dehydrogenase (isoleucine metabolism)
• Isobutyryl CoA dehydrogenase (valine metabolism)
• Alpha ketoadipic acid dehydrogenase, glutaryl CoA dehydrogenase (lysine and tryptophan metabolism)
• Choline metabolism
• Dimethylglycine dehydrogenase
• Sarcosine dehydrogenase
• Dimethylglycine dehydrogenase
• Sarcosine dehydrogenase
• Short-chain acyl-CoA dehydrogenase
• Medium-chain acyl-CoA dehydrogenase
• Very long-chain acyl-CoA dehydrogenase
• Isovaleryl CoA dehydrogenase (leucine metabolism)
• Short-/branched-chain acyl-CoA dehydrogenase (isoleucine metabolism)
• Isobutyryl CoA dehydrogenase (valine metabolism)
• Alpha ketoadipic acid dehydrogenase, glutaryl CoA dehydrogenase (lysine and tryptophan metabolism)
• Dimethylglycine dehydrogenase
• Sarcosine dehydrogenase
## Chapter Notes
18 June 2020 (me) Review posted live
29 August 2019 (pp) Original submission
• 18 June 2020 (me) Review posted live
• 29 August 2019 (pp) Original submission
## Revision History
18 June 2020 (me) Review posted live
29 August 2019 (pp) Original submission
• 18 June 2020 (me) Review posted live
• 29 August 2019 (pp) Original submission
## References
## Literature Cited
|
[
"A Alfares, M Alfadhel, T Wani, S Alsahli, I Alluhaydan, F Al Mutairi, A Alothaim, M Albalwi, L Al Subaie, S Alturki, W Al-Twaijri, M Alrifai, A Al-Rumayya, S Alameer, E Faqeeh, A Alasmari, A Alsamman, S Tashkandia, A Alghamdi, A Alhashem, B Tabarki, S AlShahwan, K Hundallah, S Wali, H Al-Hebbi, A Babiker, S Mohamed, W Eyaid, AAP Zada. A multicenter clinical exome study in unselected cohorts from a consanguineous population of Saudi Arabia demonstrated a high diagnostic yield.. Mol Genet Metab. 2017;121:91-5",
"C Angelini, D Tavian, S Missaglia. Heterogeneous phenotypes in lipid storage myopathy due to ETFDH gene mutations.. JIMD Rep. 2018;38:33-40",
"B Angle, BK Burton. Risk of sudden death and acute life-threatening events in patients with glutaric acidemia type II.. Mol Genet Metab. 2008;93:36-9",
"X Bosch, E Poch, JM Grau. Rhabdomyolysis and acute kidney injury.. N Engl J Med. 2009;361:62-72",
"N Cornelius, C Byron, I Hargreaves, PF Guerra, AK Furdek, J Land, WW Radford, F Frerman, TJ Corydon, N Gregersen, RK Olsen. Secondary coenzyme Q10 deficiency and oxidative stress in cultured fibroblasts from patients with riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency.. Hum Mol Genet. 2013;22:3819-27",
"A Creanza, M Cotugno, C Mazzaccara, G Frisso, G Parenti, B Capaldo. Successful pregnancy in a young woman with multiple acyl-CoA dehydrogenase deficiency.. JIMD Rep. 2018;39:1-6",
"A Curcoy, RK Olsen, A Ribes, V Trenchs, MA Vilaseca, J Campistol, JH Osorio, BS Andresen, N Gregersen. Late-onset form of beta-electron transfer flavoprotein deficiency.. Mol Genet Metab. 2003;78:247-9",
"M Endo, Y Hasegawa, S Fukuda, H Kobayashi, Y Yotsumoto, Y Mushimoto, H Li, J Purevsuren, S Yamaguchi. In vitro probe acylcarnitine profiling assay using cultured fibroblasts and electrospray ionization tandem mass spectrometry predicts severity of patients with glutaric aciduria type 2.. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878:1673-6",
"EO Ersoy, D Rama, Ö Ünal, S Sivri, A Topeli. Glutaric aciduria type 2 presenting with acute respiratory failure in an adult.. Respir Med Case Rep. 2015;15:92-4",
"E Freneaux, VC Sheffield, L Molin, A Shires, WJ Rhead. Glutaric acidemia type II. Heterogeneity in beta-oxidation flux, polypeptide synthesis, and complementary DNA mutations in the alpha subunit of electron transfer flavoprotein in eight patients.. J Clin Invest. 1992;90:1679-86",
"M Gautschi, C Weisstanner, J Slotboom, E Nava, T Zürcher, JM Nuoffer. Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy.. Pediatr Res. 2015;77:91-8",
"SI Goodman, RJ Binard, MR Woontner, FE Frerman. Glutaric acidemia type II: gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene.. Mol Genet Metab. 2002;77:86-90",
"SC Grünert. Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency.. Orphanet J Rare Dis. 2014;9:117",
"G Ho, A Yonezawa, S Masuda, K Inui, KG Sim, K Carpenter, RK Olsen, JJ Mitchell, WJ Rhead, G Peters, J Christodoulou. Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B.. Hum Mutat. 2011;32:E1976-84",
"D Hong, Y Yu, Y Wang, Y Xu, J. Zhang. Acute-onset multiple acyl-CoA dehydrogenase deficiency mimicking Guillain-Barré syndrome: two cases report.. BMC Neurol. 2018;18:219",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"YJ Kim, JM Ko, J Song, KA Lee. Clinical features of multiple acyl-CoA dehydrogenase deficiency with ETFDH variants in the first Korean cases.. Ann Lab Med. 2018;38:616-8",
"WC Liang, I Nishino. Lipid storage myopathy.. Curr Neurol Neurosci Rep. 2011;11:97-103",
"E Lilitsis, E Astyrakaki, E Blevrakis, S Xenaki, G Chalkiadakis, E Chrysos. Anesthetic management of a pediatric patient with electron transfer flavoprotein dehydrogenase deficiency (ETFDH) and acute appendicitis: case report and review of the literature.. BMC Anesthesiol. 2017;17:116",
"S Mosegaard, GH Bruun, KF Flyvbjerg, YT Bliksrud, N Gregersen, M Dembic, E Annexstad, T Tangeraas, RKJ Olsen, BS Andresen. An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.. Mol Genet Metab. 2017;122:182-8",
"R Navarrete, F Leal, AI Vega, A Morais-López, MT Garcia-Silva, E Martín-Hernández, P Quijada-Fraile, A Bergua, I Vives, I García-Jiménez, R Yahyaoui, C Pedrón-Giner, A Belanger-Quintana, S Stanescu, E Cañedo, O García-Campos, M Bueno-Delgado, C Delgado-Pecellín, I Vitoria, MD Rausell, E Balmaseda, ML Couce, LR Desviat, B Merinero, P Rodríguez-Pombo, M Ugarte, C Pérez-Cerdá, B Pérez. Value of genetic analysis for confirming inborn errors of metabolism detected through the Spanish neonatal screening program.. Eur J Hum Genet. 2019;27:556-62",
"RK Olsen, BS Andresen, E Christensen, P Bross, F Skovby, N Gregersen. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency.. Hum Mutat. 2003;22:12-23",
"RKJ Olsen, E Koňaříková, TA Giancaspero, S Mosegaard, V Boczonadi, L Mataković, A Veauville-Merllié, C Terrile, T Schwarzmayr, TB Haack, M Auranen, P Leone, M Galluccio, A Imbard, P Gutierrez-Rios, J Palmfeldt, E Graf, C Vianey-Saban, M Oppenheim, M Schiff, S Pichard, O Rigal, A Pyle, PF Chinnery, V Konstantopoulou, D Möslinger, RG Feichtinger, B Talim, H Topaloglu, T Coskun, S Gucer, A Botta, E Pegoraro, A Malena, L Vergani, D Mazzà, M Zollino, D Ghezzi, C Acquaviva, T Tyni, A Boneh, T Meitinger, TM Strom, N Gregersen, JA Mayr, R Horvath, M Barile, H Prokisch. Riboflavin-responsive and -non-responsive mutations in FAD synthase cause multiple acyl-CoA dehydrogenase and combined respiratory-chain deficiency.. Am J Hum Genet. 2016;98:1130-1145",
"Y Peng, M Zhu, J Zheng, Y Zhu, X Li, C Wei, D Hong. Bent spine syndrome as an initial manifestation of late-onset multiple acyl-CoA dehydrogenase deficiency: a case report and literature review.. BMC Neurol. 2015;15:114",
"M Prasad, S. Hussain. Glutaric aciduria type II presenting as myopathy and rhabdomyolysis in a teenager.. J Child Neurol. 2015;30:96-9",
"H Przyrembel, U Wendel, K Becker, HJ Bremer, L Bruinvis, D Ketting, SK Wadman. Glutaric aciduria type II: report on a previously undescribed metabolic disorder.. Clin Chim Acta. 1976;66:227-39",
"E Purevjav, M Kimura, Y Takusa, T Ohura, M Tsuchiya, N Hara, T Fukao, S Yamaguchi. Molecular study of electron transfer flavoprotein alpha-subunit deficiency in two Japanese children with different phenotypes of glutaric acidemia type II.. Eur J Clin Invest. 2002;32:707-12",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"M Schiff, R Froissart, RK Olsen, C Acquaviva, C Vianey-Saban. Electron transfer flavoprotein deficiency: functional and molecular aspects.. Mol Genet Metab. 2006;88:153-8",
"A Schulze, M Lindner, D Kohlmüller, K Olgemöller, E Mayatepek, GF Hoffmann. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.. Pediatrics. 2003;111:1399-406",
"A Shioya, H Takuma, S Yamaguchi, A Ishii, M Hiroki, T Fukuda, H Sugie, Y Shigematsu, A Tamaoka. Amelioration of acylcarnitine profile using bezafibrate and riboflavin in a case of adult-onset glutaric acidemia type 2 with novel mutations of the electron transfer flavoprotein dehydrogenase (ETFDH) gene.. J Neurol Sci. 2014;346:350-2",
"KL Stals, M Wakeling, J Baptista, R Caswell, A Parrish, J Rankin, C Tysoe, G Jones, AC Gunning, H Lango Allen, L Bradley, AF Brady, H Carley, J Carmichael, B Castle, D Cilliers, H Cox, C Deshpande, A Dixit, J Eason, F Elmslie, AE Fry, A Fryer, M Holder, T Homfray, E Kivuva, V McKay, R Newbury-Ecob, M Parker, R Savarirayan, C Searle, N Shannon, D Shears, S Smithson, E Thomas, PD Turnpenny, V Varghese, P Vasudevan, E Wakeling, EL Baple, S Ellard. Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.. Prenat Diagn. 2018;38:33-43",
"Y Sudo, A Sasaki, T Wakabayashi, C Numakura, K. Hayasaka. A novel ETFB mutation in a patient with glutaric aciduria type II.. Hum Genome Var. 2015;1:15016",
"JL Van Hove, S Grünewald, J Jaeken, P Demaerel, PE Declercq, P Bourdoux, K Niezen-Koning, JE Deanfeld, JV Leonard. D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD).. Lancet. 2003;361:1433-5",
"WJ Van Rijt, MR Heiner-Fokkema, GJ du Marchie Sarvaas, HR Waterham, RG Blokpoel, FJ van Spronsen, TG Derks. Favorable outcome after physiologic dose of sodium-D,L-3-hydroxybutyrate in severe MADD.. Pediatrics. 2014;134:e1224-8",
"P Vieira, P Myllynen, M Perhomaa, H Tuominen, R Keski-Filppula, S Rytky, L Risteli, J. Uusimaa. Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency associated with hepatoencephalomyopathy and white matter signal abnormalities on brain MRI.. Neuropediatrics. 2017;48:194-8",
"Z Wang, D Hong, W Zhang, W Li, X Shi, D Zhao, X Yang, H Lv, Y Yuan. Severe sensory neuropathy in patients with adult-onset multiple acyl-CoA dehydrogenase deficiency.. Neuromuscul Disord. 2016;26:170-5",
"ZQ Wang, XJ Chen, SX Murong, N Wang, ZY Wu. Molecular analysis of 51 unrelated pedigrees with late-onset multiple acyl-CoA dehydrogenation deficiency (MADD) in southern China confirmed the most common ETFDH mutation and high carrier frequency of c.250G>A.. J Mol Med (Berl) 2011;89:569-76",
"NJ Watmough, FE Frerman. The electron transfer flavoprotein: ubiquinone oxidoreductases.. Biochim Biophys Acta. 2010;1797:1910-6",
"B Wen, T Dai, W Li, Y Zhao, S Liu, C Zhang, H Li, J Wu, D Li, C Yan. Riboflavin-responsive lipid-storage myopathy caused by ETFDH gene mutations.. J Neurol Neurosurg Psychiatry. 2010;81:231-6",
"B Wen, D Li, W Li, Y Zhao, C. Yan. Multiple acyl-CoA dehydrogenation deficiency as decreased acyl-carnitine profile in serum.. Neurol Sci. 2015;36:853-9",
"B Wen, D Li, J Shan, S Liu, W Li, Y Zhao, P Lin, J Zheng, D Li, Y Gong, C. Yan. Increased muscle coenzyme Q10 in riboflavin responsive MADD with ETFDH gene mutations due to secondary mitochondrial proliferation.. Mol Genet Metab. 2013;109:154-60",
"CH Whitaker, KJ Felice, D Silvers, Q Wu. Fulminant lipid storage myopathy due to multiple acyl-coenzyme a dehydrogenase deficiency.. Muscle Nerve. 2015;52:289-93",
"J Xi, B Wen, J Lin, W Zhu, S Luo, C Zhao, D Li, P Lin, J Lu, C. Yan. Clinical features and ETFDH mutation spectrum in a cohort of 90 Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency.. J Inherit Metab Dis. 2014;37:399-404",
"K Yamada, H Kobayashi, R Bo, J Purevsuren, Y Mushimoto, T Takahashi, Y Hasegawa, T Taketani, S Fukuda, S Yamaguchi. Efficacy of bezafibrate on fibroblasts of glutaric acidemia type II patients evaluated using an in vitro probe acylcarnitine assay.. Brain Dev. 2017;39:48-57",
"Y Yotsumoto, Y Hasegawa, S Fukuda, H Kobayashi, M Endo, T Fukao, S Yamaguchi. Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2.. Mol Genet Metab. 2008;94:61-7",
"YW Zhao, XJ Liu, W Zhang, ZX Wang, Y Yuan. Muscle magnetic resonance imaging for the differentiation of multiple acyl-CoA dehydrogenase deficiency and immune-mediated necrotizing myopathy.. Chin Med J (Engl) 2018;131:144-50"
] |
18/6/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
majeed
|
majeed
|
[
"Phosphatidate phosphatase LPIN2",
"LPIN2",
"Majeed Syndrome"
] |
Majeed Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Hatem El-Shanti, Polly Ferguson
|
Summary Majeed syndrome is characterized by: Chronic recurrent multifocal osteomyelitis (CRMO) that is of early onset with a lifelong course; and Congenital dyserythropoietic anemia (CDA) that presents as hypochromic, microcytic anemia during the first year of life and ranges from mild to transfusion dependent. Some individuals also develop a transient inflammatory dermatosis, often manifesting as Sweet syndrome (neutrophilic skin infiltration). The diagnosis is based on clinical findings and molecular genetic testing of Majeed syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the pathogenic variants in the family are known. If the pathogenic variants in the family have been identified, prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.
|
## Diagnosis
The diagnosis of Majeed syndrome is based on the following findings [
Skeletal radiographs show irregular osteolytic (radiolucent) lesions with surrounding sclerosis, usually in the metaphyses of long bones. Hyperostosis may be present in clavicular lesions.
Tc-99 or Ga-67 skeletal scan shows increased uptake at the inflammatory lesions; silent (asymptomatic) lesions may be identified.
MRI may be required to confirm the diagnosis, follow up lesions, or guide biopsy of an active bone lesion. Active bone lesions show increased signal intensity on T
Biopsy of a bone lesion shows nonspecific inflammatory changes with granulocytic infiltration.
Hypochromic, microcytic anemia manifests during the first year of life and ranges from mild to transfusion dependent.
Bone marrow examination shows increased erythropoiesis associated with evidence of dyserythropoiesis including up to 25% of normoblasts that are binucleated and trinucleated. The Ham test is negative.
Biopsy of pustular skin lesions usually shows intraepidermal collection of neutrophils.
Laboratory testing is nonspecific:
The most consistent findings are elevated erythrocyte sedimentation rate [
The white blood cell count may or may not be elevated.
Cultures from blood, bone biopsies, and pustular lesions are always negative.
Molecular Genetic Testing Used in Majeed Syndrome
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis and scanning of the entire gene can have similar variant detection frequencies; however, variant detection rates for scanning may vary considerably between laboratories depending on the specific protocol used.
The variant detection frequency using sequence analysis in individuals with CRMO and microcytic CDA is 100%; the variant detection frequency using scanning is unknown.
Clinical evaluation to identify the three components of Majeed syndrome (may require bone biopsy of affected osteolytic lesion, bone marrow biopsy to document dyserythropoiesis, and skin biopsy to document neutrophilic dermatosis)
Sequence analysis / scanning of
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
• Skeletal radiographs show irregular osteolytic (radiolucent) lesions with surrounding sclerosis, usually in the metaphyses of long bones. Hyperostosis may be present in clavicular lesions.
• Tc-99 or Ga-67 skeletal scan shows increased uptake at the inflammatory lesions; silent (asymptomatic) lesions may be identified.
• MRI may be required to confirm the diagnosis, follow up lesions, or guide biopsy of an active bone lesion. Active bone lesions show increased signal intensity on T
• Biopsy of a bone lesion shows nonspecific inflammatory changes with granulocytic infiltration.
• Skeletal radiographs show irregular osteolytic (radiolucent) lesions with surrounding sclerosis, usually in the metaphyses of long bones. Hyperostosis may be present in clavicular lesions.
• Tc-99 or Ga-67 skeletal scan shows increased uptake at the inflammatory lesions; silent (asymptomatic) lesions may be identified.
• MRI may be required to confirm the diagnosis, follow up lesions, or guide biopsy of an active bone lesion. Active bone lesions show increased signal intensity on T
• Biopsy of a bone lesion shows nonspecific inflammatory changes with granulocytic infiltration.
•
• Hypochromic, microcytic anemia manifests during the first year of life and ranges from mild to transfusion dependent.
• Bone marrow examination shows increased erythropoiesis associated with evidence of dyserythropoiesis including up to 25% of normoblasts that are binucleated and trinucleated. The Ham test is negative.
• Hypochromic, microcytic anemia manifests during the first year of life and ranges from mild to transfusion dependent.
• Bone marrow examination shows increased erythropoiesis associated with evidence of dyserythropoiesis including up to 25% of normoblasts that are binucleated and trinucleated. The Ham test is negative.
• Biopsy of pustular skin lesions usually shows intraepidermal collection of neutrophils.
• Biopsy of pustular skin lesions usually shows intraepidermal collection of neutrophils.
• Skeletal radiographs show irregular osteolytic (radiolucent) lesions with surrounding sclerosis, usually in the metaphyses of long bones. Hyperostosis may be present in clavicular lesions.
• Tc-99 or Ga-67 skeletal scan shows increased uptake at the inflammatory lesions; silent (asymptomatic) lesions may be identified.
• MRI may be required to confirm the diagnosis, follow up lesions, or guide biopsy of an active bone lesion. Active bone lesions show increased signal intensity on T
• Biopsy of a bone lesion shows nonspecific inflammatory changes with granulocytic infiltration.
• Hypochromic, microcytic anemia manifests during the first year of life and ranges from mild to transfusion dependent.
• Bone marrow examination shows increased erythropoiesis associated with evidence of dyserythropoiesis including up to 25% of normoblasts that are binucleated and trinucleated. The Ham test is negative.
• Biopsy of pustular skin lesions usually shows intraepidermal collection of neutrophils.
• The most consistent findings are elevated erythrocyte sedimentation rate [
• The white blood cell count may or may not be elevated.
• Clinical evaluation to identify the three components of Majeed syndrome (may require bone biopsy of affected osteolytic lesion, bone marrow biopsy to document dyserythropoiesis, and skin biopsy to document neutrophilic dermatosis)
• Sequence analysis / scanning of
## Clinical Diagnosis
The diagnosis of Majeed syndrome is based on the following findings [
Skeletal radiographs show irregular osteolytic (radiolucent) lesions with surrounding sclerosis, usually in the metaphyses of long bones. Hyperostosis may be present in clavicular lesions.
Tc-99 or Ga-67 skeletal scan shows increased uptake at the inflammatory lesions; silent (asymptomatic) lesions may be identified.
MRI may be required to confirm the diagnosis, follow up lesions, or guide biopsy of an active bone lesion. Active bone lesions show increased signal intensity on T
Biopsy of a bone lesion shows nonspecific inflammatory changes with granulocytic infiltration.
Hypochromic, microcytic anemia manifests during the first year of life and ranges from mild to transfusion dependent.
Bone marrow examination shows increased erythropoiesis associated with evidence of dyserythropoiesis including up to 25% of normoblasts that are binucleated and trinucleated. The Ham test is negative.
Biopsy of pustular skin lesions usually shows intraepidermal collection of neutrophils.
• Skeletal radiographs show irregular osteolytic (radiolucent) lesions with surrounding sclerosis, usually in the metaphyses of long bones. Hyperostosis may be present in clavicular lesions.
• Tc-99 or Ga-67 skeletal scan shows increased uptake at the inflammatory lesions; silent (asymptomatic) lesions may be identified.
• MRI may be required to confirm the diagnosis, follow up lesions, or guide biopsy of an active bone lesion. Active bone lesions show increased signal intensity on T
• Biopsy of a bone lesion shows nonspecific inflammatory changes with granulocytic infiltration.
• Skeletal radiographs show irregular osteolytic (radiolucent) lesions with surrounding sclerosis, usually in the metaphyses of long bones. Hyperostosis may be present in clavicular lesions.
• Tc-99 or Ga-67 skeletal scan shows increased uptake at the inflammatory lesions; silent (asymptomatic) lesions may be identified.
• MRI may be required to confirm the diagnosis, follow up lesions, or guide biopsy of an active bone lesion. Active bone lesions show increased signal intensity on T
• Biopsy of a bone lesion shows nonspecific inflammatory changes with granulocytic infiltration.
•
• Hypochromic, microcytic anemia manifests during the first year of life and ranges from mild to transfusion dependent.
• Bone marrow examination shows increased erythropoiesis associated with evidence of dyserythropoiesis including up to 25% of normoblasts that are binucleated and trinucleated. The Ham test is negative.
• Hypochromic, microcytic anemia manifests during the first year of life and ranges from mild to transfusion dependent.
• Bone marrow examination shows increased erythropoiesis associated with evidence of dyserythropoiesis including up to 25% of normoblasts that are binucleated and trinucleated. The Ham test is negative.
• Biopsy of pustular skin lesions usually shows intraepidermal collection of neutrophils.
• Biopsy of pustular skin lesions usually shows intraepidermal collection of neutrophils.
• Skeletal radiographs show irregular osteolytic (radiolucent) lesions with surrounding sclerosis, usually in the metaphyses of long bones. Hyperostosis may be present in clavicular lesions.
• Tc-99 or Ga-67 skeletal scan shows increased uptake at the inflammatory lesions; silent (asymptomatic) lesions may be identified.
• MRI may be required to confirm the diagnosis, follow up lesions, or guide biopsy of an active bone lesion. Active bone lesions show increased signal intensity on T
• Biopsy of a bone lesion shows nonspecific inflammatory changes with granulocytic infiltration.
• Hypochromic, microcytic anemia manifests during the first year of life and ranges from mild to transfusion dependent.
• Bone marrow examination shows increased erythropoiesis associated with evidence of dyserythropoiesis including up to 25% of normoblasts that are binucleated and trinucleated. The Ham test is negative.
• Biopsy of pustular skin lesions usually shows intraepidermal collection of neutrophils.
## Testing
Laboratory testing is nonspecific:
The most consistent findings are elevated erythrocyte sedimentation rate [
The white blood cell count may or may not be elevated.
Cultures from blood, bone biopsies, and pustular lesions are always negative.
Molecular Genetic Testing Used in Majeed Syndrome
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis and scanning of the entire gene can have similar variant detection frequencies; however, variant detection rates for scanning may vary considerably between laboratories depending on the specific protocol used.
The variant detection frequency using sequence analysis in individuals with CRMO and microcytic CDA is 100%; the variant detection frequency using scanning is unknown.
• The most consistent findings are elevated erythrocyte sedimentation rate [
• The white blood cell count may or may not be elevated.
## Molecular Genetic Testing
Molecular Genetic Testing Used in Majeed Syndrome
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis and scanning of the entire gene can have similar variant detection frequencies; however, variant detection rates for scanning may vary considerably between laboratories depending on the specific protocol used.
The variant detection frequency using sequence analysis in individuals with CRMO and microcytic CDA is 100%; the variant detection frequency using scanning is unknown.
## Testing Strategy
Clinical evaluation to identify the three components of Majeed syndrome (may require bone biopsy of affected osteolytic lesion, bone marrow biopsy to document dyserythropoiesis, and skin biopsy to document neutrophilic dermatosis)
Sequence analysis / scanning of
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
• Clinical evaluation to identify the three components of Majeed syndrome (may require bone biopsy of affected osteolytic lesion, bone marrow biopsy to document dyserythropoiesis, and skin biopsy to document neutrophilic dermatosis)
• Sequence analysis / scanning of
## Clinical Characteristics
Majeed syndrome is characterized by chronic recurrent multifocal osteomyelitis (CRMO), congenital dyserythropoietic anemia (CDA), and inflammatory dermatosis.
Onset of CRMO ranges from age three weeks to no later than age two years. It is characterized by short remissions, one to three exacerbations per month with each remaining for a few days, and a prolonged, probably lifelong, course. Each exacerbation consists of high fever, severe pain, and the appearance of periarticular tender soft tissue swelling, mainly involving large joints and occasionally small joints. The CRMO in Majeed syndrome is often associated with delayed bone age, growth failure, and development of permanent flexion contractures.
CDA usually presents during the first year of life and varies in severity from mild to transfusion dependent.
The inflammatory dermatosis is not a consistent phenotypic component of Majeed syndrome, although this may be a result of its transient nature. Of the affected individuals reported to date, two brothers had Sweet syndrome, their father had psoriasis, and an affected member of another family had cutaneous pustulosis.
Hepatomegaly, neutropenia, and transient cholestatic jaundice may occur during the neonatal period. These findings have no clinical consequences because they are transient. In rare instances, neutropenia may predispose to infections.
Individuals with Majeed syndrome have linear growth retardation with short adult stature.
If left untreated, the quality of life is poor as a result of recurrent pain, chronic anemia, and possible complications of contractures and disuse atrophy of the muscles.
The oldest individual known to have Majeed syndrome has been lost to follow up since he was about 28 years old.
Although the number of individuals reported with Majeed syndrome is too small to study genotype-phenotype correlations, the affected individuals in the family with a frameshift variant [
Penetrance is 100%.
Majeed syndrome has been known by its components (i.e., CRMO, CDA, and neutrophilic dermatosis).
Majeed syndrome is very rare. The four affected families reported to date are from the Middle East:
One of Jordanian/Palestinian origin, reported from Kuwait
One Jordanian, reported from Jordan
One from Bahrain
One Turkish family residing in Denmark
• One of Jordanian/Palestinian origin, reported from Kuwait
• One Jordanian, reported from Jordan
• One from Bahrain
• One Turkish family residing in Denmark
## Clinical Description
Majeed syndrome is characterized by chronic recurrent multifocal osteomyelitis (CRMO), congenital dyserythropoietic anemia (CDA), and inflammatory dermatosis.
Onset of CRMO ranges from age three weeks to no later than age two years. It is characterized by short remissions, one to three exacerbations per month with each remaining for a few days, and a prolonged, probably lifelong, course. Each exacerbation consists of high fever, severe pain, and the appearance of periarticular tender soft tissue swelling, mainly involving large joints and occasionally small joints. The CRMO in Majeed syndrome is often associated with delayed bone age, growth failure, and development of permanent flexion contractures.
CDA usually presents during the first year of life and varies in severity from mild to transfusion dependent.
The inflammatory dermatosis is not a consistent phenotypic component of Majeed syndrome, although this may be a result of its transient nature. Of the affected individuals reported to date, two brothers had Sweet syndrome, their father had psoriasis, and an affected member of another family had cutaneous pustulosis.
Hepatomegaly, neutropenia, and transient cholestatic jaundice may occur during the neonatal period. These findings have no clinical consequences because they are transient. In rare instances, neutropenia may predispose to infections.
Individuals with Majeed syndrome have linear growth retardation with short adult stature.
If left untreated, the quality of life is poor as a result of recurrent pain, chronic anemia, and possible complications of contractures and disuse atrophy of the muscles.
The oldest individual known to have Majeed syndrome has been lost to follow up since he was about 28 years old.
## Genotype-Phenotype Correlations
Although the number of individuals reported with Majeed syndrome is too small to study genotype-phenotype correlations, the affected individuals in the family with a frameshift variant [
## Penetrance
Penetrance is 100%.
## Nomenclature
Majeed syndrome has been known by its components (i.e., CRMO, CDA, and neutrophilic dermatosis).
## Prevalence
Majeed syndrome is very rare. The four affected families reported to date are from the Middle East:
One of Jordanian/Palestinian origin, reported from Kuwait
One Jordanian, reported from Jordan
One from Bahrain
One Turkish family residing in Denmark
• One of Jordanian/Palestinian origin, reported from Kuwait
• One Jordanian, reported from Jordan
• One from Bahrain
• One Turkish family residing in Denmark
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The clinical diagnosis of Majeed syndrome is straightforward once the complete triad is established, and can be confirmed by identifying any of the various pathogenic variants in
Because of its recurrent febrile episodic course, Majeed syndrome should also be included in the differential diagnosis of the periodic fever syndromes.
The combination of bone and skin involvement, in particular, is shared by a variety of disorders including the following:
Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is believed to be the CRMO of adults with skin, bone, and synovial membrane inflammation. The contribution of genetics to the etiology of SAPHO syndrome is unclear. The early onset and CDA of Majeed syndrome distinguish it from SAPHO syndrome.
Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is characterized by oligoarticular, corticosteroid-responsive arthritis beginning in childhood. Pyoderma gangrenosum and severe cystic acne begin in adolescence. Pathogenic variants in
Sporadic nonsyndromic CRMO is an autoinflammatory bone disease characterized by bone pain with or without fever with an unpredictable course of exacerbation and spontaneous remissions [
Comparison of Sporadic CRMO and CRMO of Majeed Syndrome
CRMO = chronic recurrent multifocal osteomyelitis
Other disorders to consider:
Chronic multifocal non-bacterial osteomyelitis in
Chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome, a chronic congenital inflammatory disorder characterized by cutaneous rash, neurologic impairment, and arthropathy. CINCA is caused by heterozygous pathogenic variants in
Deficiency of the interleukin-1 receptor antagonist (DIRA), a chronic inflammatory disorder that begins in the neonatal period. It presents with generalized pustulosis and osteitis. If not recognized and treated appropriately, affected individuals can develop systemic inflammatory response syndrome (SIRS), which can be a fatal complication of the disease. DIRA is an autosomal recessive disorder caused by pathogenic variants in
Congenital dyserythropoietic anemia (CDA). The CDAs are a heterogeneous group of diseases in which the anemia is predominantly caused by dyserythropoiesis and marked ineffective erythropoiesis [
• Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is believed to be the CRMO of adults with skin, bone, and synovial membrane inflammation. The contribution of genetics to the etiology of SAPHO syndrome is unclear. The early onset and CDA of Majeed syndrome distinguish it from SAPHO syndrome.
• Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is characterized by oligoarticular, corticosteroid-responsive arthritis beginning in childhood. Pyoderma gangrenosum and severe cystic acne begin in adolescence. Pathogenic variants in
• Sporadic nonsyndromic CRMO is an autoinflammatory bone disease characterized by bone pain with or without fever with an unpredictable course of exacerbation and spontaneous remissions [
• Chronic multifocal non-bacterial osteomyelitis in
• Chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome, a chronic congenital inflammatory disorder characterized by cutaneous rash, neurologic impairment, and arthropathy. CINCA is caused by heterozygous pathogenic variants in
• Deficiency of the interleukin-1 receptor antagonist (DIRA), a chronic inflammatory disorder that begins in the neonatal period. It presents with generalized pustulosis and osteitis. If not recognized and treated appropriately, affected individuals can develop systemic inflammatory response syndrome (SIRS), which can be a fatal complication of the disease. DIRA is an autosomal recessive disorder caused by pathogenic variants in
• Congenital dyserythropoietic anemia (CDA). The CDAs are a heterogeneous group of diseases in which the anemia is predominantly caused by dyserythropoiesis and marked ineffective erythropoiesis [
## Management
To establish the extent of disease and needs in an individual diagnosed with Majeed syndrome, the following evaluations are recommended:
Skeletal radiographs, if not already performed
CBC, if not already performed
Bone marrow biopsy if significant anemia is present
Examination of the skin
Consultation with a clinical geneticist and/or genetic counselor
Because of the rarity of Majeed syndrome, treatment is empiric.
Nonsteroidal anti-inflammatory drugs (NSAIDs), which provide moderate improvement. If there is an inadequate response to NSAIDs, corticosteroids are useful in controlling CRMO and skin manifestations; however, their long-term use in children is limited by side effects such as growth delay and cataracts.
Tumor necrosis factor inhibitors and bisphosphonates have been reported to improve sporadic CRMO; however, the two individuals with Majeed syndrome treated with TNF-alpha inhibitors did not improve [
The same two affected individuals reported by Herlin et al who failed to improve with TNF blockade did respond to IL-1 blockade (IL-1 receptor antagonist [anakinra] and IL-1β antibody [canakinumab]) with clinical, radiographic, and laboratory evidence of improvement [
Physical therapy to avoid disuse atrophy of muscles or contractures
Physical therapy can help to prevent contractures.
The following are appropriate:
Routine CBC to determine if red blood cell transfusion is necessary
Regular pediatric care
Prolonged bed rest should be avoided because it can result in joint contractures and disuse atrophy.
See
Search
Three patients were treated with colchicine for four months with no improvement.
• Skeletal radiographs, if not already performed
• CBC, if not already performed
• Bone marrow biopsy if significant anemia is present
• Examination of the skin
• Consultation with a clinical geneticist and/or genetic counselor
• Nonsteroidal anti-inflammatory drugs (NSAIDs), which provide moderate improvement. If there is an inadequate response to NSAIDs, corticosteroids are useful in controlling CRMO and skin manifestations; however, their long-term use in children is limited by side effects such as growth delay and cataracts.
• Tumor necrosis factor inhibitors and bisphosphonates have been reported to improve sporadic CRMO; however, the two individuals with Majeed syndrome treated with TNF-alpha inhibitors did not improve [
• The same two affected individuals reported by Herlin et al who failed to improve with TNF blockade did respond to IL-1 blockade (IL-1 receptor antagonist [anakinra] and IL-1β antibody [canakinumab]) with clinical, radiographic, and laboratory evidence of improvement [
• Physical therapy to avoid disuse atrophy of muscles or contractures
• Routine CBC to determine if red blood cell transfusion is necessary
• Regular pediatric care
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Majeed syndrome, the following evaluations are recommended:
Skeletal radiographs, if not already performed
CBC, if not already performed
Bone marrow biopsy if significant anemia is present
Examination of the skin
Consultation with a clinical geneticist and/or genetic counselor
• Skeletal radiographs, if not already performed
• CBC, if not already performed
• Bone marrow biopsy if significant anemia is present
• Examination of the skin
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Because of the rarity of Majeed syndrome, treatment is empiric.
Nonsteroidal anti-inflammatory drugs (NSAIDs), which provide moderate improvement. If there is an inadequate response to NSAIDs, corticosteroids are useful in controlling CRMO and skin manifestations; however, their long-term use in children is limited by side effects such as growth delay and cataracts.
Tumor necrosis factor inhibitors and bisphosphonates have been reported to improve sporadic CRMO; however, the two individuals with Majeed syndrome treated with TNF-alpha inhibitors did not improve [
The same two affected individuals reported by Herlin et al who failed to improve with TNF blockade did respond to IL-1 blockade (IL-1 receptor antagonist [anakinra] and IL-1β antibody [canakinumab]) with clinical, radiographic, and laboratory evidence of improvement [
Physical therapy to avoid disuse atrophy of muscles or contractures
• Nonsteroidal anti-inflammatory drugs (NSAIDs), which provide moderate improvement. If there is an inadequate response to NSAIDs, corticosteroids are useful in controlling CRMO and skin manifestations; however, their long-term use in children is limited by side effects such as growth delay and cataracts.
• Tumor necrosis factor inhibitors and bisphosphonates have been reported to improve sporadic CRMO; however, the two individuals with Majeed syndrome treated with TNF-alpha inhibitors did not improve [
• The same two affected individuals reported by Herlin et al who failed to improve with TNF blockade did respond to IL-1 blockade (IL-1 receptor antagonist [anakinra] and IL-1β antibody [canakinumab]) with clinical, radiographic, and laboratory evidence of improvement [
• Physical therapy to avoid disuse atrophy of muscles or contractures
## Prevention of Secondary Complications
Physical therapy can help to prevent contractures.
## Surveillance
The following are appropriate:
Routine CBC to determine if red blood cell transfusion is necessary
Regular pediatric care
• Routine CBC to determine if red blood cell transfusion is necessary
• Regular pediatric care
## Agents/Circumstances to Avoid
Prolonged bed rest should be avoided because it can result in joint contractures and disuse atrophy.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Other
Three patients were treated with colchicine for four months with no improvement.
## Genetic Counseling
Majeed syndrome is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
Heterozygotes (carriers) do not have Majeed syndrome, but may have psoriasis.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) do not develop Majeed syndrome, but may have psoriasis.
Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family.
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may be affected or heterozygous. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
• Heterozygotes (carriers) do not have Majeed syndrome, but may have psoriasis.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) do not develop Majeed syndrome, but may have psoriasis.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Majeed syndrome is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
Heterozygotes (carriers) do not have Majeed syndrome, but may have psoriasis.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) do not develop Majeed syndrome, but may have psoriasis.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
• Heterozygotes (carriers) do not have Majeed syndrome, but may have psoriasis.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) do not develop Majeed syndrome, but may have psoriasis.
## Carrier (Heterozygote) Detection
Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family.
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may be affected or heterozygous. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Diagnosis
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
## Resources
Largo Gaslini, 5
Genova 16147
Italy
•
•
•
• Largo Gaslini, 5
• Genova 16147
• Italy
•
## Molecular Genetics
Majeed Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Majeed Syndrome (
The fourth nucleotide variant is a missense variant that changes an evolutionarily conserved amino acid (see
Selected
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## References
## Literature Cited
## Chapter Notes
Hatem El-Shanti, MD (2008-present)Polly Ferguson, MD (2013-present)Hasan A Majeed, FRCPI, DCH; Jordan University (2008-2009 *)
* Professor Hasan A Majeed was a distinguished pediatrician and astute scientist. He was a world-renowned expert on autoinflammatory disorders, contributing tens of manuscripts on the topic in the form of published journal articles, chapters in books, and proceedings in international conferences. Professor Majeed died in November, 2009, at the age of 75 years. He was a great teacher who took pride in educating and training hundreds of physicians. He is greatly missed by his family, friends, colleagues, students, and patients.
12 September 2019 (ma) Chapter retired: extremely rare
14 March 2013 (me) Comprehensive update posted live
23 September 2008 (cg) Review posted live
26 June 2008 (ham) Original submission
• 12 September 2019 (ma) Chapter retired: extremely rare
• 14 March 2013 (me) Comprehensive update posted live
• 23 September 2008 (cg) Review posted live
• 26 June 2008 (ham) Original submission
## Author Notes
## Author History
Hatem El-Shanti, MD (2008-present)Polly Ferguson, MD (2013-present)Hasan A Majeed, FRCPI, DCH; Jordan University (2008-2009 *)
* Professor Hasan A Majeed was a distinguished pediatrician and astute scientist. He was a world-renowned expert on autoinflammatory disorders, contributing tens of manuscripts on the topic in the form of published journal articles, chapters in books, and proceedings in international conferences. Professor Majeed died in November, 2009, at the age of 75 years. He was a great teacher who took pride in educating and training hundreds of physicians. He is greatly missed by his family, friends, colleagues, students, and patients.
## Revision History
12 September 2019 (ma) Chapter retired: extremely rare
14 March 2013 (me) Comprehensive update posted live
23 September 2008 (cg) Review posted live
26 June 2008 (ham) Original submission
• 12 September 2019 (ma) Chapter retired: extremely rare
• 14 March 2013 (me) Comprehensive update posted live
• 23 September 2008 (cg) Review posted live
• 26 June 2008 (ham) Original submission
|
[
"I Aksentijevich, SL Masters, PJ Ferguson, P Dancey, J Frenkel, A van Royen-Kerkhoff, R Laxer, U Tedgård, E Cowen, T-H Pham, M Booty, JD Estes, NG Sandler, N Plass, DL Stone, ML Turner, S Hill, JA Butman, R Schneider, P Babyn, HI El-Shanti, E Pope, K Barron, X Bing, A Laurence, C-CR Lee, D Chapelle, GI Clarke, K Ohson, M Nicholson, M Gadina, B Yang, BD Korman, PK Gregersen, PM van Hagen, AE Hak, M Huizing, P Rahman, DC Douek, EF Remmers, DL Kastner, R Goldbach-Mansky. An autoinflammatory disease with deficiency of the interleukin-1 receptor antagonist.. N Engl J Med 2009;360:2426-37",
"I Aksentijevich, M Nowak, M Mallah, JJ Chae, WT Watford, SR Hofmann, L Stein, R Russo, D Goldsmith, P Dent, HF Rosenberg, F Austin, EF Remmers, JE Balow, S Rosenzweig, H Komarow, NG Shoham, G Wood, J Jones, N Mangra, H Carrero, BS Adams, TL Moore, K Schikler, H Hoffman, DJ Lovell, R Lipnick, K Barron, JJ O'Shea, DL Kastner, R Goldbach-Mansky. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases.. Arthritis Rheum 2002;46:3340-8",
"ZS Al-Mosawi, KK Al-Saad, R Ijadi-Maghsoodi, HI El-Shanti, PJ Ferguson. A splice site mutation confirms the role of LPIN2 in Majeed syndrome.. Arthritis Rheum 2007;56:960-4",
"HI El-Shanti, PJ Ferguson. Chronic recurrent multifocal osteomyelitis: a concise review and genetic update.. Clin Orthop Relat Res 2007:11-9",
"PJ Ferguson, HI El-Shanti. Autoinflammatory bone disorders.. Curr Opin Rheumatol 2007;19:492-8",
"HJ Girschick, E Mornet, M Beer, M Warmuth-Metz, P Schneider. Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy.. BMC Pediatr 2007;7:3",
"T Herlin, B Fiirgaard, M Bjerre, G Kerndrup, H Hasle, X Bing, PJ Ferguson. Efficacy of anti-IL-1 treatment in Majeed syndrome.. Ann Rheum Dis 2013;72:410-3",
"HA Majeed, M Al-Tarawna, H El-Shanti, B Kamel, F Al-Khalaileh. The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review.. Eur J Pediatr 2001;160:705-10",
"HA Majeed, H El-Shanti, H Al-Rimawi, N Al-Masri. On mice and men: an autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia.. J Pediatr 2000;137:441-2",
"SN Wickramasinghe, WG Wood. Advances in the understanding of the congenital dyserythropoietic anaemias.. Br J Haematol 2005;131:431-46"
] |
23/9/2008
|
14/3/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
maps
|
maps
|
[
"Multiple Colorectal Adenomas, Autosomal Recessive",
"MUTYH-Associated Polyposis (MAP)",
"Multiple Colorectal Adenomas, Autosomal Recessive",
"MUTYH-Associated Polyposis (MAP)",
"Adenine DNA glycosylase",
"MUTYH",
"MUTYH Polyposis"
] |
Maartje Nielsen, Elena Infante, Randall Brand
|
Summary The diagnosis is established in a proband by identification of biallelic germline pathogenic variants in Individuals with a heterozygous germline MAP is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier with a small increased risk for CRC, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
|
## Diagnosis
A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years
A personal cumulative lifetime history of 20 or more colorectal adenomas in an individual of any age
A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps (excluding rectal and sigmoid hyperplastic polyps)
Sessile serrated polyposis syndrome:
At least five serrated polyps proximal to the sigmoid colon, of which two or more are >10 mm; OR
>20 serrated polyps of any size distributed throughout the colon (excluding hyperplastic polyps found in the rectum and sigmoid colon)
Duodenal polyp(s) and/or duodenal cancer
Colorectal cancer with or without a history of polyps and identification of a somatic
The diagnosis of MAP
For an introduction to multigene panels click
Germline Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A large (>4.2-kb) deletion encompassing exons 4-16 has been reported in three affected individuals from Spain, France, and Brazil, indicating a possible southern European founder variant [
Detection Frequency of Biallelic Germline
Based on
• A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years
• A personal cumulative lifetime history of 20 or more colorectal adenomas in an individual of any age
• A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps (excluding rectal and sigmoid hyperplastic polyps)
• Sessile serrated polyposis syndrome:
• At least five serrated polyps proximal to the sigmoid colon, of which two or more are >10 mm; OR
• >20 serrated polyps of any size distributed throughout the colon (excluding hyperplastic polyps found in the rectum and sigmoid colon)
• At least five serrated polyps proximal to the sigmoid colon, of which two or more are >10 mm; OR
• >20 serrated polyps of any size distributed throughout the colon (excluding hyperplastic polyps found in the rectum and sigmoid colon)
• Duodenal polyp(s) and/or duodenal cancer
• Colorectal cancer with or without a history of polyps and identification of a somatic
• At least five serrated polyps proximal to the sigmoid colon, of which two or more are >10 mm; OR
• >20 serrated polyps of any size distributed throughout the colon (excluding hyperplastic polyps found in the rectum and sigmoid colon)
• For an introduction to multigene panels click
## Suggestive Findings
A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years
A personal cumulative lifetime history of 20 or more colorectal adenomas in an individual of any age
A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps (excluding rectal and sigmoid hyperplastic polyps)
Sessile serrated polyposis syndrome:
At least five serrated polyps proximal to the sigmoid colon, of which two or more are >10 mm; OR
>20 serrated polyps of any size distributed throughout the colon (excluding hyperplastic polyps found in the rectum and sigmoid colon)
Duodenal polyp(s) and/or duodenal cancer
Colorectal cancer with or without a history of polyps and identification of a somatic
• A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years
• A personal cumulative lifetime history of 20 or more colorectal adenomas in an individual of any age
• A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps (excluding rectal and sigmoid hyperplastic polyps)
• Sessile serrated polyposis syndrome:
• At least five serrated polyps proximal to the sigmoid colon, of which two or more are >10 mm; OR
• >20 serrated polyps of any size distributed throughout the colon (excluding hyperplastic polyps found in the rectum and sigmoid colon)
• At least five serrated polyps proximal to the sigmoid colon, of which two or more are >10 mm; OR
• >20 serrated polyps of any size distributed throughout the colon (excluding hyperplastic polyps found in the rectum and sigmoid colon)
• Duodenal polyp(s) and/or duodenal cancer
• Colorectal cancer with or without a history of polyps and identification of a somatic
• At least five serrated polyps proximal to the sigmoid colon, of which two or more are >10 mm; OR
• >20 serrated polyps of any size distributed throughout the colon (excluding hyperplastic polyps found in the rectum and sigmoid colon)
## Establishing the Diagnosis
The diagnosis of MAP
For an introduction to multigene panels click
Germline Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A large (>4.2-kb) deletion encompassing exons 4-16 has been reported in three affected individuals from Spain, France, and Brazil, indicating a possible southern European founder variant [
Detection Frequency of Biallelic Germline
Based on
• For an introduction to multigene panels click
## Clinical Characteristics
Cancer Risks in Individuals with
US National Cancer Institute's
Unclear if the risk for this type of cancer is increased in individuals with MAP
Including basal cell carcinoma
Molecular genetic testing of individuals with CRC has revealed that up to one third of persons with biallelic germline
In the absence of timely surveillance, the lifetime risk for CRC in individuals with MAP was between 80% and 90% [
In one report, survival of individuals with
Thyroid nodules were identified in 16 of 24 individuals with MAP examined by ultrasound [
The risk for CRC in individuals heterozygous for a germline
The risk of developing extraintestinal cancer in
A heterozygous
Functional studies have shown differences in glycosylase activity between the
For other common variants, such as p.Glu324His, which has up to a 50% minor allele frequency in some populations [
An outdated term for
The gene formerly designated
It is estimated that 1%-2% of the general northern European, Australian, and US populations are heterozygous for a germline
MAP is estimated to account for 0.7% of all CRC and between 0.5% and 6% of cohorts of familial or early-onset CRC in which affected individuals have a low number of adenomas (<15-20) [
Percentage of Persons with MAP by Age at Diagnosis of CRC
Review of literature,
CRC = colorectal cancer
• Thyroid nodules were identified in 16 of 24 individuals with MAP examined by ultrasound [
## Clinical Description
Cancer Risks in Individuals with
US National Cancer Institute's
Unclear if the risk for this type of cancer is increased in individuals with MAP
Including basal cell carcinoma
Molecular genetic testing of individuals with CRC has revealed that up to one third of persons with biallelic germline
In the absence of timely surveillance, the lifetime risk for CRC in individuals with MAP was between 80% and 90% [
In one report, survival of individuals with
Thyroid nodules were identified in 16 of 24 individuals with MAP examined by ultrasound [
The risk for CRC in individuals heterozygous for a germline
The risk of developing extraintestinal cancer in
A heterozygous
• Thyroid nodules were identified in 16 of 24 individuals with MAP examined by ultrasound [
## Heterozygotes
The risk for CRC in individuals heterozygous for a germline
The risk of developing extraintestinal cancer in
A heterozygous
## Genotype-Phenotype Correlations
Functional studies have shown differences in glycosylase activity between the
For other common variants, such as p.Glu324His, which has up to a 50% minor allele frequency in some populations [
## Nomenclature
An outdated term for
The gene formerly designated
## Prevalence
It is estimated that 1%-2% of the general northern European, Australian, and US populations are heterozygous for a germline
MAP is estimated to account for 0.7% of all CRC and between 0.5% and 6% of cohorts of familial or early-onset CRC in which affected individuals have a low number of adenomas (<15-20) [
Percentage of Persons with MAP by Age at Diagnosis of CRC
Review of literature,
CRC = colorectal cancer
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of
0-100 colonic polyps
CRC risk: 70%
100 colonic polyps
Upper GI polyps
CRC risk: 100%
Small bowel
Pancreatic
Thyroid
Liver
Brain
Bile duct
Gastric
CHRPE
Osteomas
Supernumerary or missing teeth
Cutaneous lesions
Desmoid tumors
8-50 adenomatous colonic polyps
Duodenal adenomas
CRC in 16/29 individuals
Uterine
Duodenal
Breast
Premalignant endometrial lesions
2nd most common AR form of colon cancer & polyps after MAP
4% develop ≥10 polyps
Colon tumors often MSI+
CRC risk: 52%-82%
Uterine
Ovarian
Small bowel
Gastric
Urinary tract
Skin
Brain
Hepatobiliary tract
Pancreas
Prostate
GI hamartomatous polyps
Polyps most often in small bowel
Adenomatous colonic polyps can occur.
CRC risk: 39%
Gastric
Breast
Ovarian
Small bowel
Pancreas
Cervix
Uterine
Lung
Testicular
Ovarian sex cord tumors w/annular tubules
Dk-brown to dk-blue melanocytic macules (fade w/age)
Hamartomatous (juvenile) polyps in small bowel, stomach, colon, & rectum
CRC risk: 38.7%
Gastric
Upper GI tract
Pancreas
Multiple hamartomatous & mixed polyps in GI tract
CRC risk: 9%
Breast
Thyroid
Uterine
Renal
Brain
Melanoma
Thyroid disease/nodules
Uterine fibroids
Macrocephaly
Lipomas
Mucocutaneous lesions
Pigmented macules of glans penis
Hamartomatous overgrowth of tissues
Connective tissue nevi
Epidermal nevi
Hyperostoses
Adenomatous polyps, juvenile polyps, hyperplastic polyps, & polyps containing mixed histology
↑ CRC risk
Sessile serrated polyps, serrated adenomas, or hyperplastic polyps of GI tract
CRC risk: ≤54%
AD = autosomal dominant; AR = autosomal recessive; CHRPE = congenital hypertrophy of the retinal pigment epithelium; CRC = colorectal cancer; FAP = familial adenomatous polyposis; MAP =
Leads to overexpression of
• 0-100 colonic polyps
• CRC risk: 70%
• 100 colonic polyps
• Upper GI polyps
• CRC risk: 100%
• Small bowel
• Pancreatic
• Thyroid
• Liver
• Brain
• Bile duct
• Gastric
• CHRPE
• Osteomas
• Supernumerary or missing teeth
• Cutaneous lesions
• Desmoid tumors
• 8-50 adenomatous colonic polyps
• Duodenal adenomas
• CRC in 16/29 individuals
• Uterine
• Duodenal
• Breast
• Premalignant endometrial lesions
• 2nd most common AR form of colon cancer & polyps after MAP
• 4% develop ≥10 polyps
• Colon tumors often MSI+
• CRC risk: 52%-82%
• Uterine
• Ovarian
• Small bowel
• Gastric
• Urinary tract
• Skin
• Brain
• Hepatobiliary tract
• Pancreas
• Prostate
• GI hamartomatous polyps
• Polyps most often in small bowel
• Adenomatous colonic polyps can occur.
• CRC risk: 39%
• Gastric
• Breast
• Ovarian
• Small bowel
• Pancreas
• Cervix
• Uterine
• Lung
• Testicular
• Ovarian sex cord tumors w/annular tubules
• Dk-brown to dk-blue melanocytic macules (fade w/age)
• Hamartomatous (juvenile) polyps in small bowel, stomach, colon, & rectum
• CRC risk: 38.7%
• Gastric
• Upper GI tract
• Pancreas
• Multiple hamartomatous & mixed polyps in GI tract
• CRC risk: 9%
• Breast
• Thyroid
• Uterine
• Renal
• Brain
• Melanoma
• Thyroid disease/nodules
• Uterine fibroids
• Macrocephaly
• Lipomas
• Mucocutaneous lesions
• Pigmented macules of glans penis
• Hamartomatous overgrowth of tissues
• Connective tissue nevi
• Epidermal nevi
• Hyperostoses
• Adenomatous polyps, juvenile polyps, hyperplastic polyps, & polyps containing mixed histology
• ↑ CRC risk
• Sessile serrated polyps, serrated adenomas, or hyperplastic polyps of GI tract
• CRC risk: ≤54%
## Management
To establish the extent of disease and needs of an individual diagnosed with
Review of personal medical history with emphasis on those features related to MAP or colorectal cancer (CRC): colon polyps (majority are adenomas), rectal bleeding, abdominal pain and discomfort, bloating, diarrhea
Colonoscopy and review of pathology
Baseline upper endoscopy including visualization of the major ampulla starting at age 30-35 years
Baseline thyroid ultrasound examination [
Consider skin examination by a dermatologist.
Consultation with a clinical geneticist and/or genetic counselor
Currently, investigations for other extracolonic manifestations of MAP are not recommended at the time of initial diagnosis.
Practice parameters, including information on surgery, have been outlined by the following resources:
National Comprehensive Cancer Network [
American College of Gastroenterology [
American Society of Colon and Rectal Surgeons [
American Society of Clinical Oncology [
Society of Surgical Oncology [
Types of colectomy include the following:
Proctocolectomy with ileal pouch anal anastomosis (IPAA), which can be performed laparoscopically, laparoscopically assisted, or open
Total colectomy with ileorectal anastomosis (IRA)
Total proctocolectomy with permanent ileostomy
The choice of procedure depends on the clinical circumstances.
An IPAA is generally performed when the rectal polyp burden is high or as a second procedure after IRA when rectal disease burden cannot be managed endoscopically. The advantages of this procedure are near-elimination of risk for rectal cancer and relatively good preservation of bowel function. There may be an increased risk for bladder/sexual dysfunction and functional results can be variable.
An IRA is generally considered when the rectal polyp burden is low and deemed to be endoscopically manageable. It is a technically straightforward procedure with low complication rates. It is usually associated with good functional outcome and minimizes risk for sexual or urinary dysfunction. This procedure should not be performed if there is severe rectal disease or the individual cannot reliably undergo endoscopic surveillance of the remaining rectum postoperatively.
A total proctocolectomy with end ileostomy is almost never required unless a proctocolectomy is necessary (due to rectal polyp/cancer burden) and a contraindication to IPAA is present (e.g., a mesenteric desmoid preventing a pouch from reaching pelvic floor, low rectal cancer invading pelvic floor, or individual preference due to poor sphincter control).
For many individuals with MAP, colonic polyps are limited in number and surveillance with periodic colonoscopic polypectomy is sufficient to prevent CRC. Colonoscopy is therefore used for surveillance and prevention of CRC.
To reduce the risk for duodenal/periampullary adenocarcinoma, endoscopic or surgical removal of duodenal and/or ampullary adenomas should be considered if polyps exhibit villous change or severe dysplasia, exceed 1 cm in diameter, or cause symptoms.
Recommended Surveillance for Individuals with
Based on the US-based National Comprehensive Cancer Network (NCCN) guidelines [
If only small adenoma burden (<20 adenomas, <1 cm, and none with advanced histology [
Consider chromoendoscopy, which showed improved diagnostic yield in a recent study [
Based on findings using Spigelman Criteria [
Surveillance beyond existing protocols that are offered to the general population in most Western countries are not firmly recommended in the NCCN guidelines due to limited data.
One published report on 62
For
Currently, no studies have investigated external factors or lifestyle factors that could affect the severity of the manifestations of
Smoking may affect polyp development based on a case report of monozygotic twins with MAP in which a somewhat more severe phenotype was observed in the sister who smoked compared to her twin sister who did not smoke. While both twins had about 30 smaller low-grade adenomas, the twin sister who smoked also had three larger (6-10 mm) adenomas and one focal high-grade adenoma of 70 mm [
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with MAP by molecular genetic testing for the
See
Search
• Review of personal medical history with emphasis on those features related to MAP or colorectal cancer (CRC): colon polyps (majority are adenomas), rectal bleeding, abdominal pain and discomfort, bloating, diarrhea
• Colonoscopy and review of pathology
• Baseline upper endoscopy including visualization of the major ampulla starting at age 30-35 years
• Baseline thyroid ultrasound examination [
• Consider skin examination by a dermatologist.
• Consultation with a clinical geneticist and/or genetic counselor
• National Comprehensive Cancer Network [
• American College of Gastroenterology [
• American Society of Colon and Rectal Surgeons [
• American Society of Clinical Oncology [
• Society of Surgical Oncology [
• Proctocolectomy with ileal pouch anal anastomosis (IPAA), which can be performed laparoscopically, laparoscopically assisted, or open
• Total colectomy with ileorectal anastomosis (IRA)
• Total proctocolectomy with permanent ileostomy
• An IPAA is generally performed when the rectal polyp burden is high or as a second procedure after IRA when rectal disease burden cannot be managed endoscopically. The advantages of this procedure are near-elimination of risk for rectal cancer and relatively good preservation of bowel function. There may be an increased risk for bladder/sexual dysfunction and functional results can be variable.
• An IRA is generally considered when the rectal polyp burden is low and deemed to be endoscopically manageable. It is a technically straightforward procedure with low complication rates. It is usually associated with good functional outcome and minimizes risk for sexual or urinary dysfunction. This procedure should not be performed if there is severe rectal disease or the individual cannot reliably undergo endoscopic surveillance of the remaining rectum postoperatively.
• A total proctocolectomy with end ileostomy is almost never required unless a proctocolectomy is necessary (due to rectal polyp/cancer burden) and a contraindication to IPAA is present (e.g., a mesenteric desmoid preventing a pouch from reaching pelvic floor, low rectal cancer invading pelvic floor, or individual preference due to poor sphincter control).
• For
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with
Review of personal medical history with emphasis on those features related to MAP or colorectal cancer (CRC): colon polyps (majority are adenomas), rectal bleeding, abdominal pain and discomfort, bloating, diarrhea
Colonoscopy and review of pathology
Baseline upper endoscopy including visualization of the major ampulla starting at age 30-35 years
Baseline thyroid ultrasound examination [
Consider skin examination by a dermatologist.
Consultation with a clinical geneticist and/or genetic counselor
Currently, investigations for other extracolonic manifestations of MAP are not recommended at the time of initial diagnosis.
• Review of personal medical history with emphasis on those features related to MAP or colorectal cancer (CRC): colon polyps (majority are adenomas), rectal bleeding, abdominal pain and discomfort, bloating, diarrhea
• Colonoscopy and review of pathology
• Baseline upper endoscopy including visualization of the major ampulla starting at age 30-35 years
• Baseline thyroid ultrasound examination [
• Consider skin examination by a dermatologist.
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Practice parameters, including information on surgery, have been outlined by the following resources:
National Comprehensive Cancer Network [
American College of Gastroenterology [
American Society of Colon and Rectal Surgeons [
American Society of Clinical Oncology [
Society of Surgical Oncology [
Types of colectomy include the following:
Proctocolectomy with ileal pouch anal anastomosis (IPAA), which can be performed laparoscopically, laparoscopically assisted, or open
Total colectomy with ileorectal anastomosis (IRA)
Total proctocolectomy with permanent ileostomy
The choice of procedure depends on the clinical circumstances.
An IPAA is generally performed when the rectal polyp burden is high or as a second procedure after IRA when rectal disease burden cannot be managed endoscopically. The advantages of this procedure are near-elimination of risk for rectal cancer and relatively good preservation of bowel function. There may be an increased risk for bladder/sexual dysfunction and functional results can be variable.
An IRA is generally considered when the rectal polyp burden is low and deemed to be endoscopically manageable. It is a technically straightforward procedure with low complication rates. It is usually associated with good functional outcome and minimizes risk for sexual or urinary dysfunction. This procedure should not be performed if there is severe rectal disease or the individual cannot reliably undergo endoscopic surveillance of the remaining rectum postoperatively.
A total proctocolectomy with end ileostomy is almost never required unless a proctocolectomy is necessary (due to rectal polyp/cancer burden) and a contraindication to IPAA is present (e.g., a mesenteric desmoid preventing a pouch from reaching pelvic floor, low rectal cancer invading pelvic floor, or individual preference due to poor sphincter control).
• National Comprehensive Cancer Network [
• American College of Gastroenterology [
• American Society of Colon and Rectal Surgeons [
• American Society of Clinical Oncology [
• Society of Surgical Oncology [
• Proctocolectomy with ileal pouch anal anastomosis (IPAA), which can be performed laparoscopically, laparoscopically assisted, or open
• Total colectomy with ileorectal anastomosis (IRA)
• Total proctocolectomy with permanent ileostomy
• An IPAA is generally performed when the rectal polyp burden is high or as a second procedure after IRA when rectal disease burden cannot be managed endoscopically. The advantages of this procedure are near-elimination of risk for rectal cancer and relatively good preservation of bowel function. There may be an increased risk for bladder/sexual dysfunction and functional results can be variable.
• An IRA is generally considered when the rectal polyp burden is low and deemed to be endoscopically manageable. It is a technically straightforward procedure with low complication rates. It is usually associated with good functional outcome and minimizes risk for sexual or urinary dysfunction. This procedure should not be performed if there is severe rectal disease or the individual cannot reliably undergo endoscopic surveillance of the remaining rectum postoperatively.
• A total proctocolectomy with end ileostomy is almost never required unless a proctocolectomy is necessary (due to rectal polyp/cancer burden) and a contraindication to IPAA is present (e.g., a mesenteric desmoid preventing a pouch from reaching pelvic floor, low rectal cancer invading pelvic floor, or individual preference due to poor sphincter control).
## Prevention of Primary Manifestations
For many individuals with MAP, colonic polyps are limited in number and surveillance with periodic colonoscopic polypectomy is sufficient to prevent CRC. Colonoscopy is therefore used for surveillance and prevention of CRC.
To reduce the risk for duodenal/periampullary adenocarcinoma, endoscopic or surgical removal of duodenal and/or ampullary adenomas should be considered if polyps exhibit villous change or severe dysplasia, exceed 1 cm in diameter, or cause symptoms.
## Surveillance
Recommended Surveillance for Individuals with
Based on the US-based National Comprehensive Cancer Network (NCCN) guidelines [
If only small adenoma burden (<20 adenomas, <1 cm, and none with advanced histology [
Consider chromoendoscopy, which showed improved diagnostic yield in a recent study [
Based on findings using Spigelman Criteria [
Surveillance beyond existing protocols that are offered to the general population in most Western countries are not firmly recommended in the NCCN guidelines due to limited data.
One published report on 62
For
• For
## Individuals Heterozygous for a Germline
One published report on 62
For
• For
## Agents/Circumstances to Avoid
Currently, no studies have investigated external factors or lifestyle factors that could affect the severity of the manifestations of
Smoking may affect polyp development based on a case report of monozygotic twins with MAP in which a somewhat more severe phenotype was observed in the sister who smoked compared to her twin sister who did not smoke. While both twins had about 30 smaller low-grade adenomas, the twin sister who smoked also had three larger (6-10 mm) adenomas and one focal high-grade adenoma of 70 mm [
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with MAP by molecular genetic testing for the
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygous relatives of an individual with MAP are at a two- or at most threefold increased risk for late-onset colorectal cancer (CRC) (see Clinical Description,
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygous relatives of individuals with MAP are at a two- or, at most, threefold increased risk for late-onset CRC (see Clinical Description,
Unless the reproductive partner of a proband is heterozygous for a
The carrier (heterozygote) frequency in the general northern European, Australian, and US population for a
Carrier testing for at-risk relatives requires prior identification of the
Reproductive partners of individuals with one or two
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) and molecular genetic testing when this has not been done before, to young adults who are affected, are carriers, or at risk of being carriers and to their reproductive partner to determine the risk of MAP in offspring (see
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygous relatives of an individual with MAP are at a two- or at most threefold increased risk for late-onset colorectal cancer (CRC) (see Clinical Description,
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygous relatives of individuals with MAP are at a two- or, at most, threefold increased risk for late-onset CRC (see Clinical Description,
• Unless the reproductive partner of a proband is heterozygous for a
• The carrier (heterozygote) frequency in the general northern European, Australian, and US population for a
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) and molecular genetic testing when this has not been done before, to young adults who are affected, are carriers, or at risk of being carriers and to their reproductive partner to determine the risk of MAP in offspring (see
## Mode of Inheritance
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygous relatives of an individual with MAP are at a two- or at most threefold increased risk for late-onset colorectal cancer (CRC) (see Clinical Description,
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygous relatives of individuals with MAP are at a two- or, at most, threefold increased risk for late-onset CRC (see Clinical Description,
Unless the reproductive partner of a proband is heterozygous for a
The carrier (heterozygote) frequency in the general northern European, Australian, and US population for a
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygous relatives of an individual with MAP are at a two- or at most threefold increased risk for late-onset colorectal cancer (CRC) (see Clinical Description,
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygous relatives of individuals with MAP are at a two- or, at most, threefold increased risk for late-onset CRC (see Clinical Description,
• Unless the reproductive partner of a proband is heterozygous for a
• The carrier (heterozygote) frequency in the general northern European, Australian, and US population for a
## Heterozygote Detection
Carrier testing for at-risk relatives requires prior identification of the
Reproductive partners of individuals with one or two
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) and molecular genetic testing when this has not been done before, to young adults who are affected, are carriers, or at risk of being carriers and to their reproductive partner to determine the risk of MAP in offspring (see
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) and molecular genetic testing when this has not been done before, to young adults who are affected, are carriers, or at risk of being carriers and to their reproductive partner to determine the risk of MAP in offspring (see
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
MUTYH Polyposis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MUTYH Polyposis (
DNA base excision repair plays a critical role in DNA damage repair caused by ionizing radiation, various chemical oxidants, and reactive oxygen species. In humans, the most mutagenic species from oxidative damage is 8-oxo7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), which tends to mispair with adenine instead of the usual cytosine. This leads to G:C>T:A transversions in the DNA [
The following enzymes work together in DNA base excision repair to prevent mutagenesis by DNA damage-produced 8-oxo-dG:
8-oxo-dGTPase (encoded by
N-glycosylase/DNA lyase (encoded by
Adenine DNA glycosylase (encoded by
Following current
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
In general, MAP carcinomas somewhat mimic Lynch and sporadic mismatch repair (MMR)-deficient tumors with a frequently proximal location in the colon and a high number of tumor-infiltrating lymphocytes (TILs) [
Recent studies performed whole-exome sequencing in MAP carcinomas and adenomas [
The overall mutation rate in MAP carcinomas was estimated at approximately twofold higher than in microsatellite-stable (MSS) carcinomas – in contrast to MSI CRCs, which are characterized by an almost tenfold increase over MSS carcinomas [
• 8-oxo-dGTPase (encoded by
• N-glycosylase/DNA lyase (encoded by
• Adenine DNA glycosylase (encoded by
## Molecular Pathogenesis
DNA base excision repair plays a critical role in DNA damage repair caused by ionizing radiation, various chemical oxidants, and reactive oxygen species. In humans, the most mutagenic species from oxidative damage is 8-oxo7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), which tends to mispair with adenine instead of the usual cytosine. This leads to G:C>T:A transversions in the DNA [
The following enzymes work together in DNA base excision repair to prevent mutagenesis by DNA damage-produced 8-oxo-dG:
8-oxo-dGTPase (encoded by
N-glycosylase/DNA lyase (encoded by
Adenine DNA glycosylase (encoded by
Following current
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• 8-oxo-dGTPase (encoded by
• N-glycosylase/DNA lyase (encoded by
• Adenine DNA glycosylase (encoded by
## Cancer and Benign Tumors
In general, MAP carcinomas somewhat mimic Lynch and sporadic mismatch repair (MMR)-deficient tumors with a frequently proximal location in the colon and a high number of tumor-infiltrating lymphocytes (TILs) [
Recent studies performed whole-exome sequencing in MAP carcinomas and adenomas [
The overall mutation rate in MAP carcinomas was estimated at approximately twofold higher than in microsatellite-stable (MSS) carcinomas – in contrast to MSI CRCs, which are characterized by an almost tenfold increase over MSS carcinomas [
## Chapter Notes
The authors of this manuscript would like to thank Beth Dudley, MS, MPH, CGC for her assistance in editing and providing feedback about this
Randall Brand, MD (2012-present)Elena Infante, MS, CGC (2012-present)Henry Lynch, MD; Creighton University (2012-2019)Maartje Nielsen, MD (2012-present)
27 May 2021 (mn) Revision: variant removed from
10 October 2019 (sw) Comprehensive update posted live
24 September 2015 (me) Comprehensive update posted live
4 October 2012 (me) Review posted live
21 June 2011 (ei) Original submission
• 27 May 2021 (mn) Revision: variant removed from
• 10 October 2019 (sw) Comprehensive update posted live
• 24 September 2015 (me) Comprehensive update posted live
• 4 October 2012 (me) Review posted live
• 21 June 2011 (ei) Original submission
## Acknowledgments
The authors of this manuscript would like to thank Beth Dudley, MS, MPH, CGC for her assistance in editing and providing feedback about this
## Author History
Randall Brand, MD (2012-present)Elena Infante, MS, CGC (2012-present)Henry Lynch, MD; Creighton University (2012-2019)Maartje Nielsen, MD (2012-present)
## Revision History
27 May 2021 (mn) Revision: variant removed from
10 October 2019 (sw) Comprehensive update posted live
24 September 2015 (me) Comprehensive update posted live
4 October 2012 (me) Review posted live
21 June 2011 (ei) Original submission
• 27 May 2021 (mn) Revision: variant removed from
• 10 October 2019 (sw) Comprehensive update posted live
• 24 September 2015 (me) Comprehensive update posted live
• 4 October 2012 (me) Review posted live
• 21 June 2011 (ei) Original submission
## References
## Published Guidelines / Consensus Statements
## Literature Cited
|
[] |
4/10/2012
|
10/10/2019
|
27/5/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
marfan
|
marfan
|
[
"Fibrillin-1",
"FBN1",
"FBN1-Related Marfan Syndrome"
] |
Harry Dietz
|
Summary The diagnosis of Marfan syndrome is established in a proband (by definition a person without a known family history of Marfan syndrome) who has an Aortic root enlargement (z score ≥2.0) Ectopia lentis By molecular genetic testing if the In those with a rigorously defined family history of Marfan syndrome, by the presence of ONE OR MORE of the following: Ectopia lentis A systemic score ≥7 Aortic root dilatation (z score ≥2.0 for individuals age ≥20 years or z score ≥3.0 for those age <20 years) Individuals with Marfan syndrome who anticipate pregnancy or become pregnant should continue use of beta-blockers; however, some other classes of medications such as ARBs should be discontinued because of the increased risk for fetal loss, oligohydramnios, and abnormal development, often related to second- and third-trimester exposure. Marfan syndrome is inherited in an autosomal dominant manner. Approximately 75% of individuals with Marfan syndrome have an affected parent; approximately 25% have a
|
## Diagnosis
Consensus clinical diagnostic criteria for
Marfan syndrome
Aortic root enlargement (z score ≥2.0). Note: Aortic size must be standardized to age and body size for accurate interpretation. A z score ≥2.0 indicates a value at or above the 95th percentile, while a z score ≥3.0 indicates a value at or above the 99th percentile. References and calculators for this determination are available at the
Ectopia lentis; most reliably diagnosed by slit-lamp examination after maximal pupillary dilation
A systemic score ≥7 (
Calculation of the Systemic Score
A systemic score calculator and a complete description of each component evaluation can be found at the
Click
The diagnosis of
Aortic root enlargement (z score ≥2.0)
Ectopia lentis
Note: Given that many manifestations of Marfan syndrome emerge with age, the author suggests the use of tentative diagnostic designations in individuals younger than age 20 years with
Molecular genetic testing approaches (see
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings of Marfan syndrome described in
When the clinical findings suggest the diagnosis of Marfan syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from other inherited disorders with features observed in Marfan syndrome,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
In individuals with classic Marfan syndrome an
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Deletions and duplications ranging in size from one to multiple exons as well as full-gene deletions have been described (
• Aortic root enlargement (z score ≥2.0). Note: Aortic size must be standardized to age and body size for accurate interpretation. A z score ≥2.0 indicates a value at or above the 95th percentile, while a z score ≥3.0 indicates a value at or above the 99th percentile. References and calculators for this determination are available at the
• Ectopia lentis; most reliably diagnosed by slit-lamp examination after maximal pupillary dilation
• A systemic score ≥7 (
• Aortic root enlargement (z score ≥2.0)
• Ectopia lentis
• For an introduction to multigene panels click
## Suggestive Findings
Marfan syndrome
Aortic root enlargement (z score ≥2.0). Note: Aortic size must be standardized to age and body size for accurate interpretation. A z score ≥2.0 indicates a value at or above the 95th percentile, while a z score ≥3.0 indicates a value at or above the 99th percentile. References and calculators for this determination are available at the
Ectopia lentis; most reliably diagnosed by slit-lamp examination after maximal pupillary dilation
A systemic score ≥7 (
Calculation of the Systemic Score
A systemic score calculator and a complete description of each component evaluation can be found at the
Click
• Aortic root enlargement (z score ≥2.0). Note: Aortic size must be standardized to age and body size for accurate interpretation. A z score ≥2.0 indicates a value at or above the 95th percentile, while a z score ≥3.0 indicates a value at or above the 99th percentile. References and calculators for this determination are available at the
• Ectopia lentis; most reliably diagnosed by slit-lamp examination after maximal pupillary dilation
• A systemic score ≥7 (
## Establishing the Diagnosis
The diagnosis of
Aortic root enlargement (z score ≥2.0)
Ectopia lentis
Note: Given that many manifestations of Marfan syndrome emerge with age, the author suggests the use of tentative diagnostic designations in individuals younger than age 20 years with
Molecular genetic testing approaches (see
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings of Marfan syndrome described in
When the clinical findings suggest the diagnosis of Marfan syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from other inherited disorders with features observed in Marfan syndrome,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
In individuals with classic Marfan syndrome an
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Deletions and duplications ranging in size from one to multiple exons as well as full-gene deletions have been described (
• Aortic root enlargement (z score ≥2.0)
• Ectopia lentis
• For an introduction to multigene panels click
## Option 1
When the clinical findings suggest the diagnosis of Marfan syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from other inherited disorders with features observed in Marfan syndrome,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
In individuals with classic Marfan syndrome an
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Deletions and duplications ranging in size from one to multiple exons as well as full-gene deletions have been described (
## Clinical Characteristics
MFS =
Many of the features of Marfan syndrome are not recognized in infancy/childhood or develop later in life. However, in severe cases, some of these features may be present in infancy and/or childhood.
All skeletal findings can develop in young children and tend to progress during periods of rapid growth.
Due to overgrowth of the ribs that then push on the sternum
The major morbidity and early mortality in Marfan syndrome relate to the cardiovascular system.
As a general rule, clinical manifestations run true within families, suggesting that the
Myopia is a common ocular feature (>50% of affected individuals), often progressing rapidly during childhood.
Displacement of the lens from the center of the pupil (ectopia lentis) is a hallmark feature of Marfan syndrome, and is seen in approximately 60% of affected individuals.
While generally evident in early childhood, ectopia lentis can evolve later in life.
The globe is often elongated and the cornea may be flat.
Individuals with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and early cataract formation.
Paradoxically, some individuals can show reduced joint mobility, especially of the elbow and digits, and can have an exaggerated arch to the foot (pes cavus).
The extremities are disproportionately long for the size of the trunk (dolichostenomelia), leading to an increase in the arm span to height ratio (>1.05 in adults) and a decrease in the upper to lower segment ratio <0.85 in adults).
Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum).
Scoliosis is also common and can be mild or severe and progressive (see
The combination of bone overgrowth and joint laxity leads to the characteristic thumb and wrist signs.
Flat feet (pes planus) is common in Marfan syndrome and may be associated with inward rotation at the ankle (also known as hindfoot deformity), contributing to difficulty with ambulation, leg fatigue, and muscle cramps.
The acetabulum can be abnormally deep and show accelerated erosion (protrusio acetabuli). This can lead to associated pain and functional limitations (see
A long and narrow face with deeply set eyes (enophthalmos)
Downward slanting of the palpebral fissures
Flat cheek bones (malar hypoplasia)
Small and receding chin (micrognathia, retrognathia)
Highly arched and narrow palate, often associated with tooth crowding
Dilatation of the aorta at the level of the sinuses of Valsalva with a predisposition for aortic tear and rupture
Aortic dilatation tends to progress over time; however, the onset and rate of progression of aortic dilatation is highly variable.
Aortic dissection is exceedingly rare in early childhood.
In adults, a significant risk for aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 cm. Histologic examination reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media.
These histologic findings do not distinguish Marfan syndrome from other causes of aortic aneurysm.
As an aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.
Mitral valve prolapse (MVP) with or without regurgitation
Tricuspid valve prolapse with or without regurgitation
Enlargement of the proximal pulmonary artery
Valvular dysfunction can lead to volume overload with secondary left ventricular dilatation and failure. Indeed, MVP with congestive heart failure is the leading cause of cardiovascular morbidity and mortality – and the leading indication for cardiovascular surgery – in young children with severe features of Marfan syndrome. The majority of individuals with Marfan syndrome and MVP have a tolerable degree of mitral regurgitation that shows slow, if any, progression with age. A study of 87 individuals with Marfan syndrome identified enlarged pulmonary artery root in 54% [
Symptoms include low back pain, proximal leg pain, weakness and numbness above and below the knees, and genital/rectal pain.
Leaking of cerebrospinal fluid (CSF) from a dural sac can cause postural drop in CSF pressure and headache.
Few genotype-phenotype correlations exist in
As a general rule, a variant that causes the in-frame loss or gain of central coding sequence through deletions, insertions, or splicing errors is associated with more severe disease.
Pathogenic variants that create a premature termination codon (PTC) have been associated with clinical presentations that range from mild (not meeting clinical diagnostic criteria for Marfan syndrome) to classic Marfan syndrome. Ectopia lentis is less common in individuals with haploinsufficiency of FBN1.
Some, but not all, studies have suggested that pathogenic variants that create a PTC can be associated with more frequent aortic events including dissection, surgery, and death in adults with Marfan syndrome [
Other studies have emphasized a significant enrichment of in-frame pathogenic variants in a central region of
In general, identification of the precise
Although intrafamilial clinical variability can be extensive,
Outdated terms used in the description of Marfan syndrome include the following:
The estimated prevalence of
There is no apparent enrichment in any ethnic or racial group. Males and females are affected with equal frequency.
• Myopia is a common ocular feature (>50% of affected individuals), often progressing rapidly during childhood.
• Displacement of the lens from the center of the pupil (ectopia lentis) is a hallmark feature of Marfan syndrome, and is seen in approximately 60% of affected individuals.
• While generally evident in early childhood, ectopia lentis can evolve later in life.
• The globe is often elongated and the cornea may be flat.
• Individuals with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and early cataract formation.
• Paradoxically, some individuals can show reduced joint mobility, especially of the elbow and digits, and can have an exaggerated arch to the foot (pes cavus).
• The extremities are disproportionately long for the size of the trunk (dolichostenomelia), leading to an increase in the arm span to height ratio (>1.05 in adults) and a decrease in the upper to lower segment ratio <0.85 in adults).
• Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum).
• Scoliosis is also common and can be mild or severe and progressive (see
• The combination of bone overgrowth and joint laxity leads to the characteristic thumb and wrist signs.
• Flat feet (pes planus) is common in Marfan syndrome and may be associated with inward rotation at the ankle (also known as hindfoot deformity), contributing to difficulty with ambulation, leg fatigue, and muscle cramps.
• The acetabulum can be abnormally deep and show accelerated erosion (protrusio acetabuli). This can lead to associated pain and functional limitations (see
• A long and narrow face with deeply set eyes (enophthalmos)
• Downward slanting of the palpebral fissures
• Flat cheek bones (malar hypoplasia)
• Small and receding chin (micrognathia, retrognathia)
• Highly arched and narrow palate, often associated with tooth crowding
• Dilatation of the aorta at the level of the sinuses of Valsalva with a predisposition for aortic tear and rupture
• Aortic dilatation tends to progress over time; however, the onset and rate of progression of aortic dilatation is highly variable.
• Aortic dissection is exceedingly rare in early childhood.
• In adults, a significant risk for aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 cm. Histologic examination reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media.
• These histologic findings do not distinguish Marfan syndrome from other causes of aortic aneurysm.
• As an aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.
• Aortic dilatation tends to progress over time; however, the onset and rate of progression of aortic dilatation is highly variable.
• Aortic dissection is exceedingly rare in early childhood.
• In adults, a significant risk for aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 cm. Histologic examination reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media.
• These histologic findings do not distinguish Marfan syndrome from other causes of aortic aneurysm.
• As an aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.
• Mitral valve prolapse (MVP) with or without regurgitation
• Tricuspid valve prolapse with or without regurgitation
• Enlargement of the proximal pulmonary artery
• Aortic dilatation tends to progress over time; however, the onset and rate of progression of aortic dilatation is highly variable.
• Aortic dissection is exceedingly rare in early childhood.
• In adults, a significant risk for aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 cm. Histologic examination reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media.
• These histologic findings do not distinguish Marfan syndrome from other causes of aortic aneurysm.
• As an aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.
• Symptoms include low back pain, proximal leg pain, weakness and numbness above and below the knees, and genital/rectal pain.
• Leaking of cerebrospinal fluid (CSF) from a dural sac can cause postural drop in CSF pressure and headache.
• Symptoms include low back pain, proximal leg pain, weakness and numbness above and below the knees, and genital/rectal pain.
• Leaking of cerebrospinal fluid (CSF) from a dural sac can cause postural drop in CSF pressure and headache.
• Symptoms include low back pain, proximal leg pain, weakness and numbness above and below the knees, and genital/rectal pain.
• Leaking of cerebrospinal fluid (CSF) from a dural sac can cause postural drop in CSF pressure and headache.
• As a general rule, a variant that causes the in-frame loss or gain of central coding sequence through deletions, insertions, or splicing errors is associated with more severe disease.
• Pathogenic variants that create a premature termination codon (PTC) have been associated with clinical presentations that range from mild (not meeting clinical diagnostic criteria for Marfan syndrome) to classic Marfan syndrome. Ectopia lentis is less common in individuals with haploinsufficiency of FBN1.
• Some, but not all, studies have suggested that pathogenic variants that create a PTC can be associated with more frequent aortic events including dissection, surgery, and death in adults with Marfan syndrome [
• Other studies have emphasized a significant enrichment of in-frame pathogenic variants in a central region of
## Clinical Description
MFS =
Many of the features of Marfan syndrome are not recognized in infancy/childhood or develop later in life. However, in severe cases, some of these features may be present in infancy and/or childhood.
All skeletal findings can develop in young children and tend to progress during periods of rapid growth.
Due to overgrowth of the ribs that then push on the sternum
The major morbidity and early mortality in Marfan syndrome relate to the cardiovascular system.
As a general rule, clinical manifestations run true within families, suggesting that the
Myopia is a common ocular feature (>50% of affected individuals), often progressing rapidly during childhood.
Displacement of the lens from the center of the pupil (ectopia lentis) is a hallmark feature of Marfan syndrome, and is seen in approximately 60% of affected individuals.
While generally evident in early childhood, ectopia lentis can evolve later in life.
The globe is often elongated and the cornea may be flat.
Individuals with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and early cataract formation.
Paradoxically, some individuals can show reduced joint mobility, especially of the elbow and digits, and can have an exaggerated arch to the foot (pes cavus).
The extremities are disproportionately long for the size of the trunk (dolichostenomelia), leading to an increase in the arm span to height ratio (>1.05 in adults) and a decrease in the upper to lower segment ratio <0.85 in adults).
Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum).
Scoliosis is also common and can be mild or severe and progressive (see
The combination of bone overgrowth and joint laxity leads to the characteristic thumb and wrist signs.
Flat feet (pes planus) is common in Marfan syndrome and may be associated with inward rotation at the ankle (also known as hindfoot deformity), contributing to difficulty with ambulation, leg fatigue, and muscle cramps.
The acetabulum can be abnormally deep and show accelerated erosion (protrusio acetabuli). This can lead to associated pain and functional limitations (see
A long and narrow face with deeply set eyes (enophthalmos)
Downward slanting of the palpebral fissures
Flat cheek bones (malar hypoplasia)
Small and receding chin (micrognathia, retrognathia)
Highly arched and narrow palate, often associated with tooth crowding
Dilatation of the aorta at the level of the sinuses of Valsalva with a predisposition for aortic tear and rupture
Aortic dilatation tends to progress over time; however, the onset and rate of progression of aortic dilatation is highly variable.
Aortic dissection is exceedingly rare in early childhood.
In adults, a significant risk for aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 cm. Histologic examination reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media.
These histologic findings do not distinguish Marfan syndrome from other causes of aortic aneurysm.
As an aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.
Mitral valve prolapse (MVP) with or without regurgitation
Tricuspid valve prolapse with or without regurgitation
Enlargement of the proximal pulmonary artery
Valvular dysfunction can lead to volume overload with secondary left ventricular dilatation and failure. Indeed, MVP with congestive heart failure is the leading cause of cardiovascular morbidity and mortality – and the leading indication for cardiovascular surgery – in young children with severe features of Marfan syndrome. The majority of individuals with Marfan syndrome and MVP have a tolerable degree of mitral regurgitation that shows slow, if any, progression with age. A study of 87 individuals with Marfan syndrome identified enlarged pulmonary artery root in 54% [
Symptoms include low back pain, proximal leg pain, weakness and numbness above and below the knees, and genital/rectal pain.
Leaking of cerebrospinal fluid (CSF) from a dural sac can cause postural drop in CSF pressure and headache.
• Myopia is a common ocular feature (>50% of affected individuals), often progressing rapidly during childhood.
• Displacement of the lens from the center of the pupil (ectopia lentis) is a hallmark feature of Marfan syndrome, and is seen in approximately 60% of affected individuals.
• While generally evident in early childhood, ectopia lentis can evolve later in life.
• The globe is often elongated and the cornea may be flat.
• Individuals with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and early cataract formation.
• Paradoxically, some individuals can show reduced joint mobility, especially of the elbow and digits, and can have an exaggerated arch to the foot (pes cavus).
• The extremities are disproportionately long for the size of the trunk (dolichostenomelia), leading to an increase in the arm span to height ratio (>1.05 in adults) and a decrease in the upper to lower segment ratio <0.85 in adults).
• Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum).
• Scoliosis is also common and can be mild or severe and progressive (see
• The combination of bone overgrowth and joint laxity leads to the characteristic thumb and wrist signs.
• Flat feet (pes planus) is common in Marfan syndrome and may be associated with inward rotation at the ankle (also known as hindfoot deformity), contributing to difficulty with ambulation, leg fatigue, and muscle cramps.
• The acetabulum can be abnormally deep and show accelerated erosion (protrusio acetabuli). This can lead to associated pain and functional limitations (see
• A long and narrow face with deeply set eyes (enophthalmos)
• Downward slanting of the palpebral fissures
• Flat cheek bones (malar hypoplasia)
• Small and receding chin (micrognathia, retrognathia)
• Highly arched and narrow palate, often associated with tooth crowding
• Dilatation of the aorta at the level of the sinuses of Valsalva with a predisposition for aortic tear and rupture
• Aortic dilatation tends to progress over time; however, the onset and rate of progression of aortic dilatation is highly variable.
• Aortic dissection is exceedingly rare in early childhood.
• In adults, a significant risk for aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 cm. Histologic examination reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media.
• These histologic findings do not distinguish Marfan syndrome from other causes of aortic aneurysm.
• As an aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.
• Aortic dilatation tends to progress over time; however, the onset and rate of progression of aortic dilatation is highly variable.
• Aortic dissection is exceedingly rare in early childhood.
• In adults, a significant risk for aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 cm. Histologic examination reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media.
• These histologic findings do not distinguish Marfan syndrome from other causes of aortic aneurysm.
• As an aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.
• Mitral valve prolapse (MVP) with or without regurgitation
• Tricuspid valve prolapse with or without regurgitation
• Enlargement of the proximal pulmonary artery
• Aortic dilatation tends to progress over time; however, the onset and rate of progression of aortic dilatation is highly variable.
• Aortic dissection is exceedingly rare in early childhood.
• In adults, a significant risk for aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 cm. Histologic examination reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media.
• These histologic findings do not distinguish Marfan syndrome from other causes of aortic aneurysm.
• As an aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.
• Symptoms include low back pain, proximal leg pain, weakness and numbness above and below the knees, and genital/rectal pain.
• Leaking of cerebrospinal fluid (CSF) from a dural sac can cause postural drop in CSF pressure and headache.
• Symptoms include low back pain, proximal leg pain, weakness and numbness above and below the knees, and genital/rectal pain.
• Leaking of cerebrospinal fluid (CSF) from a dural sac can cause postural drop in CSF pressure and headache.
• Symptoms include low back pain, proximal leg pain, weakness and numbness above and below the knees, and genital/rectal pain.
• Leaking of cerebrospinal fluid (CSF) from a dural sac can cause postural drop in CSF pressure and headache.
## Genotype-Phenotype Correlations
Few genotype-phenotype correlations exist in
As a general rule, a variant that causes the in-frame loss or gain of central coding sequence through deletions, insertions, or splicing errors is associated with more severe disease.
Pathogenic variants that create a premature termination codon (PTC) have been associated with clinical presentations that range from mild (not meeting clinical diagnostic criteria for Marfan syndrome) to classic Marfan syndrome. Ectopia lentis is less common in individuals with haploinsufficiency of FBN1.
Some, but not all, studies have suggested that pathogenic variants that create a PTC can be associated with more frequent aortic events including dissection, surgery, and death in adults with Marfan syndrome [
Other studies have emphasized a significant enrichment of in-frame pathogenic variants in a central region of
In general, identification of the precise
• As a general rule, a variant that causes the in-frame loss or gain of central coding sequence through deletions, insertions, or splicing errors is associated with more severe disease.
• Pathogenic variants that create a premature termination codon (PTC) have been associated with clinical presentations that range from mild (not meeting clinical diagnostic criteria for Marfan syndrome) to classic Marfan syndrome. Ectopia lentis is less common in individuals with haploinsufficiency of FBN1.
• Some, but not all, studies have suggested that pathogenic variants that create a PTC can be associated with more frequent aortic events including dissection, surgery, and death in adults with Marfan syndrome [
• Other studies have emphasized a significant enrichment of in-frame pathogenic variants in a central region of
## Penetrance
Although intrafamilial clinical variability can be extensive,
## Nomenclature
Outdated terms used in the description of Marfan syndrome include the following:
## Prevalence
The estimated prevalence of
There is no apparent enrichment in any ethnic or racial group. Males and females are affected with equal frequency.
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Other
## Differential Diagnosis
Aortic aneurysms in LDS behave very differently from those in Marfan syndrome, with frequent dissection and rupture at small dimensions and in early childhood.
LDS results from a heterozygous pathogenic variant in
Comparison of Clinical Features in Marfan Syndrome, Loeys-Dietz Syndrome, and Shprintzen-Goldberg Syndrome
+ = feature is present; the presence of more than one "+" indicates that a feature is more common, with "+++" indicating most common.
− = feature is absent.
Other Connective Tissue Disorders of Interest in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; EDS = Ehlers-Danlos syndrome; ID = intellectual disability; LDS = Loeys-Dietz syndrome; MFS = Marfan syndrome; MOI = mode of inheritance; TAAD = thoracic aortic aneurysms and aortic dissections; XL = X-linked
To date, 16 genes are known to predispose to TAAD (see Table 1 in
Stickler syndrome caused by pathogenic variants in
Vascular EDS is almost always inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported.
## Management
No comprehensive or widely adopted clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Slit lamp exam through maximally dilated pupil for evidence of lens subluxation
Refraction, esp in young children at risk for amblyopia
Assessment for glaucoma & cataract
Community or
Social work involvement for parental support;
Home nursing referral.
MFS =
Marfan syndrome-specific growth curves allow accurate prediction of adult height.
Surveillance of the entire aorta with computerized tomography angiography (CTA) or magnetic resonance angiography (MRA) begins in early adulthood or after aortic root surgery (see
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Management is most effectively accomplished through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon.
Treatment of Manifestations in Individuals with
Spectacle correction is often adequate.
Prompt & aggressive assessment & correction of refractive error is mandatory in young children at risk for amblyopia.
An intraocular lens can be implanted after puberty (i.e., once growth is complete).
While intraocular lens implants are currently considered quite safe when performed in specialized centers, major complications incl retinal detachment can occur.
Rate of ↑ of aortic root diameter approaches 0.5-1.0 cm/yr; OR
There is progressive & severe aortic regurgitation.
While there is no agreed-upon absolute size threshold for aortic root surgery in childhood, many centers use adult guideline of 5.0 cm given extreme rarity of aortic dissection in young children.
Every effort is made to allow aortic annulus to reach size of ≥2.0-2.2 cm, allowing placement of aortic graft of sufficient size to accommodate body growth.
Max measurement approaches 5.0 cm; OR
Rate of ↑ of aortic root diameter approaches 1.0 cm/yr; OR
There is progressive & severe aortic regurgitation.
More aggressive therapy may be indicated in persons w/family history of early aortic dissection.
Many persons can receive a valve-sparing procedure that precludes need for chronic anticoagulation.
Hernias tend to recur after surgical intervention.
A supporting mesh can be used during surgical repair to minimize recurrence risk.
Pneumothorax can be a recurrent problem.
Optimal mgmt may require chemical or surgical pleurodesis or surgical removal of pulmonary blebs.
MFS =
Complications can include the psychosocial burden of accelerated puberty, an accelerated rate of growth prior to final closure of the growth plate, and perhaps the undesirable consequences of the increased blood pressure associated with puberty on progression of aortic dilatation.
Cardiovascular manifestations should be managed by a cardiologist familiar with
Guidelines are based on far less clinical experience than for adults and older children, and need to be tailored to the clinical situation at hand.
When congestive heart failure is present, afterload-reducing agents (in combination with a beta-blocker) can improve cardiovascular function, but surgical intervention may be indicated in refractory cases. Most often the mitral valve can be repaired rather than replaced.
In this circumstance, caution is warranted when considering concomitant aortic root surgery, as the increased length and complexity of the procedure can put extra strain on the myocardium and delay or compromise postoperative recovery.
Medications that reduce hemodynamic stress on the aortic wall, such as beta-blockers or angiotensin receptor blockers (ARBs), are routinely prescribed. This therapy should be managed by a cardiologist or clinical geneticist familiar with its use. Therapy is generally initiated at the time of diagnosis of Marfan syndrome at any age or upon appreciation of progressive aortic root dilatation even in the absence of a definitive diagnosis.
The confluence of data from clinical trials of beta-blockers or ARBs suggests that both classes of medication can be effective at reducing aortic root growth rate and are safe and well tolerated. A meta-analysis of seven studies and more than 1,500 individuals with Marfan syndrome documented that ARBs significantly reduce normalized aortic root and ascending aortic growth rate when compared to placebo [
General principles applied by the author include:
Initiation of therapy at the time of diagnosis with Marfan syndrome. This would include children without aortic enlargement if there is a family history of Marfan syndrome with aortic involvement or the identified pathogenic variant has previously been associated with significant aortic involvement in unrelated individuals.
Targeting of high dosing (as tolerated) irrespective of blood pressure in recognition that benefit likely relates to desirable biochemical effects in the aortic wall that do not strictly correlate with hemodynamic parameters
Dose optimization of one agent (e.g., an ARB) before consideration of adding another (e.g., a beta-blocker)
Avoidance of ARBs in pregnant individuals or if pregnancy is imminently anticipated
Avoidance of other classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) in the absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome
Recommended Surveillance for Individuals with
Annually when aortic dimension is relatively small & rate of aortic dilatation is relatively slow
More often than annually when aortic root diameter > ~4.5 cm in adults, rate of aortic dilatation > ~0.3 cm/yr, or if there is significant aortic regurgitation
Other indications for more frequent echocardiographic imaging incl significant or progressive valve dysfunction or left ventricular enlargement or dysfunction.
A subset of children with severe Marfan syndrome can show evidence of severe malnutrition that may require intervention by a nutritionist or gastroenterologist.
Radiographs and referral to an orthopedist may be indicated in those with moderate-to-severe features.
More frequent evaluations by a cardiologist are indicated with severe or progressive valve or ventricular dysfunction or with documented or suspected arrhythmia.
The following should be avoided:
Contact sports, competitive sports, and isometric exercise. Note: Individuals can and should remain active with aerobic activities performed in moderation.
Activities that cause joint injury or pain
Agents that stimulate the cardiovascular system including routine use of decongestants. Caffeine can aggravate a tendency for arrhythmia.
Agents that cause vasoconstriction, including triptans
LASIK eye surgery to correct refractive errors
For individuals at risk for recurrent pneumothorax, breathing against resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., SCUBA diving)
Fluoroquinolone antibiotics due to the considerable evidence suggesting exacerbation of predisposition for aneurysm and dissection
Avoidance of classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) where there is an absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome
It is recommended that the genetic status of relatives of any age at risk for Marfan syndrome be clarified either by molecular genetic testing or by clinical examination so that affected individuals can undergo routine surveillance for early detection of medically significant complications, particularly potentially life-threatening cardiac manifestations. Approaches include the following:
If the
In the presence of a rigorously defined family history of Marfan syndrome, clinical examination can establish the clinical diagnosis of Marfan syndrome in a first-degree relative of an affected individual who has any one of the following three findings [
Ectopia lentis
Systemic score ≥7 (See
Aortic root enlargement (z score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) (see
See
It is recommended that an individual with Marfan syndrome consider pregnancy only after appropriate counseling from a clinical geneticist or cardiologist familiar with this condition, a genetic counselor, and a high-risk obstetrician because of the risk of more rapid dilation of the aorta or aortic dissection during pregnancy, delivery, or in the immediate postpartum period. This is especially relevant to individuals who begin pregnancy with a maximal aortic dimension that exceeds 4.0 cm. Note: Some individuals with Marfan syndrome and aortic root dilatation opt for elective aortic repair with a valve-sparing procedure prior to reaching a conventional threshold for surgical intervention (i.e., at a root dimension <5.0 cm) before becoming pregnant. While this is thought to decrease the risk for ascending aortic dissection in association with pregnancy, it will not lessen risk for descending aortic dissection or other potential cardiovascular manifestations of Marfan syndrome.
Pregnant individuals with Marfan syndrome should be followed by a high-risk obstetrician both during pregnancy and through the immediate postpartum period.
Individuals with Marfan syndrome who anticipate pregnancy or become pregnant should continue use of beta-blockers; however, some other classes of medications such as ARBs should be discontinued because of the increased risk for fetal loss, oligohydramnios, and abnormal development, often related to second- and third-trimester exposure.
See
Efforts should be made to minimize cardiovascular stress through pregnancy and delivery.
Cardiovascular imaging with echocardiography should be performed every two to three months during pregnancy to monitor aortic root size and growth. Monitoring should continue in the immediate postpartum period because of the increased risk for aortic dissection.
The choice between a controlled vaginal delivery and cesarean section remains controversial and should be tailored to the specific clinical context.
Search
• Slit lamp exam through maximally dilated pupil for evidence of lens subluxation
• Refraction, esp in young children at risk for amblyopia
• Assessment for glaucoma & cataract
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Spectacle correction is often adequate.
• Prompt & aggressive assessment & correction of refractive error is mandatory in young children at risk for amblyopia.
• An intraocular lens can be implanted after puberty (i.e., once growth is complete).
• While intraocular lens implants are currently considered quite safe when performed in specialized centers, major complications incl retinal detachment can occur.
• Rate of ↑ of aortic root diameter approaches 0.5-1.0 cm/yr; OR
• There is progressive & severe aortic regurgitation.
• While there is no agreed-upon absolute size threshold for aortic root surgery in childhood, many centers use adult guideline of 5.0 cm given extreme rarity of aortic dissection in young children.
• Every effort is made to allow aortic annulus to reach size of ≥2.0-2.2 cm, allowing placement of aortic graft of sufficient size to accommodate body growth.
• Max measurement approaches 5.0 cm; OR
• Rate of ↑ of aortic root diameter approaches 1.0 cm/yr; OR
• There is progressive & severe aortic regurgitation.
• More aggressive therapy may be indicated in persons w/family history of early aortic dissection.
• Many persons can receive a valve-sparing procedure that precludes need for chronic anticoagulation.
• Hernias tend to recur after surgical intervention.
• A supporting mesh can be used during surgical repair to minimize recurrence risk.
• Pneumothorax can be a recurrent problem.
• Optimal mgmt may require chemical or surgical pleurodesis or surgical removal of pulmonary blebs.
• Initiation of therapy at the time of diagnosis with Marfan syndrome. This would include children without aortic enlargement if there is a family history of Marfan syndrome with aortic involvement or the identified pathogenic variant has previously been associated with significant aortic involvement in unrelated individuals.
• Targeting of high dosing (as tolerated) irrespective of blood pressure in recognition that benefit likely relates to desirable biochemical effects in the aortic wall that do not strictly correlate with hemodynamic parameters
• Dose optimization of one agent (e.g., an ARB) before consideration of adding another (e.g., a beta-blocker)
• Avoidance of ARBs in pregnant individuals or if pregnancy is imminently anticipated
• Avoidance of other classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) in the absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome
• Annually when aortic dimension is relatively small & rate of aortic dilatation is relatively slow
• More often than annually when aortic root diameter > ~4.5 cm in adults, rate of aortic dilatation > ~0.3 cm/yr, or if there is significant aortic regurgitation
• Other indications for more frequent echocardiographic imaging incl significant or progressive valve dysfunction or left ventricular enlargement or dysfunction.
• Contact sports, competitive sports, and isometric exercise. Note: Individuals can and should remain active with aerobic activities performed in moderation.
• Activities that cause joint injury or pain
• Agents that stimulate the cardiovascular system including routine use of decongestants. Caffeine can aggravate a tendency for arrhythmia.
• Agents that cause vasoconstriction, including triptans
• LASIK eye surgery to correct refractive errors
• For individuals at risk for recurrent pneumothorax, breathing against resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., SCUBA diving)
• Fluoroquinolone antibiotics due to the considerable evidence suggesting exacerbation of predisposition for aneurysm and dissection
• Avoidance of classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) where there is an absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome
• If the
• In the presence of a rigorously defined family history of Marfan syndrome, clinical examination can establish the clinical diagnosis of Marfan syndrome in a first-degree relative of an affected individual who has any one of the following three findings [
• Ectopia lentis
• Systemic score ≥7 (See
• Aortic root enlargement (z score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) (see
• Ectopia lentis
• Systemic score ≥7 (See
• Aortic root enlargement (z score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) (see
• Ectopia lentis
• Systemic score ≥7 (See
• Aortic root enlargement (z score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) (see
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Slit lamp exam through maximally dilated pupil for evidence of lens subluxation
Refraction, esp in young children at risk for amblyopia
Assessment for glaucoma & cataract
Community or
Social work involvement for parental support;
Home nursing referral.
MFS =
Marfan syndrome-specific growth curves allow accurate prediction of adult height.
Surveillance of the entire aorta with computerized tomography angiography (CTA) or magnetic resonance angiography (MRA) begins in early adulthood or after aortic root surgery (see
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Slit lamp exam through maximally dilated pupil for evidence of lens subluxation
• Refraction, esp in young children at risk for amblyopia
• Assessment for glaucoma & cataract
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Management is most effectively accomplished through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon.
Treatment of Manifestations in Individuals with
Spectacle correction is often adequate.
Prompt & aggressive assessment & correction of refractive error is mandatory in young children at risk for amblyopia.
An intraocular lens can be implanted after puberty (i.e., once growth is complete).
While intraocular lens implants are currently considered quite safe when performed in specialized centers, major complications incl retinal detachment can occur.
Rate of ↑ of aortic root diameter approaches 0.5-1.0 cm/yr; OR
There is progressive & severe aortic regurgitation.
While there is no agreed-upon absolute size threshold for aortic root surgery in childhood, many centers use adult guideline of 5.0 cm given extreme rarity of aortic dissection in young children.
Every effort is made to allow aortic annulus to reach size of ≥2.0-2.2 cm, allowing placement of aortic graft of sufficient size to accommodate body growth.
Max measurement approaches 5.0 cm; OR
Rate of ↑ of aortic root diameter approaches 1.0 cm/yr; OR
There is progressive & severe aortic regurgitation.
More aggressive therapy may be indicated in persons w/family history of early aortic dissection.
Many persons can receive a valve-sparing procedure that precludes need for chronic anticoagulation.
Hernias tend to recur after surgical intervention.
A supporting mesh can be used during surgical repair to minimize recurrence risk.
Pneumothorax can be a recurrent problem.
Optimal mgmt may require chemical or surgical pleurodesis or surgical removal of pulmonary blebs.
MFS =
Complications can include the psychosocial burden of accelerated puberty, an accelerated rate of growth prior to final closure of the growth plate, and perhaps the undesirable consequences of the increased blood pressure associated with puberty on progression of aortic dilatation.
Cardiovascular manifestations should be managed by a cardiologist familiar with
Guidelines are based on far less clinical experience than for adults and older children, and need to be tailored to the clinical situation at hand.
When congestive heart failure is present, afterload-reducing agents (in combination with a beta-blocker) can improve cardiovascular function, but surgical intervention may be indicated in refractory cases. Most often the mitral valve can be repaired rather than replaced.
In this circumstance, caution is warranted when considering concomitant aortic root surgery, as the increased length and complexity of the procedure can put extra strain on the myocardium and delay or compromise postoperative recovery.
• Spectacle correction is often adequate.
• Prompt & aggressive assessment & correction of refractive error is mandatory in young children at risk for amblyopia.
• An intraocular lens can be implanted after puberty (i.e., once growth is complete).
• While intraocular lens implants are currently considered quite safe when performed in specialized centers, major complications incl retinal detachment can occur.
• Rate of ↑ of aortic root diameter approaches 0.5-1.0 cm/yr; OR
• There is progressive & severe aortic regurgitation.
• While there is no agreed-upon absolute size threshold for aortic root surgery in childhood, many centers use adult guideline of 5.0 cm given extreme rarity of aortic dissection in young children.
• Every effort is made to allow aortic annulus to reach size of ≥2.0-2.2 cm, allowing placement of aortic graft of sufficient size to accommodate body growth.
• Max measurement approaches 5.0 cm; OR
• Rate of ↑ of aortic root diameter approaches 1.0 cm/yr; OR
• There is progressive & severe aortic regurgitation.
• More aggressive therapy may be indicated in persons w/family history of early aortic dissection.
• Many persons can receive a valve-sparing procedure that precludes need for chronic anticoagulation.
• Hernias tend to recur after surgical intervention.
• A supporting mesh can be used during surgical repair to minimize recurrence risk.
• Pneumothorax can be a recurrent problem.
• Optimal mgmt may require chemical or surgical pleurodesis or surgical removal of pulmonary blebs.
## Prevention of Primary Manifestations
Medications that reduce hemodynamic stress on the aortic wall, such as beta-blockers or angiotensin receptor blockers (ARBs), are routinely prescribed. This therapy should be managed by a cardiologist or clinical geneticist familiar with its use. Therapy is generally initiated at the time of diagnosis of Marfan syndrome at any age or upon appreciation of progressive aortic root dilatation even in the absence of a definitive diagnosis.
The confluence of data from clinical trials of beta-blockers or ARBs suggests that both classes of medication can be effective at reducing aortic root growth rate and are safe and well tolerated. A meta-analysis of seven studies and more than 1,500 individuals with Marfan syndrome documented that ARBs significantly reduce normalized aortic root and ascending aortic growth rate when compared to placebo [
General principles applied by the author include:
Initiation of therapy at the time of diagnosis with Marfan syndrome. This would include children without aortic enlargement if there is a family history of Marfan syndrome with aortic involvement or the identified pathogenic variant has previously been associated with significant aortic involvement in unrelated individuals.
Targeting of high dosing (as tolerated) irrespective of blood pressure in recognition that benefit likely relates to desirable biochemical effects in the aortic wall that do not strictly correlate with hemodynamic parameters
Dose optimization of one agent (e.g., an ARB) before consideration of adding another (e.g., a beta-blocker)
Avoidance of ARBs in pregnant individuals or if pregnancy is imminently anticipated
Avoidance of other classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) in the absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome
• Initiation of therapy at the time of diagnosis with Marfan syndrome. This would include children without aortic enlargement if there is a family history of Marfan syndrome with aortic involvement or the identified pathogenic variant has previously been associated with significant aortic involvement in unrelated individuals.
• Targeting of high dosing (as tolerated) irrespective of blood pressure in recognition that benefit likely relates to desirable biochemical effects in the aortic wall that do not strictly correlate with hemodynamic parameters
• Dose optimization of one agent (e.g., an ARB) before consideration of adding another (e.g., a beta-blocker)
• Avoidance of ARBs in pregnant individuals or if pregnancy is imminently anticipated
• Avoidance of other classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) in the absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome
## Surveillance
Recommended Surveillance for Individuals with
Annually when aortic dimension is relatively small & rate of aortic dilatation is relatively slow
More often than annually when aortic root diameter > ~4.5 cm in adults, rate of aortic dilatation > ~0.3 cm/yr, or if there is significant aortic regurgitation
Other indications for more frequent echocardiographic imaging incl significant or progressive valve dysfunction or left ventricular enlargement or dysfunction.
A subset of children with severe Marfan syndrome can show evidence of severe malnutrition that may require intervention by a nutritionist or gastroenterologist.
Radiographs and referral to an orthopedist may be indicated in those with moderate-to-severe features.
More frequent evaluations by a cardiologist are indicated with severe or progressive valve or ventricular dysfunction or with documented or suspected arrhythmia.
• Annually when aortic dimension is relatively small & rate of aortic dilatation is relatively slow
• More often than annually when aortic root diameter > ~4.5 cm in adults, rate of aortic dilatation > ~0.3 cm/yr, or if there is significant aortic regurgitation
• Other indications for more frequent echocardiographic imaging incl significant or progressive valve dysfunction or left ventricular enlargement or dysfunction.
## Agents/Circumstances to Avoid
The following should be avoided:
Contact sports, competitive sports, and isometric exercise. Note: Individuals can and should remain active with aerobic activities performed in moderation.
Activities that cause joint injury or pain
Agents that stimulate the cardiovascular system including routine use of decongestants. Caffeine can aggravate a tendency for arrhythmia.
Agents that cause vasoconstriction, including triptans
LASIK eye surgery to correct refractive errors
For individuals at risk for recurrent pneumothorax, breathing against resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., SCUBA diving)
Fluoroquinolone antibiotics due to the considerable evidence suggesting exacerbation of predisposition for aneurysm and dissection
Avoidance of classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) where there is an absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome
• Contact sports, competitive sports, and isometric exercise. Note: Individuals can and should remain active with aerobic activities performed in moderation.
• Activities that cause joint injury or pain
• Agents that stimulate the cardiovascular system including routine use of decongestants. Caffeine can aggravate a tendency for arrhythmia.
• Agents that cause vasoconstriction, including triptans
• LASIK eye surgery to correct refractive errors
• For individuals at risk for recurrent pneumothorax, breathing against resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., SCUBA diving)
• Fluoroquinolone antibiotics due to the considerable evidence suggesting exacerbation of predisposition for aneurysm and dissection
• Avoidance of classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) where there is an absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome
## Evaluation of Relatives at Risk
It is recommended that the genetic status of relatives of any age at risk for Marfan syndrome be clarified either by molecular genetic testing or by clinical examination so that affected individuals can undergo routine surveillance for early detection of medically significant complications, particularly potentially life-threatening cardiac manifestations. Approaches include the following:
If the
In the presence of a rigorously defined family history of Marfan syndrome, clinical examination can establish the clinical diagnosis of Marfan syndrome in a first-degree relative of an affected individual who has any one of the following three findings [
Ectopia lentis
Systemic score ≥7 (See
Aortic root enlargement (z score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) (see
See
• If the
• In the presence of a rigorously defined family history of Marfan syndrome, clinical examination can establish the clinical diagnosis of Marfan syndrome in a first-degree relative of an affected individual who has any one of the following three findings [
• Ectopia lentis
• Systemic score ≥7 (See
• Aortic root enlargement (z score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) (see
• Ectopia lentis
• Systemic score ≥7 (See
• Aortic root enlargement (z score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) (see
• Ectopia lentis
• Systemic score ≥7 (See
• Aortic root enlargement (z score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) (see
## Pregnancy Management
It is recommended that an individual with Marfan syndrome consider pregnancy only after appropriate counseling from a clinical geneticist or cardiologist familiar with this condition, a genetic counselor, and a high-risk obstetrician because of the risk of more rapid dilation of the aorta or aortic dissection during pregnancy, delivery, or in the immediate postpartum period. This is especially relevant to individuals who begin pregnancy with a maximal aortic dimension that exceeds 4.0 cm. Note: Some individuals with Marfan syndrome and aortic root dilatation opt for elective aortic repair with a valve-sparing procedure prior to reaching a conventional threshold for surgical intervention (i.e., at a root dimension <5.0 cm) before becoming pregnant. While this is thought to decrease the risk for ascending aortic dissection in association with pregnancy, it will not lessen risk for descending aortic dissection or other potential cardiovascular manifestations of Marfan syndrome.
Pregnant individuals with Marfan syndrome should be followed by a high-risk obstetrician both during pregnancy and through the immediate postpartum period.
Individuals with Marfan syndrome who anticipate pregnancy or become pregnant should continue use of beta-blockers; however, some other classes of medications such as ARBs should be discontinued because of the increased risk for fetal loss, oligohydramnios, and abnormal development, often related to second- and third-trimester exposure.
See
Efforts should be made to minimize cardiovascular stress through pregnancy and delivery.
Cardiovascular imaging with echocardiography should be performed every two to three months during pregnancy to monitor aortic root size and growth. Monitoring should continue in the immediate postpartum period because of the increased risk for aortic dissection.
The choice between a controlled vaginal delivery and cesarean section remains controversial and should be tailored to the specific clinical context.
## Therapies Under Investigation
Search
## Genetic Counseling
Approximately 75% of individuals diagnosed with Marfan syndrome have an affected parent.
Approximately 25% of individuals diagnosed with Marfan syndrome have the disorder as the result of a
If the proband appears to represent a simplex case (i.e., the only family member known to have Marfan syndrome), it is appropriate to evaluate both parents of the proband for manifestations of Marfan syndrome by performing a comprehensive clinical examination and echocardiogram. Molecular genetic testing for the
If the
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. *
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with Marfan syndrome may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Sibs who inherit an
If the
Each child of an individual with
The penetrance of
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Approximately 75% of individuals diagnosed with Marfan syndrome have an affected parent.
• Approximately 25% of individuals diagnosed with Marfan syndrome have the disorder as the result of a
• If the proband appears to represent a simplex case (i.e., the only family member known to have Marfan syndrome), it is appropriate to evaluate both parents of the proband for manifestations of Marfan syndrome by performing a comprehensive clinical examination and echocardiogram. Molecular genetic testing for the
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. *
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. *
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for an
• The family history of some individuals diagnosed with Marfan syndrome may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. *
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for an
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Sibs who inherit an
• If the
• Each child of an individual with
• The penetrance of
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Mode of Inheritance
## Risk to Family Members
Approximately 75% of individuals diagnosed with Marfan syndrome have an affected parent.
Approximately 25% of individuals diagnosed with Marfan syndrome have the disorder as the result of a
If the proband appears to represent a simplex case (i.e., the only family member known to have Marfan syndrome), it is appropriate to evaluate both parents of the proband for manifestations of Marfan syndrome by performing a comprehensive clinical examination and echocardiogram. Molecular genetic testing for the
If the
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. *
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with Marfan syndrome may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Sibs who inherit an
If the
Each child of an individual with
The penetrance of
• Approximately 75% of individuals diagnosed with Marfan syndrome have an affected parent.
• Approximately 25% of individuals diagnosed with Marfan syndrome have the disorder as the result of a
• If the proband appears to represent a simplex case (i.e., the only family member known to have Marfan syndrome), it is appropriate to evaluate both parents of the proband for manifestations of Marfan syndrome by performing a comprehensive clinical examination and echocardiogram. Molecular genetic testing for the
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. *
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. *
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for an
• The family history of some individuals diagnosed with Marfan syndrome may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. *
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for an
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Sibs who inherit an
• If the
• Each child of an individual with
• The penetrance of
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
22 Manhasset Avenue
Port Washington, 11050
•
• Canada
•
•
•
•
•
•
• 22 Manhasset Avenue
• Port Washington, 11050
•
## Molecular Genetics
FBN1-Related Marfan Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FBN1-Related Marfan Syndrome (
Fibrillin-1 is an extracellular matrix protein that contributes to large structures called microfibrils that are found in both elastic and non-elastic tissues. They participate in the formation and homeostasis of the elastic matrix, in matrix-cell attachments, and in the regulation of selected growth factors.
The pathogenesis of Marfan syndrome is complex. Abnormal forms of fibrillin-1 are believed to have dominant-negative activity. In affected individuals, the residual level of protein is generally far below the 50% level predicted by the presence of a wild type copy of
Studies in animal models of Marfan syndrome have demonstrated that microfibrils regulate the matrix sequestration and activation of the growth factor TGFβ. Excess TGFβ signaling has been observed in the developing lung, the mitral valve, the skeletal muscle, the dura, and the ascending aorta [
Missense changes associated with disease include:
Missense variant that creates or destroys a cysteine residue;
Missense variant affecting conserved residues in the EGF-like domain consensus sequence (D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F) (m and n represent variable numbers of residues).
• Missense variant that creates or destroys a cysteine residue;
• Missense variant affecting conserved residues in the EGF-like domain consensus sequence (D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F) (m and n represent variable numbers of residues).
## Molecular Pathogenesis
Fibrillin-1 is an extracellular matrix protein that contributes to large structures called microfibrils that are found in both elastic and non-elastic tissues. They participate in the formation and homeostasis of the elastic matrix, in matrix-cell attachments, and in the regulation of selected growth factors.
The pathogenesis of Marfan syndrome is complex. Abnormal forms of fibrillin-1 are believed to have dominant-negative activity. In affected individuals, the residual level of protein is generally far below the 50% level predicted by the presence of a wild type copy of
Studies in animal models of Marfan syndrome have demonstrated that microfibrils regulate the matrix sequestration and activation of the growth factor TGFβ. Excess TGFβ signaling has been observed in the developing lung, the mitral valve, the skeletal muscle, the dura, and the ascending aorta [
Missense changes associated with disease include:
Missense variant that creates or destroys a cysteine residue;
Missense variant affecting conserved residues in the EGF-like domain consensus sequence (D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F) (m and n represent variable numbers of residues).
• Missense variant that creates or destroys a cysteine residue;
• Missense variant affecting conserved residues in the EGF-like domain consensus sequence (D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F) (m and n represent variable numbers of residues).
## Chapter Notes
Harry (Hal) Dietz is the Victor A McKusick Professor of Medicine and Genetics in the Institute of Genetic Medicine at the Johns Hopkins University School of Medicine and an Investigator in the Howard Hughes Medical Institute. He serves on the Professional Advisory Board of the Marfan Foundation. His research focuses on the development of rational therapeutic strategies for Marfan syndrome and related conditions through elucidation of disease pathogenesis using animal models of disease. He directs a multidisciplinary clinic for the diagnosis and management of Marfan syndrome and other connective tissue disorders affecting the cardiovascular system.
17 February 2022 (ma) Comprehensive update posted live
12 October 2017 (bp) Comprehensive update posted live
12 June 2014 (me) Comprehensive update posted live
1 December 2011 (me) Comprehensive update posted live
30 June 2009 (me) Comprehensive update posted live
26 October 2005 (me) Comprehensive update posted live
22 September 2003 (me) Comprehensive update posted live
18 April 2001 (pb) Review posted live
January 2001 (hd) Original submission
• 17 February 2022 (ma) Comprehensive update posted live
• 12 October 2017 (bp) Comprehensive update posted live
• 12 June 2014 (me) Comprehensive update posted live
• 1 December 2011 (me) Comprehensive update posted live
• 30 June 2009 (me) Comprehensive update posted live
• 26 October 2005 (me) Comprehensive update posted live
• 22 September 2003 (me) Comprehensive update posted live
• 18 April 2001 (pb) Review posted live
• January 2001 (hd) Original submission
## Author Notes
Harry (Hal) Dietz is the Victor A McKusick Professor of Medicine and Genetics in the Institute of Genetic Medicine at the Johns Hopkins University School of Medicine and an Investigator in the Howard Hughes Medical Institute. He serves on the Professional Advisory Board of the Marfan Foundation. His research focuses on the development of rational therapeutic strategies for Marfan syndrome and related conditions through elucidation of disease pathogenesis using animal models of disease. He directs a multidisciplinary clinic for the diagnosis and management of Marfan syndrome and other connective tissue disorders affecting the cardiovascular system.
## Revision History
17 February 2022 (ma) Comprehensive update posted live
12 October 2017 (bp) Comprehensive update posted live
12 June 2014 (me) Comprehensive update posted live
1 December 2011 (me) Comprehensive update posted live
30 June 2009 (me) Comprehensive update posted live
26 October 2005 (me) Comprehensive update posted live
22 September 2003 (me) Comprehensive update posted live
18 April 2001 (pb) Review posted live
January 2001 (hd) Original submission
• 17 February 2022 (ma) Comprehensive update posted live
• 12 October 2017 (bp) Comprehensive update posted live
• 12 June 2014 (me) Comprehensive update posted live
• 1 December 2011 (me) Comprehensive update posted live
• 30 June 2009 (me) Comprehensive update posted live
• 26 October 2005 (me) Comprehensive update posted live
• 22 September 2003 (me) Comprehensive update posted live
• 18 April 2001 (pb) Review posted live
• January 2001 (hd) Original submission
## References
## Literature Cited
|
[] |
18/4/2001
|
17/2/2022
|
2/2/2017
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mbd5-dis
|
mbd5-dis
|
[
"2q23.1 Microdeletion Syndrome",
"Pseudo-Angelman Syndrome",
"2q23.1 Microdeletion Syndrome",
"Methyl-CpG-binding domain protein 5",
"MBD5",
"MBD5 Haploinsufficiency"
] |
Sureni V Mullegama, Roberto Mendoza-Londono, Sarah H Elsea
|
Summary The diagnosis of
|
## Diagnosis
Motor delays
Severe speech and language impairment
Intellectual disability (ID), usually moderate to severe
Seizures
Sleep disturbance
Hypotonia
Feeding difficulties, often related to hypotonia
Short attention span
Autistic-like behaviors that include gaze avoidance, inattention, and repetitive behaviors
Self-injury and/or aggressive behaviors
The diagnosis of
Deletion of 2q23.1 that encompasses all or part of
Intragenic deletion involving one or more exons of
A heterozygous pathogenic (or likely pathogenic) sequence variant in
Rarely, an apparently balanced complex chromosome rearrangement of the 2q23.1 region involving
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing may not. Because many inherited disorders share the phenotypic findings of ID, seizures, and behavior problems, most children with
Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Note: In individuals with features that are highly suggestive of
Molecular Genetic Testing Used in
See
See
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis should include analysis of noncoding exon 1.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
• Motor delays
• Severe speech and language impairment
• Intellectual disability (ID), usually moderate to severe
• Seizures
• Sleep disturbance
• Hypotonia
• Feeding difficulties, often related to hypotonia
• Short attention span
• Autistic-like behaviors that include gaze avoidance, inattention, and repetitive behaviors
• Self-injury and/or aggressive behaviors
• Deletion of 2q23.1 that encompasses all or part of
• Intragenic deletion involving one or more exons of
• A heterozygous pathogenic (or likely pathogenic) sequence variant in
• Rarely, an apparently balanced complex chromosome rearrangement of the 2q23.1 region involving
## Suggestive Findings
Motor delays
Severe speech and language impairment
Intellectual disability (ID), usually moderate to severe
Seizures
Sleep disturbance
Hypotonia
Feeding difficulties, often related to hypotonia
Short attention span
Autistic-like behaviors that include gaze avoidance, inattention, and repetitive behaviors
Self-injury and/or aggressive behaviors
• Motor delays
• Severe speech and language impairment
• Intellectual disability (ID), usually moderate to severe
• Seizures
• Sleep disturbance
• Hypotonia
• Feeding difficulties, often related to hypotonia
• Short attention span
• Autistic-like behaviors that include gaze avoidance, inattention, and repetitive behaviors
• Self-injury and/or aggressive behaviors
## Establishing the Diagnosis
The diagnosis of
Deletion of 2q23.1 that encompasses all or part of
Intragenic deletion involving one or more exons of
A heterozygous pathogenic (or likely pathogenic) sequence variant in
Rarely, an apparently balanced complex chromosome rearrangement of the 2q23.1 region involving
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing may not. Because many inherited disorders share the phenotypic findings of ID, seizures, and behavior problems, most children with
Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Note: In individuals with features that are highly suggestive of
Molecular Genetic Testing Used in
See
See
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis should include analysis of noncoding exon 1.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
• Deletion of 2q23.1 that encompasses all or part of
• Intragenic deletion involving one or more exons of
• A heterozygous pathogenic (or likely pathogenic) sequence variant in
• Rarely, an apparently balanced complex chromosome rearrangement of the 2q23.1 region involving
## Recommended First-Tier Testing
Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from
## Options for Second-Tier Testing
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Note: In individuals with features that are highly suggestive of
Molecular Genetic Testing Used in
See
See
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis should include analysis of noncoding exon 1.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
## Clinical Characteristics
Select Features of
Motor delays with poor coordination and broad-based/ataxic gait are seen in more than 70% of individuals. The average age of walking is two to three years [
Language development is severely impaired [
Although seizure types have not been well characterized, typically only one seizure type is observed in an individual. Seizure types most often include generalized tonic-clonic, focal, atypical absence, tonic, drop attacks, and myoclonic seizures. Atonic, sleep-related, and startle-induced atonic seizures have also been reported [
In the few instances in which EEG studies have been performed, patterns were nonspecific; however, a few individuals were reported to have focal spikes and spike-wave complexes [
Other musculoskeletal abnormalities mentioned in at least two affected individuals each are hip dysplasia, joint laxity, and scoliosis.
No genotype-phenotype correlations distinguish individuals with pathogenic sequence variants from those with
Penetrance is predicted to be complete.
The commonly used term, "
The prevalence of
Approximately 1% of 4,808 individuals (from 3 cohorts) ascertained for autism spectrum disorder were found to have
## Clinical Description
Select Features of
Motor delays with poor coordination and broad-based/ataxic gait are seen in more than 70% of individuals. The average age of walking is two to three years [
Language development is severely impaired [
Although seizure types have not been well characterized, typically only one seizure type is observed in an individual. Seizure types most often include generalized tonic-clonic, focal, atypical absence, tonic, drop attacks, and myoclonic seizures. Atonic, sleep-related, and startle-induced atonic seizures have also been reported [
In the few instances in which EEG studies have been performed, patterns were nonspecific; however, a few individuals were reported to have focal spikes and spike-wave complexes [
Other musculoskeletal abnormalities mentioned in at least two affected individuals each are hip dysplasia, joint laxity, and scoliosis.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations distinguish individuals with pathogenic sequence variants from those with
## Penetrance
Penetrance is predicted to be complete.
## Nomenclature
The commonly used term, "
## Prevalence
The prevalence of
Approximately 1% of 4,808 individuals (from 3 cohorts) ascertained for autism spectrum disorder were found to have
## Genetically Related Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Because the phenotypic features associated with
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or online
Social work involvement for parental support;
Home nursing referral.
Ensure that IEP is in place.
Counsel parents re guardianship & adult services.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
A multidisciplinary approach to manage the features and specific issues identified is recommended. Specialists in the following fields are often involved: clinical genetics, neurology, child development, behavioral therapy, nutrition/feeding, speech and language therapy, and occupational and physical therapy.
Treatment of Manifestations in Individuals with
ASM such as valproate, clonazepam, zonisamide, & clobazam appear to be effective in reducing incidence of seizures.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one-on-one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), sleep disturbance, and behavior issues when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
Monitor developmental progress & educational needs.
Physical medicine, OT/PT assessment of mobility, self-help skills
Monitor those w/seizures as clinically indicated.
Assess for new seizures.
Assessment for sleep disturbance
Assessment for anxiety, attention, & aggressive or self-injurious behavior
Eval of nutritional status
Monitor for constipation.
OT = occupational therapy; PT = physical therapy
See
Search
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or online
• Social work involvement for parental support;
• Home nursing referral.
• Ensure that IEP is in place.
• Counsel parents re guardianship & adult services.
• ASM such as valproate, clonazepam, zonisamide, & clobazam appear to be effective in reducing incidence of seizures.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Monitor developmental progress & educational needs.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Monitor those w/seizures as clinically indicated.
• Assess for new seizures.
• Assessment for sleep disturbance
• Assessment for anxiety, attention, & aggressive or self-injurious behavior
• Eval of nutritional status
• Monitor for constipation.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or online
Social work involvement for parental support;
Home nursing referral.
Ensure that IEP is in place.
Counsel parents re guardianship & adult services.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or online
• Social work involvement for parental support;
• Home nursing referral.
• Ensure that IEP is in place.
• Counsel parents re guardianship & adult services.
## Treatment of Manifestations
A multidisciplinary approach to manage the features and specific issues identified is recommended. Specialists in the following fields are often involved: clinical genetics, neurology, child development, behavioral therapy, nutrition/feeding, speech and language therapy, and occupational and physical therapy.
Treatment of Manifestations in Individuals with
ASM such as valproate, clonazepam, zonisamide, & clobazam appear to be effective in reducing incidence of seizures.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one-on-one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), sleep disturbance, and behavior issues when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• ASM such as valproate, clonazepam, zonisamide, & clobazam appear to be effective in reducing incidence of seizures.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one-on-one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), sleep disturbance, and behavior issues when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
Monitor developmental progress & educational needs.
Physical medicine, OT/PT assessment of mobility, self-help skills
Monitor those w/seizures as clinically indicated.
Assess for new seizures.
Assessment for sleep disturbance
Assessment for anxiety, attention, & aggressive or self-injurious behavior
Eval of nutritional status
Monitor for constipation.
OT = occupational therapy; PT = physical therapy
• Monitor developmental progress & educational needs.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Monitor those w/seizures as clinically indicated.
• Assess for new seizures.
• Assessment for sleep disturbance
• Assessment for anxiety, attention, & aggressive or self-injurious behavior
• Eval of nutritional status
• Monitor for constipation.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most probands with
Rarely, a proband with
For accurate assessment of recurrence risk, evaluation of the parents by molecular genetic or genomic testing that will detect the genetic alteration identified in the proband is recommended. Parental testing for a balanced chromosome rearrangement involving the 2q23.1 region is also recommended.
If the genetic alteration identified in the proband is not identified in a parent, neither parent has a chromosome rearrangement, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Parental mosaicism has been reported in several families [
The family history of some individuals diagnosed with
If a parent of the proband has the genetic alteration identified in the proband, the risk to each sib of inheriting the genetic alteration is 50%. Several families with
If a parent has a balanced structural chromosome rearrangement involving the 2q23.1 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
If the causative genetic alteration identified in the proband is not identified in the parents and neither parent has a chromosome rearrangement, the risk to sibs is presumed to be slightly greater than that of the general population because of the possibility of parental germline mosaicism [
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with
Once the genetic alteration resulting in
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most probands with
• Rarely, a proband with
• For accurate assessment of recurrence risk, evaluation of the parents by molecular genetic or genomic testing that will detect the genetic alteration identified in the proband is recommended. Parental testing for a balanced chromosome rearrangement involving the 2q23.1 region is also recommended.
• If the genetic alteration identified in the proband is not identified in a parent, neither parent has a chromosome rearrangement, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Parental mosaicism has been reported in several families [
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Parental mosaicism has been reported in several families [
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Parental mosaicism has been reported in several families [
• If a parent of the proband has the genetic alteration identified in the proband, the risk to each sib of inheriting the genetic alteration is 50%. Several families with
• If a parent has a balanced structural chromosome rearrangement involving the 2q23.1 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• If the causative genetic alteration identified in the proband is not identified in the parents and neither parent has a chromosome rearrangement, the risk to sibs is presumed to be slightly greater than that of the general population because of the possibility of parental germline mosaicism [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with
## Mode of Inheritance
## Risk to Family Members
Most probands with
Rarely, a proband with
For accurate assessment of recurrence risk, evaluation of the parents by molecular genetic or genomic testing that will detect the genetic alteration identified in the proband is recommended. Parental testing for a balanced chromosome rearrangement involving the 2q23.1 region is also recommended.
If the genetic alteration identified in the proband is not identified in a parent, neither parent has a chromosome rearrangement, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Parental mosaicism has been reported in several families [
The family history of some individuals diagnosed with
If a parent of the proband has the genetic alteration identified in the proband, the risk to each sib of inheriting the genetic alteration is 50%. Several families with
If a parent has a balanced structural chromosome rearrangement involving the 2q23.1 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
If the causative genetic alteration identified in the proband is not identified in the parents and neither parent has a chromosome rearrangement, the risk to sibs is presumed to be slightly greater than that of the general population because of the possibility of parental germline mosaicism [
• Most probands with
• Rarely, a proband with
• For accurate assessment of recurrence risk, evaluation of the parents by molecular genetic or genomic testing that will detect the genetic alteration identified in the proband is recommended. Parental testing for a balanced chromosome rearrangement involving the 2q23.1 region is also recommended.
• If the genetic alteration identified in the proband is not identified in a parent, neither parent has a chromosome rearrangement, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Parental mosaicism has been reported in several families [
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Parental mosaicism has been reported in several families [
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Parental mosaicism has been reported in several families [
• If a parent of the proband has the genetic alteration identified in the proband, the risk to each sib of inheriting the genetic alteration is 50%. Several families with
• If a parent has a balanced structural chromosome rearrangement involving the 2q23.1 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• If the causative genetic alteration identified in the proband is not identified in the parents and neither parent has a chromosome rearrangement, the risk to sibs is presumed to be slightly greater than that of the general population because of the possibility of parental germline mosaicism [
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with
## Prenatal Testing and Preimplantation Genetic Testing
Once the genetic alteration resulting in
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
MBD5 Haploinsufficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MBD5 Haploinsufficiency (
MBD5 belongs to MBD family of proteins, which includes MBD1-6 and MeCp2 (encoded by
## Molecular Pathogenesis
MBD5 belongs to MBD family of proteins, which includes MBD1-6 and MeCp2 (encoded by
## Chapter Notes
The parent Facebook group
The authors would like to thank the individuals with MAND and their families for their continued interest and support of MAND research. The parents with children of MAND are the true experts on this disorder; without their help this review and the ongoing research to better define and understand MAND would not be possible.
28 April 2022 (sw) Comprehensive update posted live
27 October 2016 (bp) Review posted live
12 January 2016 (svm) Original submission
• 28 April 2022 (sw) Comprehensive update posted live
• 27 October 2016 (bp) Review posted live
• 12 January 2016 (svm) Original submission
## Author Notes
The parent Facebook group
## Acknowledgments
The authors would like to thank the individuals with MAND and their families for their continued interest and support of MAND research. The parents with children of MAND are the true experts on this disorder; without their help this review and the ongoing research to better define and understand MAND would not be possible.
## Revision History
28 April 2022 (sw) Comprehensive update posted live
27 October 2016 (bp) Review posted live
12 January 2016 (svm) Original submission
• 28 April 2022 (sw) Comprehensive update posted live
• 27 October 2016 (bp) Review posted live
• 12 January 2016 (svm) Original submission
## References
## Literature Cited
|
[] |
27/10/2016
|
28/4/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mbtps1-semd
|
mbtps1-semd
|
[
"Spondyloepiphyseal Dysplasia, Kondo-Fu Type (SEDKF)",
"Spondyloepiphyseal Dysplasia, Kondo-Fu Type (SEDKF)",
"Membrane-bound transcription factor site-1 protease",
"MBTPS1",
"MBTPS1-Related Spondyloepimetaphyseal Dysplasia with Elevated Lysosomal Enzymes"
] |
Hua Wang, Andrea Wierenga, Sandeep Prabhu, Klaas Wierenga
|
Summary The diagnosis of
|
## Diagnosis
Postnatal-onset short stature
Kyphosis and/or scoliosis
Inguinal hernia
Protruding abdomen
Cataracts (often congenital)
Developmental delay (gross motor and/or speech)
Dysmorphic facial features, including prominent forehead, prominent cheekbones, retromicrognathia, wide mouth, and large, prominent ears
Diffuse osteopenia
Copper-beaten appearance of the skull
Dysplasia of multiple thoracolumbar vertebrae: irregular cortex of the vertebrae (rough rather than smooth vertebral outline), end plate bone defects, ovoid lumbar vertebrae, and narrow intervertebral spaces [
Long bones with small and irregular epiphyses and mildly enlarged and irregular metaphyses; long bones may be short and bowed
Significant hip dysplasia with small, fragmented sclerotic femoral heads
Short metacarpals and metatarsals with small epiphyses [
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other skeletal dysplasias,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• Postnatal-onset short stature
• Kyphosis and/or scoliosis
• Inguinal hernia
• Protruding abdomen
• Cataracts (often congenital)
• Developmental delay (gross motor and/or speech)
• Dysmorphic facial features, including prominent forehead, prominent cheekbones, retromicrognathia, wide mouth, and large, prominent ears
• Diffuse osteopenia
• Copper-beaten appearance of the skull
• Dysplasia of multiple thoracolumbar vertebrae: irregular cortex of the vertebrae (rough rather than smooth vertebral outline), end plate bone defects, ovoid lumbar vertebrae, and narrow intervertebral spaces [
• Long bones with small and irregular epiphyses and mildly enlarged and irregular metaphyses; long bones may be short and bowed
• Significant hip dysplasia with small, fragmented sclerotic femoral heads
• Short metacarpals and metatarsals with small epiphyses [
## Suggestive Findings
Postnatal-onset short stature
Kyphosis and/or scoliosis
Inguinal hernia
Protruding abdomen
Cataracts (often congenital)
Developmental delay (gross motor and/or speech)
Dysmorphic facial features, including prominent forehead, prominent cheekbones, retromicrognathia, wide mouth, and large, prominent ears
Diffuse osteopenia
Copper-beaten appearance of the skull
Dysplasia of multiple thoracolumbar vertebrae: irregular cortex of the vertebrae (rough rather than smooth vertebral outline), end plate bone defects, ovoid lumbar vertebrae, and narrow intervertebral spaces [
Long bones with small and irregular epiphyses and mildly enlarged and irregular metaphyses; long bones may be short and bowed
Significant hip dysplasia with small, fragmented sclerotic femoral heads
Short metacarpals and metatarsals with small epiphyses [
• Postnatal-onset short stature
• Kyphosis and/or scoliosis
• Inguinal hernia
• Protruding abdomen
• Cataracts (often congenital)
• Developmental delay (gross motor and/or speech)
• Dysmorphic facial features, including prominent forehead, prominent cheekbones, retromicrognathia, wide mouth, and large, prominent ears
• Diffuse osteopenia
• Copper-beaten appearance of the skull
• Dysplasia of multiple thoracolumbar vertebrae: irregular cortex of the vertebrae (rough rather than smooth vertebral outline), end plate bone defects, ovoid lumbar vertebrae, and narrow intervertebral spaces [
• Long bones with small and irregular epiphyses and mildly enlarged and irregular metaphyses; long bones may be short and bowed
• Significant hip dysplasia with small, fragmented sclerotic femoral heads
• Short metacarpals and metatarsals with small epiphyses [
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other skeletal dysplasias,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
## Option 1
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other skeletal dysplasias,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
## Clinical Characteristics
Hip dislocation with coxa vara was reported in one individual [
Craniosynostosis was identified in two individuals [
Short neck and rhizomelia were reported in one individual [
Generalized seizure activity (1 individual) [
Accumulation of fat on the chest and abdomen (1 individual) [
Epicanthal folds and high nasal bridge (1 individual) [
No genotype-phenotype correlations have been identified.
The prevalence of this condition is unknown. To date, only six individuals from six families have been reported in literature. There are an additional three individuals known to the authors, including an affected fetus.
• Generalized seizure activity (1 individual) [
• Accumulation of fat on the chest and abdomen (1 individual) [
• Epicanthal folds and high nasal bridge (1 individual) [
## Clinical Description
Hip dislocation with coxa vara was reported in one individual [
Craniosynostosis was identified in two individuals [
Short neck and rhizomelia were reported in one individual [
Generalized seizure activity (1 individual) [
Accumulation of fat on the chest and abdomen (1 individual) [
Epicanthal folds and high nasal bridge (1 individual) [
• Generalized seizure activity (1 individual) [
• Accumulation of fat on the chest and abdomen (1 individual) [
• Epicanthal folds and high nasal bridge (1 individual) [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Prevalence
The prevalence of this condition is unknown. To date, only six individuals from six families have been reported in literature. There are an additional three individuals known to the authors, including an affected fetus.
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of
Growth deficiency
Relative macrocephaly
Frontal bossing or prominent forehead
Body asymmetry
Brachytelephalangy
Nasomaxillary hypoplasia
Postnatal short stature
Stippled epiphyses
Calcifications
Vertebral abnormalities
Severe disproportionate short stature, short extremities
Hypertelorism, flat profile, Pierre Robin sequence
Myopia & hearing loss
Delayed/poor ossification of vertebrae & pubic bones
Short long bones w/hypoplastic epiphyses
↑ risk for cervical instability & spinal cord compression
Mild-to-moderate disproportionate short stature & short extremities
Brachydactyly type E, short ulnae, variable clubfeet, cleft palate
Myopia & hearing loss
Ovoid vertebra
Delayed ossification of pubic bones
Flattened & irregular epiphyses in long bones
Premature hip arthrosis causes joint pain.
Severe disproportionate short stature, short neck, short thorax, short extremities
Myopia, vitreous abnormalities, & retinal detachment
Platyspondyly w/anterior wedging & coronal clefting of lumbar vertebral bodies
Delayed ossification in distal femoral & proximal tibial epiphyseal ossification centers
Short long bones w/large metaphyses & epiphyses
Growth deficiency
Frontal bossing; depressed nasal bridge; sparse eyebrows & lashes, often asymmetric
Rhizomelia
Scoliosis
Abnormalities of skin, hair, & nails; ocular anomaly
Marked disproportionate short stature w/short trunk
Ulnar deviation of wrists
Pectus carinatum & flaring of lower rib cage
Gibbus, kyphosis, & scoliosis
Genu valgum
Hypermobile joints
Waddling gait w/frequent falls
Odontoid hypoplasia w/subsequent cervical instability
Short ulnas & delayed bone maturation
Short metacarpals
Flared iliac wings, flattening of femoral epiphyses, & coxa valga
Short stature (below 15th centile in adults)
Kyphoscoliosis
Joint laxity
Axial & appendicular dysostosis multiplex
Platyspondyly
Odontoid hypoplasia
Coxa/genu valga
Small to low-normal anthropometric measurements for gestational age
Restricted range of passive motion in shoulders
Flat face, shallow orbits, depressed nasal bridge
Thick skin w/wax-like texture
Variable musculoskeletal findings
Growth rate deceleration
Joint stiffness of fingers, shoulders, & hips
Gradual mild coarsening of facial features
Genu valgum
Spinal deformities incl scoliosis & hyperlordosis
No organomegaly
Mild-to-moderate dysostosis multiplex
Hypoplastic iliac bones w/flared iliac wings
Shallow & irregular acetabula & moderate-to-severe dysplasia of proximal femoral epiphyses giving rise to coxa valga
Disproportionate short stature in adolescence or adulthood w/short trunk & barrel-shaped chest.
Short neck, dorsal kyphosis, scoliosis, & lumbar hyperlordosis may be evident by puberty.
Early-onset osteoarthritis
Multiple epiphyseal abnormalities
Platyspondyly; characteristic superior & inferior "humping" on lateral radiograph
Hypoplastic odontoid process
Short femoral necks
Coxa vara
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; SEDC = spondyloepiphyseal dysplasia congenita; XL = X-linked
Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes Silver-Russell syndrome (SRS) in 35%-50% of individuals; maternal uniparental disomy causes SRS in 7%-10% of individuals. A small number of affected individuals have duplications, deletions, or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7. Rarely, SRS is caused by pathogenic variants in
Type II collagen disorders are inherited in an autosomal dominant manner. However, rare instances of autosomal recessive inheritance in spondyloepiphyseal dysplasia congenita have been reported.
• Growth deficiency
• Relative macrocephaly
• Frontal bossing or prominent forehead
• Body asymmetry
• Brachytelephalangy
• Nasomaxillary hypoplasia
• Postnatal short stature
• Stippled epiphyses
• Calcifications
• Vertebral abnormalities
• Severe disproportionate short stature, short extremities
• Hypertelorism, flat profile, Pierre Robin sequence
• Myopia & hearing loss
• Delayed/poor ossification of vertebrae & pubic bones
• Short long bones w/hypoplastic epiphyses
• ↑ risk for cervical instability & spinal cord compression
• Mild-to-moderate disproportionate short stature & short extremities
• Brachydactyly type E, short ulnae, variable clubfeet, cleft palate
• Myopia & hearing loss
• Ovoid vertebra
• Delayed ossification of pubic bones
• Flattened & irregular epiphyses in long bones
• Premature hip arthrosis causes joint pain.
• Severe disproportionate short stature, short neck, short thorax, short extremities
• Myopia, vitreous abnormalities, & retinal detachment
• Platyspondyly w/anterior wedging & coronal clefting of lumbar vertebral bodies
• Delayed ossification in distal femoral & proximal tibial epiphyseal ossification centers
• Short long bones w/large metaphyses & epiphyses
• Growth deficiency
• Frontal bossing; depressed nasal bridge; sparse eyebrows & lashes, often asymmetric
• Rhizomelia
• Scoliosis
• Abnormalities of skin, hair, & nails; ocular anomaly
• Marked disproportionate short stature w/short trunk
• Ulnar deviation of wrists
• Pectus carinatum & flaring of lower rib cage
• Gibbus, kyphosis, & scoliosis
• Genu valgum
• Hypermobile joints
• Waddling gait w/frequent falls
• Odontoid hypoplasia w/subsequent cervical instability
• Short ulnas & delayed bone maturation
• Short metacarpals
• Flared iliac wings, flattening of femoral epiphyses, & coxa valga
• Short stature (below 15th centile in adults)
• Kyphoscoliosis
• Joint laxity
• Axial & appendicular dysostosis multiplex
• Platyspondyly
• Odontoid hypoplasia
• Coxa/genu valga
• Small to low-normal anthropometric measurements for gestational age
• Restricted range of passive motion in shoulders
• Flat face, shallow orbits, depressed nasal bridge
• Thick skin w/wax-like texture
• Variable musculoskeletal findings
• Growth rate deceleration
• Joint stiffness of fingers, shoulders, & hips
• Gradual mild coarsening of facial features
• Genu valgum
• Spinal deformities incl scoliosis & hyperlordosis
• No organomegaly
• Mild-to-moderate dysostosis multiplex
• Hypoplastic iliac bones w/flared iliac wings
• Shallow & irregular acetabula & moderate-to-severe dysplasia of proximal femoral epiphyses giving rise to coxa valga
• Disproportionate short stature in adolescence or adulthood w/short trunk & barrel-shaped chest.
• Short neck, dorsal kyphosis, scoliosis, & lumbar hyperlordosis may be evident by puberty.
• Early-onset osteoarthritis
• Multiple epiphyseal abnormalities
• Platyspondyly; characteristic superior & inferior "humping" on lateral radiograph
• Hypoplastic odontoid process
• Short femoral necks
• Coxa vara
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Assess growth.
Gastroenterology / nutrition / feeding team eval
Skeletal survey
Orthopedist / PT & OT eval
DXA scan
Community or
Social work involvement for parental support
DXA = dual x-ray absorptiometry;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
GH therapy can be tried, but outcome is uncertain.
It is unknown if GH therapy can lead to worsening of disproportionate growth in those w/spinal dysplasia.
Operative mgmt may be warranted in those w/neurologic manifestations.
In those w/o neurologic compromise, procedures such as vertebroplasty & kyphoplasty may be considered for vertebral augmentation.
Early intervention programs
Early childhood education
Early & periodic screening, diagnosis, & treatment (EPSDT)
GH = growth hormone
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
In children with significant kyphoscoliosis, sports that place stress on the spine (e.g., heavy lifting, weight-bearing exercises) should be avoided.
See
No pregnancies have been reported in individuals with
Search
• Assess growth.
• Gastroenterology / nutrition / feeding team eval
• Skeletal survey
• Orthopedist / PT & OT eval
• DXA scan
• Community or
• Social work involvement for parental support
• GH therapy can be tried, but outcome is uncertain.
• It is unknown if GH therapy can lead to worsening of disproportionate growth in those w/spinal dysplasia.
• Operative mgmt may be warranted in those w/neurologic manifestations.
• In those w/o neurologic compromise, procedures such as vertebroplasty & kyphoplasty may be considered for vertebral augmentation.
• Early intervention programs
• Early childhood education
• Early & periodic screening, diagnosis, & treatment (EPSDT)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Assess growth.
Gastroenterology / nutrition / feeding team eval
Skeletal survey
Orthopedist / PT & OT eval
DXA scan
Community or
Social work involvement for parental support
DXA = dual x-ray absorptiometry;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assess growth.
• Gastroenterology / nutrition / feeding team eval
• Skeletal survey
• Orthopedist / PT & OT eval
• DXA scan
• Community or
• Social work involvement for parental support
## Treatment of Manifestations
GH therapy can be tried, but outcome is uncertain.
It is unknown if GH therapy can lead to worsening of disproportionate growth in those w/spinal dysplasia.
Operative mgmt may be warranted in those w/neurologic manifestations.
In those w/o neurologic compromise, procedures such as vertebroplasty & kyphoplasty may be considered for vertebral augmentation.
Early intervention programs
Early childhood education
Early & periodic screening, diagnosis, & treatment (EPSDT)
GH = growth hormone
• GH therapy can be tried, but outcome is uncertain.
• It is unknown if GH therapy can lead to worsening of disproportionate growth in those w/spinal dysplasia.
• Operative mgmt may be warranted in those w/neurologic manifestations.
• In those w/o neurologic compromise, procedures such as vertebroplasty & kyphoplasty may be considered for vertebral augmentation.
• Early intervention programs
• Early childhood education
• Early & periodic screening, diagnosis, & treatment (EPSDT)
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
## Agents/Circumstances to Avoid
In children with significant kyphoscoliosis, sports that place stress on the spine (e.g., heavy lifting, weight-bearing exercises) should be avoided.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
No pregnancies have been reported in individuals with
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
## Molecular Genetics
MBTPS1-Related Spondyloepimetaphyseal Dysplasia with Elevated Lysosomal Enzymes: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MBTPS1-Related Spondyloepimetaphyseal Dysplasia with Elevated Lysosomal Enzymes (
Membrane-bound transcription factor site-1 protease (MBTPS1; also known as S1P) is a serine protease located in the Golgi. MBTPS1 has been shown to regulate lipogenesis, endoplasmic reticulum (ER) function, and lysosome biogenesis in mice and cultured cells [
## Molecular Pathogenesis
Membrane-bound transcription factor site-1 protease (MBTPS1; also known as S1P) is a serine protease located in the Golgi. MBTPS1 has been shown to regulate lipogenesis, endoplasmic reticulum (ER) function, and lysosome biogenesis in mice and cultured cells [
## Chapter Notes
Klaas Wierenga, MD, Hua Wang, MD, PhD, Lijun Xia, MD (
Contact the previously mentioned physicians and researchers to inquire about review of
This research group aims to increase the understanding of
We thank the patients and families that have contributed to the accumulating information about
30 November 2023 (sw) Review posted live
24 July 2023 (kw) Original submission
• 30 November 2023 (sw) Review posted live
• 24 July 2023 (kw) Original submission
## Author Notes
Klaas Wierenga, MD, Hua Wang, MD, PhD, Lijun Xia, MD (
Contact the previously mentioned physicians and researchers to inquire about review of
This research group aims to increase the understanding of
## Acknowledgments
We thank the patients and families that have contributed to the accumulating information about
## Revision History
30 November 2023 (sw) Review posted live
24 July 2023 (kw) Original submission
• 30 November 2023 (sw) Review posted live
• 24 July 2023 (kw) Original submission
## References
## Literature Cited
Craniofacial features of several children with
Reproduced with permission from
Clinical features of several children with
A. Affected child at age six years with kyphoscoliosis (black arrows point to the prominent spinous processes)
B. Affected child at age 40 months with shortening of limbs and kyphoscoliosis
C. Affected child at age ten years with triangular face, prominent cheekbones, micrognathia, short neck, protruding abdomen, shortening of limbs, and genu valgum
D, E. Affected child at age six years with laterally protruding ears, retromicrognathia, sternal malformation, protruding abdomen, and kyphoscoliosis
Reproduced with permission from
Radiographs of a child with
Reproduced with permission from
Radiographs of children with
A. Irregularities more pronounced in the femoral heads, coxa vara, right hip dislocation with external rotation of the lower limbs, and short tubular bones with bowing deformity of the left tibia
B. Left genu valgus and bowing deformity of the left tibia
C, D. Bowed right humerus and short metacarpals
Reproduced with permission from
Skull and spine radiographs of child, age six years, with MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes. Straightened physiologic curvature of the cervical, thoracic, and lumbar spine. Irregular morphology and reduced bone density of the vertebral bodies, C2-C3 and C3-C4 intervertebral disc space narrowing, and bilateral shallow acetabulae.
Reproduced with permission from
Radiographs and spine CT of child age 12 years with
A, B, E, F. No obvious abnormalities in long bones or lateral skull radiograph
C, G. Radiographs show dysplasia of multiple thoracolumbar vertebrae and scoliosis.
D, H. Spine CT shows rough edges of vertebra, end plate bone defects, and narrow intervertebral spaces.
Reproduced with permission from
|
[] |
30/11/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
mc-def
|
mc-def
|
[
"Adenylyltransferase and sulfurtransferase MOCS3",
"Gephyrin",
"Molybdenum cofactor biosynthesis protein 1",
"Molybdopterin synthase catalytic subunit",
"GPHN",
"MOCS1",
"MOCS2",
"MOCS3",
"Molybdenum Cofactor Deficiency"
] |
Molybdenum Cofactor Deficiency
|
Albert Misko, Karishma Mahtani, Jessica Abbott, Guenter Schwarz, Paldeep Atwal
|
Summary Molybdenum cofactor deficiency (MoCD) represents a spectrum, with some individuals experiencing significant signs and symptoms in the neonatal period and early infancy (termed early-onset or severe MoCD) and others developing signs and symptoms in childhood or adulthood (termed late-onset or mild MoCD). Individuals with early-onset MoCD typically present in the first days of life with severe encephalopathy, including refractory seizures, opisthotonos, axial and appendicular hypotonia, feeding difficulties, and apnea. Head imaging may demonstrate loss of gray and white matter differentiation, gyral swelling, sulci injury (typically assessed by evaluating the depth of focal lesional injury within the sulci), diffusely elevated T Late-onset MoCD is typically characterized by milder symptoms, such as acute neurologic decompensation in the setting of infection. Episodes vary in nature but commonly consist of altered mental status, dystonia, choreoathetosis, ataxia, nystagmus, and fluctuating hypotonia and hypertonia. These features may improve after resolution of the inciting infection or progress in a gradual or stochastic manner over the lifetime. Brain imaging may be normal or may demonstrate T The diagnosis of molybdenum cofactor deficiency is established by identification of biallelic pathogenic variants in Molybdenum cofactor deficiency (MoCD) is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an MoCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the MoCD-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
|
## Diagnosis
Formal clinical diagnostic criteria for molybdenum cofactor deficiency have not been established.
Molybdenum cofactor deficiency (MoCD) typically manifests in the neonatal period and
Acute encephalopathy
Intractable seizures
Poor feeding
Hyperekplexia (excessive startle reaction to loud noises, touch, or movement)
Apnea
Pyramidal and extrapyramidal dysfunction
Severe developmental delay / intellectual disability
Acquired microcephaly
Nonspecific craniofacial dysmorphic features (See
Ophthalmologic manifestations (e.g., ectopia lentis)
Variable course of stochastic regression, sometimes around infection
Elevated taurine and decreased cystine concentrations on plasma amino acid analysis
Decreased plasma total homocysteine concentration
Elevated xanthine and hypoxanthine concentrations on urine pyrimidine analysis
Decreased plasma uric acid concentration
Elevated urine levels of S-sulfocysteine and thiosulfate on targeted measurement
Note: Because elevations of these metabolites individually are not entirely specific to molybdenum cofactor deficiency, follow-up testing is required to establish or rule out the diagnosis of molybdenum cofactor deficiency (see
Diffusion restriction and elevated T
Gyral swelling
In some affected individuals in the first days of life, imaging features suggestive of prenatal-associated injury
Atrophy of the cortex, subcortical white matter, basal ganglia, corpus callosum, and/or cerebellum
High T
Cavitary leukomalacia
Ulegyria (mushroom-shaped morphology of gyri resulting from injury and contraction of sulci; also seen in neonatal hypoxic ischemic injury)
Lactate doublet
Glutamine-glutamate (Glx) peak
The diagnosis of molybdenum cofactor deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of MoCD, molecular genetic testing typically includes use of a
For an introduction to multigene panels click
When the phenotype is indistinguishable from other inherited disorders characterized by neonatal seizures, epilepsy, or neurodegeneration,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Molybdenum Cofactor Deficiency (MoCD)
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Phenotype is sometimes referred to as molybdenum cofactor deficiency type C.
Percentages based on number of individuals reported in the literature; see also
A common deleted area within exons 3-5 in the G domain of the protein encoded by
Sometimes referred to as molybdenum cofactor deficiency type A
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Sometimes referred to as molybdenum cofactor deficiency type B
To date, the only individual with pathogenic variants in this gene had mild features of MoCD (see
• Acute encephalopathy
• Intractable seizures
• Poor feeding
• Hyperekplexia (excessive startle reaction to loud noises, touch, or movement)
• Apnea
• Pyramidal and extrapyramidal dysfunction
• Severe developmental delay / intellectual disability
• Acquired microcephaly
• Nonspecific craniofacial dysmorphic features (See
• Ophthalmologic manifestations (e.g., ectopia lentis)
• Variable course of stochastic regression, sometimes around infection
• Elevated taurine and decreased cystine concentrations on plasma amino acid analysis
• Decreased plasma total homocysteine concentration
• Elevated xanthine and hypoxanthine concentrations on urine pyrimidine analysis
• Decreased plasma uric acid concentration
• Elevated urine levels of S-sulfocysteine and thiosulfate on targeted measurement
•
• Diffusion restriction and elevated T
• Gyral swelling
• In some affected individuals in the first days of life, imaging features suggestive of prenatal-associated injury
• Diffusion restriction and elevated T
• Gyral swelling
• In some affected individuals in the first days of life, imaging features suggestive of prenatal-associated injury
•
• Atrophy of the cortex, subcortical white matter, basal ganglia, corpus callosum, and/or cerebellum
• High T
• Cavitary leukomalacia
• Ulegyria (mushroom-shaped morphology of gyri resulting from injury and contraction of sulci; also seen in neonatal hypoxic ischemic injury)
• Atrophy of the cortex, subcortical white matter, basal ganglia, corpus callosum, and/or cerebellum
• High T
• Cavitary leukomalacia
• Ulegyria (mushroom-shaped morphology of gyri resulting from injury and contraction of sulci; also seen in neonatal hypoxic ischemic injury)
•
• Lactate doublet
• Glutamine-glutamate (Glx) peak
• Lactate doublet
• Glutamine-glutamate (Glx) peak
• Diffusion restriction and elevated T
• Gyral swelling
• In some affected individuals in the first days of life, imaging features suggestive of prenatal-associated injury
• Atrophy of the cortex, subcortical white matter, basal ganglia, corpus callosum, and/or cerebellum
• High T
• Cavitary leukomalacia
• Ulegyria (mushroom-shaped morphology of gyri resulting from injury and contraction of sulci; also seen in neonatal hypoxic ischemic injury)
• Lactate doublet
• Glutamine-glutamate (Glx) peak
## Suggestive Findings
Molybdenum cofactor deficiency (MoCD) typically manifests in the neonatal period and
Acute encephalopathy
Intractable seizures
Poor feeding
Hyperekplexia (excessive startle reaction to loud noises, touch, or movement)
Apnea
Pyramidal and extrapyramidal dysfunction
Severe developmental delay / intellectual disability
Acquired microcephaly
Nonspecific craniofacial dysmorphic features (See
Ophthalmologic manifestations (e.g., ectopia lentis)
Variable course of stochastic regression, sometimes around infection
Elevated taurine and decreased cystine concentrations on plasma amino acid analysis
Decreased plasma total homocysteine concentration
Elevated xanthine and hypoxanthine concentrations on urine pyrimidine analysis
Decreased plasma uric acid concentration
Elevated urine levels of S-sulfocysteine and thiosulfate on targeted measurement
Note: Because elevations of these metabolites individually are not entirely specific to molybdenum cofactor deficiency, follow-up testing is required to establish or rule out the diagnosis of molybdenum cofactor deficiency (see
Diffusion restriction and elevated T
Gyral swelling
In some affected individuals in the first days of life, imaging features suggestive of prenatal-associated injury
Atrophy of the cortex, subcortical white matter, basal ganglia, corpus callosum, and/or cerebellum
High T
Cavitary leukomalacia
Ulegyria (mushroom-shaped morphology of gyri resulting from injury and contraction of sulci; also seen in neonatal hypoxic ischemic injury)
Lactate doublet
Glutamine-glutamate (Glx) peak
• Acute encephalopathy
• Intractable seizures
• Poor feeding
• Hyperekplexia (excessive startle reaction to loud noises, touch, or movement)
• Apnea
• Pyramidal and extrapyramidal dysfunction
• Severe developmental delay / intellectual disability
• Acquired microcephaly
• Nonspecific craniofacial dysmorphic features (See
• Ophthalmologic manifestations (e.g., ectopia lentis)
• Variable course of stochastic regression, sometimes around infection
• Elevated taurine and decreased cystine concentrations on plasma amino acid analysis
• Decreased plasma total homocysteine concentration
• Elevated xanthine and hypoxanthine concentrations on urine pyrimidine analysis
• Decreased plasma uric acid concentration
• Elevated urine levels of S-sulfocysteine and thiosulfate on targeted measurement
•
• Diffusion restriction and elevated T
• Gyral swelling
• In some affected individuals in the first days of life, imaging features suggestive of prenatal-associated injury
• Diffusion restriction and elevated T
• Gyral swelling
• In some affected individuals in the first days of life, imaging features suggestive of prenatal-associated injury
•
• Atrophy of the cortex, subcortical white matter, basal ganglia, corpus callosum, and/or cerebellum
• High T
• Cavitary leukomalacia
• Ulegyria (mushroom-shaped morphology of gyri resulting from injury and contraction of sulci; also seen in neonatal hypoxic ischemic injury)
• Atrophy of the cortex, subcortical white matter, basal ganglia, corpus callosum, and/or cerebellum
• High T
• Cavitary leukomalacia
• Ulegyria (mushroom-shaped morphology of gyri resulting from injury and contraction of sulci; also seen in neonatal hypoxic ischemic injury)
•
• Lactate doublet
• Glutamine-glutamate (Glx) peak
• Lactate doublet
• Glutamine-glutamate (Glx) peak
• Diffusion restriction and elevated T
• Gyral swelling
• In some affected individuals in the first days of life, imaging features suggestive of prenatal-associated injury
• Atrophy of the cortex, subcortical white matter, basal ganglia, corpus callosum, and/or cerebellum
• High T
• Cavitary leukomalacia
• Ulegyria (mushroom-shaped morphology of gyri resulting from injury and contraction of sulci; also seen in neonatal hypoxic ischemic injury)
• Lactate doublet
• Glutamine-glutamate (Glx) peak
## Establishing the Diagnosis
The diagnosis of molybdenum cofactor deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of MoCD, molecular genetic testing typically includes use of a
For an introduction to multigene panels click
When the phenotype is indistinguishable from other inherited disorders characterized by neonatal seizures, epilepsy, or neurodegeneration,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Molybdenum Cofactor Deficiency (MoCD)
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Phenotype is sometimes referred to as molybdenum cofactor deficiency type C.
Percentages based on number of individuals reported in the literature; see also
A common deleted area within exons 3-5 in the G domain of the protein encoded by
Sometimes referred to as molybdenum cofactor deficiency type A
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Sometimes referred to as molybdenum cofactor deficiency type B
To date, the only individual with pathogenic variants in this gene had mild features of MoCD (see
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of MoCD, molecular genetic testing typically includes use of a
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from other inherited disorders characterized by neonatal seizures, epilepsy, or neurodegeneration,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Molybdenum Cofactor Deficiency (MoCD)
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Phenotype is sometimes referred to as molybdenum cofactor deficiency type C.
Percentages based on number of individuals reported in the literature; see also
A common deleted area within exons 3-5 in the G domain of the protein encoded by
Sometimes referred to as molybdenum cofactor deficiency type A
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Sometimes referred to as molybdenum cofactor deficiency type B
To date, the only individual with pathogenic variants in this gene had mild features of MoCD (see
## Clinical Characteristics
More than 100 individuals with a molybdenum cofactor deficiency have been identified [
Affected individuals typically present in the first days of life (median1 day; range 1-50 days) with severe encephalopathy, including refractory seizures, opisthotonos, axial hypotonia and appendicular hypertonia, feeding difficulties, and apnea [
Select Features of Early-Onset or Severe Molybdenum Cofactor Deficiency
ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability
It is particularly important to distinguish those with MoCD from those with hypoxic ischemic encephalopathy (HIE) because of the potential use of fosdenopterin (NULIBRY
Mega cisterna magna or Dandy-Walker malformation
Hypoplastic/atrophic corpus callosum or cerebellum
Evidence of prenatal brain degeneration present at the time of birth (cortical atrophy, cystic leukomalacia, or basal ganglia degeneration).
While these features are inconsistently present across all individuals with early-onset or severe MoCD, their presence should suggest MoCD in the right clinical setting. Absence of these findings does not exclude the diagnosis of MoCD.
A variety of seizure semiologies have been reported including subtle, clonic, tonic myoclonic, multifocal, and partial migrating.
A case of epileptic spasms diagnosed at 26 days of life has also been described [
Accompanying EEG changes for those with infantile spasms may include burst suppression, multifocal epileptiform discharges, unilateral discharges, generalized or focal slowing, and hypsarrhythmia.
The diversity of reported semiologies suggests that seizures in those with typical MoCD are secondary to the diffuse cortical degeneration seen on ancillary brain imaging and not specific to the underlying pathophysiology.
Although structural malformations of the gastrointestinal tract are not typically seen in association with MoCD, pyloric stenosis has been diagnosed in two individuals with MoCD and in two individuals with isolated sulfite oxidase deficiency, suggesting a possible connection with sulfite intoxication [
A less severe phenotype with late-onset presentation (1 year; range 4 months to 23 years) and milder symptoms has been recognized (see
Select Features of Late-Onset or Mild Molybdenum Cofactor Deficiency
No clear phenotype correlations have been observed. However, to date the only individuals described with a pathogenic variant in
Sometimes MoCD is divided into subtypes based on the causative gene. This has become more important now that a targeted treatment is available for one subtype (see Management,
No genotype-phenotype correlations are known to be associated with biallelic pathogenic variants in any gene associated with MoCD.
The global incidence of MoCD is estimated at 1:100,000-1:200,000 live births. Like many other rare diseases, the true incidence remains uncertain, as MoCD is likely underdiagnosed.
• Mega cisterna magna or Dandy-Walker malformation
• Hypoplastic/atrophic corpus callosum or cerebellum
• Evidence of prenatal brain degeneration present at the time of birth (cortical atrophy, cystic leukomalacia, or basal ganglia degeneration).
• A variety of seizure semiologies have been reported including subtle, clonic, tonic myoclonic, multifocal, and partial migrating.
• A case of epileptic spasms diagnosed at 26 days of life has also been described [
• Accompanying EEG changes for those with infantile spasms may include burst suppression, multifocal epileptiform discharges, unilateral discharges, generalized or focal slowing, and hypsarrhythmia.
• The diversity of reported semiologies suggests that seizures in those with typical MoCD are secondary to the diffuse cortical degeneration seen on ancillary brain imaging and not specific to the underlying pathophysiology.
## Clinical Description
More than 100 individuals with a molybdenum cofactor deficiency have been identified [
Affected individuals typically present in the first days of life (median1 day; range 1-50 days) with severe encephalopathy, including refractory seizures, opisthotonos, axial hypotonia and appendicular hypertonia, feeding difficulties, and apnea [
Select Features of Early-Onset or Severe Molybdenum Cofactor Deficiency
ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability
It is particularly important to distinguish those with MoCD from those with hypoxic ischemic encephalopathy (HIE) because of the potential use of fosdenopterin (NULIBRY
Mega cisterna magna or Dandy-Walker malformation
Hypoplastic/atrophic corpus callosum or cerebellum
Evidence of prenatal brain degeneration present at the time of birth (cortical atrophy, cystic leukomalacia, or basal ganglia degeneration).
While these features are inconsistently present across all individuals with early-onset or severe MoCD, their presence should suggest MoCD in the right clinical setting. Absence of these findings does not exclude the diagnosis of MoCD.
A variety of seizure semiologies have been reported including subtle, clonic, tonic myoclonic, multifocal, and partial migrating.
A case of epileptic spasms diagnosed at 26 days of life has also been described [
Accompanying EEG changes for those with infantile spasms may include burst suppression, multifocal epileptiform discharges, unilateral discharges, generalized or focal slowing, and hypsarrhythmia.
The diversity of reported semiologies suggests that seizures in those with typical MoCD are secondary to the diffuse cortical degeneration seen on ancillary brain imaging and not specific to the underlying pathophysiology.
Although structural malformations of the gastrointestinal tract are not typically seen in association with MoCD, pyloric stenosis has been diagnosed in two individuals with MoCD and in two individuals with isolated sulfite oxidase deficiency, suggesting a possible connection with sulfite intoxication [
A less severe phenotype with late-onset presentation (1 year; range 4 months to 23 years) and milder symptoms has been recognized (see
Select Features of Late-Onset or Mild Molybdenum Cofactor Deficiency
• Mega cisterna magna or Dandy-Walker malformation
• Hypoplastic/atrophic corpus callosum or cerebellum
• Evidence of prenatal brain degeneration present at the time of birth (cortical atrophy, cystic leukomalacia, or basal ganglia degeneration).
• A variety of seizure semiologies have been reported including subtle, clonic, tonic myoclonic, multifocal, and partial migrating.
• A case of epileptic spasms diagnosed at 26 days of life has also been described [
• Accompanying EEG changes for those with infantile spasms may include burst suppression, multifocal epileptiform discharges, unilateral discharges, generalized or focal slowing, and hypsarrhythmia.
• The diversity of reported semiologies suggests that seizures in those with typical MoCD are secondary to the diffuse cortical degeneration seen on ancillary brain imaging and not specific to the underlying pathophysiology.
## Early-Onset or Severe MoCD
Affected individuals typically present in the first days of life (median1 day; range 1-50 days) with severe encephalopathy, including refractory seizures, opisthotonos, axial hypotonia and appendicular hypertonia, feeding difficulties, and apnea [
Select Features of Early-Onset or Severe Molybdenum Cofactor Deficiency
ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability
It is particularly important to distinguish those with MoCD from those with hypoxic ischemic encephalopathy (HIE) because of the potential use of fosdenopterin (NULIBRY
Mega cisterna magna or Dandy-Walker malformation
Hypoplastic/atrophic corpus callosum or cerebellum
Evidence of prenatal brain degeneration present at the time of birth (cortical atrophy, cystic leukomalacia, or basal ganglia degeneration).
While these features are inconsistently present across all individuals with early-onset or severe MoCD, their presence should suggest MoCD in the right clinical setting. Absence of these findings does not exclude the diagnosis of MoCD.
A variety of seizure semiologies have been reported including subtle, clonic, tonic myoclonic, multifocal, and partial migrating.
A case of epileptic spasms diagnosed at 26 days of life has also been described [
Accompanying EEG changes for those with infantile spasms may include burst suppression, multifocal epileptiform discharges, unilateral discharges, generalized or focal slowing, and hypsarrhythmia.
The diversity of reported semiologies suggests that seizures in those with typical MoCD are secondary to the diffuse cortical degeneration seen on ancillary brain imaging and not specific to the underlying pathophysiology.
Although structural malformations of the gastrointestinal tract are not typically seen in association with MoCD, pyloric stenosis has been diagnosed in two individuals with MoCD and in two individuals with isolated sulfite oxidase deficiency, suggesting a possible connection with sulfite intoxication [
• Mega cisterna magna or Dandy-Walker malformation
• Hypoplastic/atrophic corpus callosum or cerebellum
• Evidence of prenatal brain degeneration present at the time of birth (cortical atrophy, cystic leukomalacia, or basal ganglia degeneration).
• A variety of seizure semiologies have been reported including subtle, clonic, tonic myoclonic, multifocal, and partial migrating.
• A case of epileptic spasms diagnosed at 26 days of life has also been described [
• Accompanying EEG changes for those with infantile spasms may include burst suppression, multifocal epileptiform discharges, unilateral discharges, generalized or focal slowing, and hypsarrhythmia.
• The diversity of reported semiologies suggests that seizures in those with typical MoCD are secondary to the diffuse cortical degeneration seen on ancillary brain imaging and not specific to the underlying pathophysiology.
## Late-Onset or Mild MoCD
A less severe phenotype with late-onset presentation (1 year; range 4 months to 23 years) and milder symptoms has been recognized (see
Select Features of Late-Onset or Mild Molybdenum Cofactor Deficiency
## Phenotype Correlations by Gene
No clear phenotype correlations have been observed. However, to date the only individuals described with a pathogenic variant in
## Nomenclature
Sometimes MoCD is divided into subtypes based on the causative gene. This has become more important now that a targeted treatment is available for one subtype (see Management,
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are known to be associated with biallelic pathogenic variants in any gene associated with MoCD.
## Prevalence
The global incidence of MoCD is estimated at 1:100,000-1:200,000 live births. Like many other rare diseases, the true incidence remains uncertain, as MoCD is likely underdiagnosed.
## Genetically Related (Allelic) Disorders
At present, no phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Early-Onset or Severe Molybdenum Cofactor Deficiency
↑ plasma taurine
↑ urinary thiosulfate & S-sulfocysteine
↓↓ plasma levels of total homocysteine & cystine
Neonates w/pyridoxine-responsive seizures refractory to ASM & encephalopathy
Thinning of corpus callosum & mega cisterna magna on brain MRI
↑ alpha-aminoadipic semialdehyde in urine & plasma
↑ pipecolic acid in urine & CSF
↑ plasma lactate
Hypoglycemia
Normal to ↑ plasma glycine
Normal to ↑ plasma threonine
↓ plasma arginine
↑ plasma lactate
Metabolic acidosis
AD = autosomal dominant; AR = autosomal recessive; ASM = anti-seizure medication; ID = intellectual disability; MoCD = molybdenum cofactor deficiency; MOI = mode of inheritance; XL = X-linked
It should be noted that alpha-aminoadipic semialdehyde excretion has been detected in some individuals with molybdenum cofactor deficiency and isolated sulfite oxidase deficiency [
The differential diagnosis of late onset or mild molybdenum cofactor deficiency includes acquired conditions (e.g., cerebral palsy) and hereditary disorders of basal ganglia and development with extrapyramidal signs and developmental delay including juvenile-onset
• ↑ plasma taurine
• ↑ urinary thiosulfate & S-sulfocysteine
• ↓↓ plasma levels of total homocysteine & cystine
• Neonates w/pyridoxine-responsive seizures refractory to ASM & encephalopathy
• Thinning of corpus callosum & mega cisterna magna on brain MRI
• ↑ alpha-aminoadipic semialdehyde in urine & plasma
• ↑ pipecolic acid in urine & CSF
• ↑ plasma lactate
• Hypoglycemia
• Normal to ↑ plasma glycine
• Normal to ↑ plasma threonine
• ↓ plasma arginine
• ↑ plasma lactate
• Metabolic acidosis
## Early-Onset or Severe Molybdenum Cofactor Deficiency
Genes of Interest in the Differential Diagnosis of Early-Onset or Severe Molybdenum Cofactor Deficiency
↑ plasma taurine
↑ urinary thiosulfate & S-sulfocysteine
↓↓ plasma levels of total homocysteine & cystine
Neonates w/pyridoxine-responsive seizures refractory to ASM & encephalopathy
Thinning of corpus callosum & mega cisterna magna on brain MRI
↑ alpha-aminoadipic semialdehyde in urine & plasma
↑ pipecolic acid in urine & CSF
↑ plasma lactate
Hypoglycemia
Normal to ↑ plasma glycine
Normal to ↑ plasma threonine
↓ plasma arginine
↑ plasma lactate
Metabolic acidosis
AD = autosomal dominant; AR = autosomal recessive; ASM = anti-seizure medication; ID = intellectual disability; MoCD = molybdenum cofactor deficiency; MOI = mode of inheritance; XL = X-linked
It should be noted that alpha-aminoadipic semialdehyde excretion has been detected in some individuals with molybdenum cofactor deficiency and isolated sulfite oxidase deficiency [
• ↑ plasma taurine
• ↑ urinary thiosulfate & S-sulfocysteine
• ↓↓ plasma levels of total homocysteine & cystine
• Neonates w/pyridoxine-responsive seizures refractory to ASM & encephalopathy
• Thinning of corpus callosum & mega cisterna magna on brain MRI
• ↑ alpha-aminoadipic semialdehyde in urine & plasma
• ↑ pipecolic acid in urine & CSF
• ↑ plasma lactate
• Hypoglycemia
• Normal to ↑ plasma glycine
• Normal to ↑ plasma threonine
• ↓ plasma arginine
• ↑ plasma lactate
• Metabolic acidosis
## Late-Onset or Mild Molybdenum Cofactor Deficiency
The differential diagnosis of late onset or mild molybdenum cofactor deficiency includes acquired conditions (e.g., cerebral palsy) and hereditary disorders of basal ganglia and development with extrapyramidal signs and developmental delay including juvenile-onset
## Management
When molybdenum cofactor deficiency (MoCD) is suspected during the diagnostic evaluation (i.e., due to laboratory findings consistent with the condition), metabolic treatment should be initiated immediately. If laboratory findings and/or clinical presentation are highly suggestive, treatment should be initiated prior to the availability of confirmatory genetic testing.
No consensus clinical treatment guidelines have been published.
To establish the extent of disease and needs in an individual diagnosed with MoCD, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of Molybdenum Cofactor Deficiency
Aspiration risk & nutritional status;
Gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
After a new diagnosis of molybdenum cofactor deficiency in an infant, the closest hospital and local pediatrician should also be informed.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for MoCD. However, targeted therapies for individuals with all subtypes of MoCD and specifically for
Targeted Therapies for Molybdenum Cofactor Deficiency
Dose is dependent on weight & age; each vial contains 9.5 mg of fosdenopterin.
Fosdenopterin is administered as a daily IV infusion that requires an indwelling catheter (port) for parents to administer outside of a health care setting.
Fosdenopterin must be initiated in a very short window after manifestations of symptoms to have maximum therapeutic benefit.
The most common adverse reactions are infusion catheter-related complications, pyrexia, viral infection, pneumonia, otitis media, vomiting, cough/sneezing, viral upper respiratory infection, gastroenteritis, bacteremia, & diarrhea.
Persons treated w/fosdenopterin or their caregivers should avoid or minimize exposure to direct sunlight or artificial UV light (i.e., UVA or UVB phototherapy) & adopt precautionary measures.
In severely affected persons diet modification may ↓ irritability but does not affect disease course.
In mildly affected persons diet may promote neurodevelopment & ↓ frequency of episodic decompensations.
In individuals with MoCD type A, the first of the four synthetic steps in the formation of molybdenum cofactor is interrupted, and GTP cannot be converted into cyclic pyranopterin monophosphate (cPMP). Fosdenopterin is a synthetic version of cPMP (see
The efficacy of fosdenopterin (NULIBRY
Replacement therapy with fosdenopterin in individuals with MoCD type A permits the remaining molybdenum cofactor synthesis steps to proceed, with activation of the apoenzyme SOUX resulting in restored mitochondrial-associated sulfite elimination.
Precautionary measures may include wearing protective clothing and hats, using broad-spectrum sunscreen with high sun protection factor (SPF) in those greater than age six months, and wearing sunglasses when exposed to the sun.
There is limited evidence to support the use of a cysteine-restricted diet in persons with this condition.
For example, initial treatment in a neonate may include 1.75g/kg/day protein (with gradual reduction in g/kg protein as the child ages) and protein-free formula/milk.
Often requires monitoring of essential amino acids; see
Supportive care to improve quality of life, maximize function, and reduce complications is recommended, ideally involving multidisciplinary care by specialists in relevant fields (see
Supportive Treatment of Manifestations in Individuals with Molybdenum Cofactor Deficiency
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Avoid valproate, as sulfite intoxication impairs mitochondrial function in vitro.
Education of parents/caregivers
Infants: 1.2 mg/day
Children & adolescents: 50 mg/1x/day ‒ 100 mg/2x/day
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASAA = alpha-aminoadipic semialdehyde; ASM = anti-seizure medication; DD = developmental delay; FTT = failure to thrive; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
It should be noted that alpha-aminoadipic semialdehyde excretion has been detected in some persons with molybdenum cofactor deficiency [
Magnesium is also an N-methyl D-aspartate (NMDA) receptor blocker and could have added benefit in the setting of S-sulfocysteine mediated NMDA receptor overactivation.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States. Standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
In addition to regular evaluations by a metabolic specialist, the following are recommended.
Recommended Surveillance for Individuals with Molybdenum Cofactor Deficiency
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures, changes in tone, mvmt disorders, & headaches.
Neuropsychological testing using age-appropriate standardized assessment batteries
Standardized quality-of-life assessment tools for affected persons & parents/caregivers
OT = occupational therapy; PT = physical therapy
Which may include phenylalanine, valine, threonine, tryptophan, methionine, leucine, isoleucine, lysine, and histidine
Valproate should be avoided if possible, as sulfite intoxication impairs mitochondrial function in vitro.
For individuals on fosdenopterin (NULIBRY
For at-risk newborn sibs when prenatal testing was not performed, metabolic treatment should be initiated immediately and continued until such a time as the diagnosis has been excluded. Postnatal diagnostic evaluations can include the following:
Molecular genetic testing if the pathogenic variants in the family are known
If the pathogenic variants in the family are not known, measure serum uric acid and urinary: sulfite, s-sulfocysteine, xanthine, hypoxanthine, and uric acid.
See
Search
• Aspiration risk & nutritional status;
• Gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Dose is dependent on weight & age; each vial contains 9.5 mg of fosdenopterin.
• Fosdenopterin is administered as a daily IV infusion that requires an indwelling catheter (port) for parents to administer outside of a health care setting.
• Fosdenopterin must be initiated in a very short window after manifestations of symptoms to have maximum therapeutic benefit.
• The most common adverse reactions are infusion catheter-related complications, pyrexia, viral infection, pneumonia, otitis media, vomiting, cough/sneezing, viral upper respiratory infection, gastroenteritis, bacteremia, & diarrhea.
• Persons treated w/fosdenopterin or their caregivers should avoid or minimize exposure to direct sunlight or artificial UV light (i.e., UVA or UVB phototherapy) & adopt precautionary measures.
• In severely affected persons diet modification may ↓ irritability but does not affect disease course.
• In mildly affected persons diet may promote neurodevelopment & ↓ frequency of episodic decompensations.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Avoid valproate, as sulfite intoxication impairs mitochondrial function in vitro.
• Education of parents/caregivers
• Infants: 1.2 mg/day
• Children & adolescents: 50 mg/1x/day ‒ 100 mg/2x/day
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures, changes in tone, mvmt disorders, & headaches.
• Neuropsychological testing using age-appropriate standardized assessment batteries
• Standardized quality-of-life assessment tools for affected persons & parents/caregivers
• Molecular genetic testing if the pathogenic variants in the family are known
• If the pathogenic variants in the family are not known, measure serum uric acid and urinary: sulfite, s-sulfocysteine, xanthine, hypoxanthine, and uric acid.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MoCD, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of Molybdenum Cofactor Deficiency
Aspiration risk & nutritional status;
Gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
After a new diagnosis of molybdenum cofactor deficiency in an infant, the closest hospital and local pediatrician should also be informed.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Aspiration risk & nutritional status;
• Gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
## Treatment of Manifestations
There is no cure for MoCD. However, targeted therapies for individuals with all subtypes of MoCD and specifically for
Targeted Therapies for Molybdenum Cofactor Deficiency
Dose is dependent on weight & age; each vial contains 9.5 mg of fosdenopterin.
Fosdenopterin is administered as a daily IV infusion that requires an indwelling catheter (port) for parents to administer outside of a health care setting.
Fosdenopterin must be initiated in a very short window after manifestations of symptoms to have maximum therapeutic benefit.
The most common adverse reactions are infusion catheter-related complications, pyrexia, viral infection, pneumonia, otitis media, vomiting, cough/sneezing, viral upper respiratory infection, gastroenteritis, bacteremia, & diarrhea.
Persons treated w/fosdenopterin or their caregivers should avoid or minimize exposure to direct sunlight or artificial UV light (i.e., UVA or UVB phototherapy) & adopt precautionary measures.
In severely affected persons diet modification may ↓ irritability but does not affect disease course.
In mildly affected persons diet may promote neurodevelopment & ↓ frequency of episodic decompensations.
In individuals with MoCD type A, the first of the four synthetic steps in the formation of molybdenum cofactor is interrupted, and GTP cannot be converted into cyclic pyranopterin monophosphate (cPMP). Fosdenopterin is a synthetic version of cPMP (see
The efficacy of fosdenopterin (NULIBRY
Replacement therapy with fosdenopterin in individuals with MoCD type A permits the remaining molybdenum cofactor synthesis steps to proceed, with activation of the apoenzyme SOUX resulting in restored mitochondrial-associated sulfite elimination.
Precautionary measures may include wearing protective clothing and hats, using broad-spectrum sunscreen with high sun protection factor (SPF) in those greater than age six months, and wearing sunglasses when exposed to the sun.
There is limited evidence to support the use of a cysteine-restricted diet in persons with this condition.
For example, initial treatment in a neonate may include 1.75g/kg/day protein (with gradual reduction in g/kg protein as the child ages) and protein-free formula/milk.
Often requires monitoring of essential amino acids; see
Supportive care to improve quality of life, maximize function, and reduce complications is recommended, ideally involving multidisciplinary care by specialists in relevant fields (see
Supportive Treatment of Manifestations in Individuals with Molybdenum Cofactor Deficiency
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Avoid valproate, as sulfite intoxication impairs mitochondrial function in vitro.
Education of parents/caregivers
Infants: 1.2 mg/day
Children & adolescents: 50 mg/1x/day ‒ 100 mg/2x/day
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASAA = alpha-aminoadipic semialdehyde; ASM = anti-seizure medication; DD = developmental delay; FTT = failure to thrive; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
It should be noted that alpha-aminoadipic semialdehyde excretion has been detected in some persons with molybdenum cofactor deficiency [
Magnesium is also an N-methyl D-aspartate (NMDA) receptor blocker and could have added benefit in the setting of S-sulfocysteine mediated NMDA receptor overactivation.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States. Standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Dose is dependent on weight & age; each vial contains 9.5 mg of fosdenopterin.
• Fosdenopterin is administered as a daily IV infusion that requires an indwelling catheter (port) for parents to administer outside of a health care setting.
• Fosdenopterin must be initiated in a very short window after manifestations of symptoms to have maximum therapeutic benefit.
• The most common adverse reactions are infusion catheter-related complications, pyrexia, viral infection, pneumonia, otitis media, vomiting, cough/sneezing, viral upper respiratory infection, gastroenteritis, bacteremia, & diarrhea.
• Persons treated w/fosdenopterin or their caregivers should avoid or minimize exposure to direct sunlight or artificial UV light (i.e., UVA or UVB phototherapy) & adopt precautionary measures.
• In severely affected persons diet modification may ↓ irritability but does not affect disease course.
• In mildly affected persons diet may promote neurodevelopment & ↓ frequency of episodic decompensations.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Avoid valproate, as sulfite intoxication impairs mitochondrial function in vitro.
• Education of parents/caregivers
• Infants: 1.2 mg/day
• Children & adolescents: 50 mg/1x/day ‒ 100 mg/2x/day
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Targeted Therapies
There is no cure for MoCD. However, targeted therapies for individuals with all subtypes of MoCD and specifically for
Targeted Therapies for Molybdenum Cofactor Deficiency
Dose is dependent on weight & age; each vial contains 9.5 mg of fosdenopterin.
Fosdenopterin is administered as a daily IV infusion that requires an indwelling catheter (port) for parents to administer outside of a health care setting.
Fosdenopterin must be initiated in a very short window after manifestations of symptoms to have maximum therapeutic benefit.
The most common adverse reactions are infusion catheter-related complications, pyrexia, viral infection, pneumonia, otitis media, vomiting, cough/sneezing, viral upper respiratory infection, gastroenteritis, bacteremia, & diarrhea.
Persons treated w/fosdenopterin or their caregivers should avoid or minimize exposure to direct sunlight or artificial UV light (i.e., UVA or UVB phototherapy) & adopt precautionary measures.
In severely affected persons diet modification may ↓ irritability but does not affect disease course.
In mildly affected persons diet may promote neurodevelopment & ↓ frequency of episodic decompensations.
In individuals with MoCD type A, the first of the four synthetic steps in the formation of molybdenum cofactor is interrupted, and GTP cannot be converted into cyclic pyranopterin monophosphate (cPMP). Fosdenopterin is a synthetic version of cPMP (see
The efficacy of fosdenopterin (NULIBRY
Replacement therapy with fosdenopterin in individuals with MoCD type A permits the remaining molybdenum cofactor synthesis steps to proceed, with activation of the apoenzyme SOUX resulting in restored mitochondrial-associated sulfite elimination.
Precautionary measures may include wearing protective clothing and hats, using broad-spectrum sunscreen with high sun protection factor (SPF) in those greater than age six months, and wearing sunglasses when exposed to the sun.
There is limited evidence to support the use of a cysteine-restricted diet in persons with this condition.
For example, initial treatment in a neonate may include 1.75g/kg/day protein (with gradual reduction in g/kg protein as the child ages) and protein-free formula/milk.
Often requires monitoring of essential amino acids; see
• Dose is dependent on weight & age; each vial contains 9.5 mg of fosdenopterin.
• Fosdenopterin is administered as a daily IV infusion that requires an indwelling catheter (port) for parents to administer outside of a health care setting.
• Fosdenopterin must be initiated in a very short window after manifestations of symptoms to have maximum therapeutic benefit.
• The most common adverse reactions are infusion catheter-related complications, pyrexia, viral infection, pneumonia, otitis media, vomiting, cough/sneezing, viral upper respiratory infection, gastroenteritis, bacteremia, & diarrhea.
• Persons treated w/fosdenopterin or their caregivers should avoid or minimize exposure to direct sunlight or artificial UV light (i.e., UVA or UVB phototherapy) & adopt precautionary measures.
• In severely affected persons diet modification may ↓ irritability but does not affect disease course.
• In mildly affected persons diet may promote neurodevelopment & ↓ frequency of episodic decompensations.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended, ideally involving multidisciplinary care by specialists in relevant fields (see
Supportive Treatment of Manifestations in Individuals with Molybdenum Cofactor Deficiency
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Avoid valproate, as sulfite intoxication impairs mitochondrial function in vitro.
Education of parents/caregivers
Infants: 1.2 mg/day
Children & adolescents: 50 mg/1x/day ‒ 100 mg/2x/day
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASAA = alpha-aminoadipic semialdehyde; ASM = anti-seizure medication; DD = developmental delay; FTT = failure to thrive; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
It should be noted that alpha-aminoadipic semialdehyde excretion has been detected in some persons with molybdenum cofactor deficiency [
Magnesium is also an N-methyl D-aspartate (NMDA) receptor blocker and could have added benefit in the setting of S-sulfocysteine mediated NMDA receptor overactivation.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States. Standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Avoid valproate, as sulfite intoxication impairs mitochondrial function in vitro.
• Education of parents/caregivers
• Infants: 1.2 mg/day
• Children & adolescents: 50 mg/1x/day ‒ 100 mg/2x/day
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
##
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States. Standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
##
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
##
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
In addition to regular evaluations by a metabolic specialist, the following are recommended.
Recommended Surveillance for Individuals with Molybdenum Cofactor Deficiency
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures, changes in tone, mvmt disorders, & headaches.
Neuropsychological testing using age-appropriate standardized assessment batteries
Standardized quality-of-life assessment tools for affected persons & parents/caregivers
OT = occupational therapy; PT = physical therapy
Which may include phenylalanine, valine, threonine, tryptophan, methionine, leucine, isoleucine, lysine, and histidine
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures, changes in tone, mvmt disorders, & headaches.
• Neuropsychological testing using age-appropriate standardized assessment batteries
• Standardized quality-of-life assessment tools for affected persons & parents/caregivers
## Agents/Circumstances to Avoid
Valproate should be avoided if possible, as sulfite intoxication impairs mitochondrial function in vitro.
For individuals on fosdenopterin (NULIBRY
## Evaluation of Relatives at Risk
For at-risk newborn sibs when prenatal testing was not performed, metabolic treatment should be initiated immediately and continued until such a time as the diagnosis has been excluded. Postnatal diagnostic evaluations can include the following:
Molecular genetic testing if the pathogenic variants in the family are known
If the pathogenic variants in the family are not known, measure serum uric acid and urinary: sulfite, s-sulfocysteine, xanthine, hypoxanthine, and uric acid.
See
• Molecular genetic testing if the pathogenic variants in the family are known
• If the pathogenic variants in the family are not known, measure serum uric acid and urinary: sulfite, s-sulfocysteine, xanthine, hypoxanthine, and uric acid.
## Therapies Under Investigation
Search
## Genetic Counseling
Molybdenum cofactor deficiency (MoCD) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an MoCD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an MoCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the MoCD-causing pathogenic variants in the family.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the MoCD-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an MoCD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an MoCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
Molybdenum cofactor deficiency (MoCD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an MoCD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an MoCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an MoCD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an MoCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the MoCD-causing pathogenic variants in the family.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the MoCD-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Molybdenum Cofactor Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Molybdenum Cofactor Deficiency (
The molybdenum cofactor (Moco) is synthesized from guanosine triphosphate (GTP) via a biochemical pathway that can be divided into four steps according to four intermediates: cyclic pyranopterin monophosphate (cPMP; also known previously as precursor Z), MPT, adenylated MPT (MPT-AMP), and Moco. See
Although four human enzymes are dependent on Moco for catalytic function (sulfite oxidase, the mitochondrial amidoxime reducing component, xanthine oxidase, and aldehyde oxidase), the loss of sulfite oxidase activity alone is necessary and sufficient to give rise to the phenotype of MoCD. Sulfite oxidase catalyzes the oxidation of sulfite to sulfate in the last step of methionine and cysteine catabolism (the sulfur-containing amino acids). In the absence of sulfite oxidase, sulfite accumulates in the blood, urine, and CSF of affected individuals. Because the enzyme is highly expressed in liver and kidney, these organs may be responsible for the generation of sulfite in affected individuals.
Data suggest that sulfite and S sulfocysteine (the reaction product of sulfite and cystine) are the toxic metabolites responsible for neurodegeneration in individuals with MoCD and isolated sulfite oxidase deficiency. Sulfite depletes intracellular ATP in cultured neuronal cell lines and impairs mitochondrial respiration. S sulfocysteine is stereochemically similar to glutamate and activates NMDA receptors [
Xanthine oxidase requires Moco for the breakdown of nucleotides to uric acid. Aldehyde oxidase requires Moco to catalyze a number of hydroxylation reactions. Mitochondrial amidoxime-reducing component, together with NADH-cytochrome b5 reductase and cytochrome b5, is thought to require Moco for catalyzation detoxification of mutagenic N-hydroxylated bases, although the exact function is as yet unclear.
## Molecular Pathogenesis
The molybdenum cofactor (Moco) is synthesized from guanosine triphosphate (GTP) via a biochemical pathway that can be divided into four steps according to four intermediates: cyclic pyranopterin monophosphate (cPMP; also known previously as precursor Z), MPT, adenylated MPT (MPT-AMP), and Moco. See
Although four human enzymes are dependent on Moco for catalytic function (sulfite oxidase, the mitochondrial amidoxime reducing component, xanthine oxidase, and aldehyde oxidase), the loss of sulfite oxidase activity alone is necessary and sufficient to give rise to the phenotype of MoCD. Sulfite oxidase catalyzes the oxidation of sulfite to sulfate in the last step of methionine and cysteine catabolism (the sulfur-containing amino acids). In the absence of sulfite oxidase, sulfite accumulates in the blood, urine, and CSF of affected individuals. Because the enzyme is highly expressed in liver and kidney, these organs may be responsible for the generation of sulfite in affected individuals.
Data suggest that sulfite and S sulfocysteine (the reaction product of sulfite and cystine) are the toxic metabolites responsible for neurodegeneration in individuals with MoCD and isolated sulfite oxidase deficiency. Sulfite depletes intracellular ATP in cultured neuronal cell lines and impairs mitochondrial respiration. S sulfocysteine is stereochemically similar to glutamate and activates NMDA receptors [
Xanthine oxidase requires Moco for the breakdown of nucleotides to uric acid. Aldehyde oxidase requires Moco to catalyze a number of hydroxylation reactions. Mitochondrial amidoxime-reducing component, together with NADH-cytochrome b5 reductase and cytochrome b5, is thought to require Moco for catalyzation detoxification of mutagenic N-hydroxylated bases, although the exact function is as yet unclear.
## Chapter Notes
2 February 2023 (pa/ma) Revision: fosdenopterin added as targeted treatment for
2 December 2021 (ma) Review posted live
4 January 2021 (pa) Original submission
• 2 February 2023 (pa/ma) Revision: fosdenopterin added as targeted treatment for
• 2 December 2021 (ma) Review posted live
• 4 January 2021 (pa) Original submission
## Revision History
2 February 2023 (pa/ma) Revision: fosdenopterin added as targeted treatment for
2 December 2021 (ma) Review posted live
4 January 2021 (pa) Original submission
• 2 February 2023 (pa/ma) Revision: fosdenopterin added as targeted treatment for
• 2 December 2021 (ma) Review posted live
• 4 January 2021 (pa) Original submission
## Key Sections in this
## References
## Literature Cited
Synthesis of molybdendum cofactor (Moco). GTP is converted to cPMP by
|
[] |
2/12/2021
|
2/2/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mcad
|
mcad
|
[
"MCAD Deficiency",
"MCAD Deficiency",
"Medium-chain specific acyl-CoA dehydrogenase, mitochondrial",
"ACADM",
"Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"
] |
Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency
|
Irene J Chang, Christina Lam, Jerry Vockley
|
Summary Individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency typically appear normal at birth, and many are diagnosed through newborn screening programs. Symptomatic individuals experience hypoketotic hypoglycemia in response to either prolonged fasting (e.g., weaning the infant from nighttime feedings) or during intercurrent and common infections (e.g., viral gastrointestinal or upper respiratory tract infections), which typically cause loss of appetite and increased energy requirements when fever is present. Untreated severe hypoglycemic episodes can be accompanied by seizures, vomiting, lethargy, coma, and death. Metabolic decompensation during these episodes can result in elevated liver transaminases and hyperammonemia. Individuals with MCAD deficiency who have experienced the effects of uncontrolled metabolic decompensation are also at risk for chronic myopathy. Early identification and avoidance of prolonged fasting can ameliorate these findings. However, children with MCAD deficiency are at risk for obesity after initiation of treatment due to the frequency of feeding. The diagnosis of MCAD deficiency is established in a proband through biochemical testing (prominent accumulation of C8-acylcarnitine (octanoylcarnitine) with lesser elevations of C6-, C10-, and C10:1-acylcarnitines and elevated C8/C2 and C8/C10 ratios) AND/OR by identification of biallelic pathogenic variants in MCAD deficiency is inherited in an autosomal recessive manner. At conception, the sibs of an affected individual are at a 25% risk of being affected, a 50% risk of being asymptomatic carriers, and a 25% risk of being unaffected and not carriers. Because of the high carrier frequency for the
|
## Diagnosis
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common inherited fatty acid beta-oxidation disorder; it leaves affected individuals unable to break down medium-chain fats for energy. Fatty acid beta-oxidation produces reducing equivalents and tricarboxylic acid cycle intermediates for energy generation in all tissues during times of physiologic stress and fasting. It also fuels hepatic ketogenesis, a major source of energy for peripheral tissues after glycogen stores are depleted during prolonged fasting and periods of higher energy demands.
NBS for MCAD deficiency is primarily based on results of a quantitative acylcarnitine profile on dried blood spots (DBS). It is included in most NBS programs worldwide and in every state's NBS program in the United States.
Elevations of C8-acylcarnitine with lesser elevations of C6- and C10-acylcarnitine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing. The cutoff values for C8 differ by NBS program and may be combined with elevated secondary markers (including C0, C2, and C10:1, and the ratios of C8/C2 and C8/C10) in presumptive positive cases to aid in NBS sensitivity.
The 99th centile values in aggregate North American newborn screening samples are as follows (see
C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
C6 of 2.44 nmol/mL (n=1,832)
C10 of 2.38 nmol/mL (n=1,869)
C10:1 of 2.44 nmol/mL (n=1,779)
C8/C2 ratio of 2.43 (n=1,896)
C8/C10 ratio of 2.53 (n=1,879)
Note: (1) The positive predictive value for elevations of C8-acylcarnitines is currently considered to be very high with the use of tandem mass spectrometry (MS/MS). False positives for elevations of C8-acylcarnitines are not common but can be seen in term infants who are appropriate for gestational age and heterozygous for the common
Follow-up testing includes (see also Establishing the Diagnosis,
Plasma acylcarnitine analysis;
Urine organic acid analysis;
Urine acylglycine analysis;
Plasma free and total carnitine levels.
If the follow-up biochemical testing supports the likelihood of MCAD deficiency, additional testing is required to establish the diagnosis (see
Published reports on NBS outcomes document that individuals identified and treated presymptomatically are protected from metabolic decompensations and relevant sequelae [
Avoidance of fasting
Emergency management that includes supplying enteral or intravenous glucose if normal oral intake is interrupted
Note: A newborn whose blood sample has been submitted for NBS can become symptomatic before screening results are available. Severe and lethal presentations in the first days of life (i.e., before NBS results are available) have been reported [
A symptomatic individual who was previously healthy OR a person with sudden, unexpected death in whom NBS was not performed or caregivers were not adherent to recommended treatment following a positive NBS result may present with the following supportive – but nonspecific – clinical findings, preliminary laboratory/pathology findings, and family history.
Note: Late-onset presentations have been described in adults after prolonged fasting, including after fasting for surgery or with alcohol intoxication [
Rapid clinical deterioration that is disproportionate in the setting of a common and generally benign infection
Vomiting that can progress to lethargy, seizures, and coma triggered by a common illness
Hepatomegaly and acute liver disease (sometimes confused with a diagnosis of Reye syndrome, which is characterized by acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver).
Sudden and unexpected death, often with evidence of lethargy, vomiting, and/or fasting in the 48 hours prior to death
Hypoketotic hypoglycemia
Hyperammonemia, more typically in older infants who may have mildly elevated ammonia levels that are in the range of 1.5 to 2 times the normal
Elevated liver function tests
Autopsy demonstrating cerebral edema and fatty infiltration of the liver, kidneys, and heart
Note: Postmortem acylcarnitine analysis for MCAD deficiency can be performed on original NBS DBS cards, which can be stored at 4-8 °C for up to at least a decade [
The diagnosis of MCAD deficiency
Note: (1)
Testing should include
Plasma acylcarnitine analysis demonstrates:
Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
Elevated C8/C2 and C8/C10 ratios.
Note: Secondary decreased levels of free carnitine (C0) and acetylcarnitine (C2) can be present in carnitine deficiency and cause lower elevations of C8-, C6-, and C10-acylcarnitines, or even normal acylcarnitine profiles [
Urine organic acid analysis during an acute episode demonstrates:
Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
Note: (1) Individuals receiving medium-chain triglyceride (MCT) oil supplements or MCT-containing foods (e.g., MCT-supplemented infant formulas, coconut oil) often have elevated concentrations of octanoic acid and decanoic acid in urine but have normal
Urine acylglycine analysis demonstrates n-hexanoylglycine, 3-phenylpropionylglycine, and suberylglycine.
Note: This test is more sensitive and specific for the identification of asymptomatic individuals, including newborns and immediately after birth, and those with mild or intermittent biochemical phenotypes that may be missed by organic acid analysis alone.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency
See
See
The c.985A>G (p.Lys329Glu) pathogenic variant accounts for between 56% and 91% of MCAD deficiency-causing alleles [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
MCAD enzyme activity is routinely measured in the Netherlands and can guide NBS risk stratification [
Molecular genetic testing of
Note: Different screening jurisdictions store leftover DBS samples for variable lengths of time following NBS testing. These samples typically can be retrieved with parent/patient consent for retrospective biochemical or molecular genetic testing.
• The 99th centile values in aggregate North American newborn screening samples are as follows (see
• C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
• C6 of 2.44 nmol/mL (n=1,832)
• C10 of 2.38 nmol/mL (n=1,869)
• C10:1 of 2.44 nmol/mL (n=1,779)
• C8/C2 ratio of 2.43 (n=1,896)
• C8/C10 ratio of 2.53 (n=1,879)
• Note: (1) The positive predictive value for elevations of C8-acylcarnitines is currently considered to be very high with the use of tandem mass spectrometry (MS/MS). False positives for elevations of C8-acylcarnitines are not common but can be seen in term infants who are appropriate for gestational age and heterozygous for the common
• C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
• C6 of 2.44 nmol/mL (n=1,832)
• C10 of 2.38 nmol/mL (n=1,869)
• C10:1 of 2.44 nmol/mL (n=1,779)
• C8/C2 ratio of 2.43 (n=1,896)
• C8/C10 ratio of 2.53 (n=1,879)
• Follow-up testing includes (see also Establishing the Diagnosis,
• Plasma acylcarnitine analysis;
• Urine organic acid analysis;
• Urine acylglycine analysis;
• Plasma free and total carnitine levels.
• Plasma acylcarnitine analysis;
• Urine organic acid analysis;
• Urine acylglycine analysis;
• Plasma free and total carnitine levels.
• If the follow-up biochemical testing supports the likelihood of MCAD deficiency, additional testing is required to establish the diagnosis (see
• C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
• C6 of 2.44 nmol/mL (n=1,832)
• C10 of 2.38 nmol/mL (n=1,869)
• C10:1 of 2.44 nmol/mL (n=1,779)
• C8/C2 ratio of 2.43 (n=1,896)
• C8/C10 ratio of 2.53 (n=1,879)
• Plasma acylcarnitine analysis;
• Urine organic acid analysis;
• Urine acylglycine analysis;
• Plasma free and total carnitine levels.
• Avoidance of fasting
• Emergency management that includes supplying enteral or intravenous glucose if normal oral intake is interrupted
• Rapid clinical deterioration that is disproportionate in the setting of a common and generally benign infection
• Vomiting that can progress to lethargy, seizures, and coma triggered by a common illness
• Hepatomegaly and acute liver disease (sometimes confused with a diagnosis of Reye syndrome, which is characterized by acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver).
• Sudden and unexpected death, often with evidence of lethargy, vomiting, and/or fasting in the 48 hours prior to death
• Hypoketotic hypoglycemia
• Hyperammonemia, more typically in older infants who may have mildly elevated ammonia levels that are in the range of 1.5 to 2 times the normal
• Elevated liver function tests
• Autopsy demonstrating cerebral edema and fatty infiltration of the liver, kidneys, and heart
• Plasma acylcarnitine analysis demonstrates:
• Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
• Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
• Elevated C8/C2 and C8/C10 ratios.
• Note: Secondary decreased levels of free carnitine (C0) and acetylcarnitine (C2) can be present in carnitine deficiency and cause lower elevations of C8-, C6-, and C10-acylcarnitines, or even normal acylcarnitine profiles [
• Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
• Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
• Elevated C8/C2 and C8/C10 ratios.
• Urine organic acid analysis during an acute episode demonstrates:
• Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
• Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
• Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
• Note: (1) Individuals receiving medium-chain triglyceride (MCT) oil supplements or MCT-containing foods (e.g., MCT-supplemented infant formulas, coconut oil) often have elevated concentrations of octanoic acid and decanoic acid in urine but have normal
• Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
• Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
• Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
• Urine acylglycine analysis demonstrates n-hexanoylglycine, 3-phenylpropionylglycine, and suberylglycine.
• Note: This test is more sensitive and specific for the identification of asymptomatic individuals, including newborns and immediately after birth, and those with mild or intermittent biochemical phenotypes that may be missed by organic acid analysis alone.
• Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
• Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
• Elevated C8/C2 and C8/C10 ratios.
• Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
• Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
• Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
• For an introduction to multigene panels click
• MCAD enzyme activity is routinely measured in the Netherlands and can guide NBS risk stratification [
## Suggestive Findings
NBS for MCAD deficiency is primarily based on results of a quantitative acylcarnitine profile on dried blood spots (DBS). It is included in most NBS programs worldwide and in every state's NBS program in the United States.
Elevations of C8-acylcarnitine with lesser elevations of C6- and C10-acylcarnitine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing. The cutoff values for C8 differ by NBS program and may be combined with elevated secondary markers (including C0, C2, and C10:1, and the ratios of C8/C2 and C8/C10) in presumptive positive cases to aid in NBS sensitivity.
The 99th centile values in aggregate North American newborn screening samples are as follows (see
C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
C6 of 2.44 nmol/mL (n=1,832)
C10 of 2.38 nmol/mL (n=1,869)
C10:1 of 2.44 nmol/mL (n=1,779)
C8/C2 ratio of 2.43 (n=1,896)
C8/C10 ratio of 2.53 (n=1,879)
Note: (1) The positive predictive value for elevations of C8-acylcarnitines is currently considered to be very high with the use of tandem mass spectrometry (MS/MS). False positives for elevations of C8-acylcarnitines are not common but can be seen in term infants who are appropriate for gestational age and heterozygous for the common
Follow-up testing includes (see also Establishing the Diagnosis,
Plasma acylcarnitine analysis;
Urine organic acid analysis;
Urine acylglycine analysis;
Plasma free and total carnitine levels.
If the follow-up biochemical testing supports the likelihood of MCAD deficiency, additional testing is required to establish the diagnosis (see
Published reports on NBS outcomes document that individuals identified and treated presymptomatically are protected from metabolic decompensations and relevant sequelae [
Avoidance of fasting
Emergency management that includes supplying enteral or intravenous glucose if normal oral intake is interrupted
Note: A newborn whose blood sample has been submitted for NBS can become symptomatic before screening results are available. Severe and lethal presentations in the first days of life (i.e., before NBS results are available) have been reported [
A symptomatic individual who was previously healthy OR a person with sudden, unexpected death in whom NBS was not performed or caregivers were not adherent to recommended treatment following a positive NBS result may present with the following supportive – but nonspecific – clinical findings, preliminary laboratory/pathology findings, and family history.
Note: Late-onset presentations have been described in adults after prolonged fasting, including after fasting for surgery or with alcohol intoxication [
Rapid clinical deterioration that is disproportionate in the setting of a common and generally benign infection
Vomiting that can progress to lethargy, seizures, and coma triggered by a common illness
Hepatomegaly and acute liver disease (sometimes confused with a diagnosis of Reye syndrome, which is characterized by acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver).
Sudden and unexpected death, often with evidence of lethargy, vomiting, and/or fasting in the 48 hours prior to death
Hypoketotic hypoglycemia
Hyperammonemia, more typically in older infants who may have mildly elevated ammonia levels that are in the range of 1.5 to 2 times the normal
Elevated liver function tests
Autopsy demonstrating cerebral edema and fatty infiltration of the liver, kidneys, and heart
Note: Postmortem acylcarnitine analysis for MCAD deficiency can be performed on original NBS DBS cards, which can be stored at 4-8 °C for up to at least a decade [
• The 99th centile values in aggregate North American newborn screening samples are as follows (see
• C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
• C6 of 2.44 nmol/mL (n=1,832)
• C10 of 2.38 nmol/mL (n=1,869)
• C10:1 of 2.44 nmol/mL (n=1,779)
• C8/C2 ratio of 2.43 (n=1,896)
• C8/C10 ratio of 2.53 (n=1,879)
• Note: (1) The positive predictive value for elevations of C8-acylcarnitines is currently considered to be very high with the use of tandem mass spectrometry (MS/MS). False positives for elevations of C8-acylcarnitines are not common but can be seen in term infants who are appropriate for gestational age and heterozygous for the common
• C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
• C6 of 2.44 nmol/mL (n=1,832)
• C10 of 2.38 nmol/mL (n=1,869)
• C10:1 of 2.44 nmol/mL (n=1,779)
• C8/C2 ratio of 2.43 (n=1,896)
• C8/C10 ratio of 2.53 (n=1,879)
• Follow-up testing includes (see also Establishing the Diagnosis,
• Plasma acylcarnitine analysis;
• Urine organic acid analysis;
• Urine acylglycine analysis;
• Plasma free and total carnitine levels.
• Plasma acylcarnitine analysis;
• Urine organic acid analysis;
• Urine acylglycine analysis;
• Plasma free and total carnitine levels.
• If the follow-up biochemical testing supports the likelihood of MCAD deficiency, additional testing is required to establish the diagnosis (see
• C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
• C6 of 2.44 nmol/mL (n=1,832)
• C10 of 2.38 nmol/mL (n=1,869)
• C10:1 of 2.44 nmol/mL (n=1,779)
• C8/C2 ratio of 2.43 (n=1,896)
• C8/C10 ratio of 2.53 (n=1,879)
• Plasma acylcarnitine analysis;
• Urine organic acid analysis;
• Urine acylglycine analysis;
• Plasma free and total carnitine levels.
• Avoidance of fasting
• Emergency management that includes supplying enteral or intravenous glucose if normal oral intake is interrupted
• Rapid clinical deterioration that is disproportionate in the setting of a common and generally benign infection
• Vomiting that can progress to lethargy, seizures, and coma triggered by a common illness
• Hepatomegaly and acute liver disease (sometimes confused with a diagnosis of Reye syndrome, which is characterized by acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver).
• Sudden and unexpected death, often with evidence of lethargy, vomiting, and/or fasting in the 48 hours prior to death
• Hypoketotic hypoglycemia
• Hyperammonemia, more typically in older infants who may have mildly elevated ammonia levels that are in the range of 1.5 to 2 times the normal
• Elevated liver function tests
• Autopsy demonstrating cerebral edema and fatty infiltration of the liver, kidneys, and heart
## Scenario 1: Abnormal Newborn Screening (NBS) Result
NBS for MCAD deficiency is primarily based on results of a quantitative acylcarnitine profile on dried blood spots (DBS). It is included in most NBS programs worldwide and in every state's NBS program in the United States.
Elevations of C8-acylcarnitine with lesser elevations of C6- and C10-acylcarnitine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing. The cutoff values for C8 differ by NBS program and may be combined with elevated secondary markers (including C0, C2, and C10:1, and the ratios of C8/C2 and C8/C10) in presumptive positive cases to aid in NBS sensitivity.
The 99th centile values in aggregate North American newborn screening samples are as follows (see
C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
C6 of 2.44 nmol/mL (n=1,832)
C10 of 2.38 nmol/mL (n=1,869)
C10:1 of 2.44 nmol/mL (n=1,779)
C8/C2 ratio of 2.43 (n=1,896)
C8/C10 ratio of 2.53 (n=1,879)
Note: (1) The positive predictive value for elevations of C8-acylcarnitines is currently considered to be very high with the use of tandem mass spectrometry (MS/MS). False positives for elevations of C8-acylcarnitines are not common but can be seen in term infants who are appropriate for gestational age and heterozygous for the common
Follow-up testing includes (see also Establishing the Diagnosis,
Plasma acylcarnitine analysis;
Urine organic acid analysis;
Urine acylglycine analysis;
Plasma free and total carnitine levels.
If the follow-up biochemical testing supports the likelihood of MCAD deficiency, additional testing is required to establish the diagnosis (see
Published reports on NBS outcomes document that individuals identified and treated presymptomatically are protected from metabolic decompensations and relevant sequelae [
Avoidance of fasting
Emergency management that includes supplying enteral or intravenous glucose if normal oral intake is interrupted
Note: A newborn whose blood sample has been submitted for NBS can become symptomatic before screening results are available. Severe and lethal presentations in the first days of life (i.e., before NBS results are available) have been reported [
• The 99th centile values in aggregate North American newborn screening samples are as follows (see
• C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
• C6 of 2.44 nmol/mL (n=1,832)
• C10 of 2.38 nmol/mL (n=1,869)
• C10:1 of 2.44 nmol/mL (n=1,779)
• C8/C2 ratio of 2.43 (n=1,896)
• C8/C10 ratio of 2.53 (n=1,879)
• Note: (1) The positive predictive value for elevations of C8-acylcarnitines is currently considered to be very high with the use of tandem mass spectrometry (MS/MS). False positives for elevations of C8-acylcarnitines are not common but can be seen in term infants who are appropriate for gestational age and heterozygous for the common
• C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
• C6 of 2.44 nmol/mL (n=1,832)
• C10 of 2.38 nmol/mL (n=1,869)
• C10:1 of 2.44 nmol/mL (n=1,779)
• C8/C2 ratio of 2.43 (n=1,896)
• C8/C10 ratio of 2.53 (n=1,879)
• Follow-up testing includes (see also Establishing the Diagnosis,
• Plasma acylcarnitine analysis;
• Urine organic acid analysis;
• Urine acylglycine analysis;
• Plasma free and total carnitine levels.
• Plasma acylcarnitine analysis;
• Urine organic acid analysis;
• Urine acylglycine analysis;
• Plasma free and total carnitine levels.
• If the follow-up biochemical testing supports the likelihood of MCAD deficiency, additional testing is required to establish the diagnosis (see
• C8 of 2.46 nmol/mL (n=1,832); however, due to differences in sample analysis, C8 values may not to be directly comparable to local results.
• C6 of 2.44 nmol/mL (n=1,832)
• C10 of 2.38 nmol/mL (n=1,869)
• C10:1 of 2.44 nmol/mL (n=1,779)
• C8/C2 ratio of 2.43 (n=1,896)
• C8/C10 ratio of 2.53 (n=1,879)
• Plasma acylcarnitine analysis;
• Urine organic acid analysis;
• Urine acylglycine analysis;
• Plasma free and total carnitine levels.
• Avoidance of fasting
• Emergency management that includes supplying enteral or intravenous glucose if normal oral intake is interrupted
## Scenario 2: Symptomatic Individual
A symptomatic individual who was previously healthy OR a person with sudden, unexpected death in whom NBS was not performed or caregivers were not adherent to recommended treatment following a positive NBS result may present with the following supportive – but nonspecific – clinical findings, preliminary laboratory/pathology findings, and family history.
Note: Late-onset presentations have been described in adults after prolonged fasting, including after fasting for surgery or with alcohol intoxication [
Rapid clinical deterioration that is disproportionate in the setting of a common and generally benign infection
Vomiting that can progress to lethargy, seizures, and coma triggered by a common illness
Hepatomegaly and acute liver disease (sometimes confused with a diagnosis of Reye syndrome, which is characterized by acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver).
Sudden and unexpected death, often with evidence of lethargy, vomiting, and/or fasting in the 48 hours prior to death
Hypoketotic hypoglycemia
Hyperammonemia, more typically in older infants who may have mildly elevated ammonia levels that are in the range of 1.5 to 2 times the normal
Elevated liver function tests
Autopsy demonstrating cerebral edema and fatty infiltration of the liver, kidneys, and heart
Note: Postmortem acylcarnitine analysis for MCAD deficiency can be performed on original NBS DBS cards, which can be stored at 4-8 °C for up to at least a decade [
• Rapid clinical deterioration that is disproportionate in the setting of a common and generally benign infection
• Vomiting that can progress to lethargy, seizures, and coma triggered by a common illness
• Hepatomegaly and acute liver disease (sometimes confused with a diagnosis of Reye syndrome, which is characterized by acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver).
• Sudden and unexpected death, often with evidence of lethargy, vomiting, and/or fasting in the 48 hours prior to death
• Hypoketotic hypoglycemia
• Hyperammonemia, more typically in older infants who may have mildly elevated ammonia levels that are in the range of 1.5 to 2 times the normal
• Elevated liver function tests
• Autopsy demonstrating cerebral edema and fatty infiltration of the liver, kidneys, and heart
## Establishing the Diagnosis
The diagnosis of MCAD deficiency
Note: (1)
Testing should include
Plasma acylcarnitine analysis demonstrates:
Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
Elevated C8/C2 and C8/C10 ratios.
Note: Secondary decreased levels of free carnitine (C0) and acetylcarnitine (C2) can be present in carnitine deficiency and cause lower elevations of C8-, C6-, and C10-acylcarnitines, or even normal acylcarnitine profiles [
Urine organic acid analysis during an acute episode demonstrates:
Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
Note: (1) Individuals receiving medium-chain triglyceride (MCT) oil supplements or MCT-containing foods (e.g., MCT-supplemented infant formulas, coconut oil) often have elevated concentrations of octanoic acid and decanoic acid in urine but have normal
Urine acylglycine analysis demonstrates n-hexanoylglycine, 3-phenylpropionylglycine, and suberylglycine.
Note: This test is more sensitive and specific for the identification of asymptomatic individuals, including newborns and immediately after birth, and those with mild or intermittent biochemical phenotypes that may be missed by organic acid analysis alone.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency
See
See
The c.985A>G (p.Lys329Glu) pathogenic variant accounts for between 56% and 91% of MCAD deficiency-causing alleles [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
MCAD enzyme activity is routinely measured in the Netherlands and can guide NBS risk stratification [
Molecular genetic testing of
Note: Different screening jurisdictions store leftover DBS samples for variable lengths of time following NBS testing. These samples typically can be retrieved with parent/patient consent for retrospective biochemical or molecular genetic testing.
• Plasma acylcarnitine analysis demonstrates:
• Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
• Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
• Elevated C8/C2 and C8/C10 ratios.
• Note: Secondary decreased levels of free carnitine (C0) and acetylcarnitine (C2) can be present in carnitine deficiency and cause lower elevations of C8-, C6-, and C10-acylcarnitines, or even normal acylcarnitine profiles [
• Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
• Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
• Elevated C8/C2 and C8/C10 ratios.
• Urine organic acid analysis during an acute episode demonstrates:
• Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
• Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
• Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
• Note: (1) Individuals receiving medium-chain triglyceride (MCT) oil supplements or MCT-containing foods (e.g., MCT-supplemented infant formulas, coconut oil) often have elevated concentrations of octanoic acid and decanoic acid in urine but have normal
• Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
• Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
• Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
• Urine acylglycine analysis demonstrates n-hexanoylglycine, 3-phenylpropionylglycine, and suberylglycine.
• Note: This test is more sensitive and specific for the identification of asymptomatic individuals, including newborns and immediately after birth, and those with mild or intermittent biochemical phenotypes that may be missed by organic acid analysis alone.
• Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
• Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
• Elevated C8/C2 and C8/C10 ratios.
• Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
• Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
• Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
• For an introduction to multigene panels click
• MCAD enzyme activity is routinely measured in the Netherlands and can guide NBS risk stratification [
## Biochemical Testing
Testing should include
Plasma acylcarnitine analysis demonstrates:
Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
Elevated C8/C2 and C8/C10 ratios.
Note: Secondary decreased levels of free carnitine (C0) and acetylcarnitine (C2) can be present in carnitine deficiency and cause lower elevations of C8-, C6-, and C10-acylcarnitines, or even normal acylcarnitine profiles [
Urine organic acid analysis during an acute episode demonstrates:
Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
Note: (1) Individuals receiving medium-chain triglyceride (MCT) oil supplements or MCT-containing foods (e.g., MCT-supplemented infant formulas, coconut oil) often have elevated concentrations of octanoic acid and decanoic acid in urine but have normal
Urine acylglycine analysis demonstrates n-hexanoylglycine, 3-phenylpropionylglycine, and suberylglycine.
Note: This test is more sensitive and specific for the identification of asymptomatic individuals, including newborns and immediately after birth, and those with mild or intermittent biochemical phenotypes that may be missed by organic acid analysis alone.
• Plasma acylcarnitine analysis demonstrates:
• Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
• Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
• Elevated C8/C2 and C8/C10 ratios.
• Note: Secondary decreased levels of free carnitine (C0) and acetylcarnitine (C2) can be present in carnitine deficiency and cause lower elevations of C8-, C6-, and C10-acylcarnitines, or even normal acylcarnitine profiles [
• Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
• Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
• Elevated C8/C2 and C8/C10 ratios.
• Urine organic acid analysis during an acute episode demonstrates:
• Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
• Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
• Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
• Note: (1) Individuals receiving medium-chain triglyceride (MCT) oil supplements or MCT-containing foods (e.g., MCT-supplemented infant formulas, coconut oil) often have elevated concentrations of octanoic acid and decanoic acid in urine but have normal
• Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
• Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
• Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
• Urine acylglycine analysis demonstrates n-hexanoylglycine, 3-phenylpropionylglycine, and suberylglycine.
• Note: This test is more sensitive and specific for the identification of asymptomatic individuals, including newborns and immediately after birth, and those with mild or intermittent biochemical phenotypes that may be missed by organic acid analysis alone.
• Prominent accumulation of C8-acylcarnitine (octanoylcarnitine);
• Lesser elevations of C6-, C10-, and C10:1-acylcarnitines;
• Elevated C8/C2 and C8/C10 ratios.
• Elevated medium-chain dicarboxylic acids in a characteristic pattern of hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10);
• Inappropriately low urine or serum ketones by serum beta-hydroxybutyrate analysis or urine organic acid analysis or ketostix;
• Elevated suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) on urine organic acids.
## Molecular Genetic Testing
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency
See
See
The c.985A>G (p.Lys329Glu) pathogenic variant accounts for between 56% and 91% of MCAD deficiency-causing alleles [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• For an introduction to multigene panels click
## Enzyme Activity Analysis
MCAD enzyme activity is routinely measured in the Netherlands and can guide NBS risk stratification [
• MCAD enzyme activity is routinely measured in the Netherlands and can guide NBS risk stratification [
## Confirmatory Postmortem Testing
Molecular genetic testing of
Note: Different screening jurisdictions store leftover DBS samples for variable lengths of time following NBS testing. These samples typically can be retrieved with parent/patient consent for retrospective biochemical or molecular genetic testing.
## Clinical Characteristics
Fatty acid beta-oxidation generates cellular energy in all tissues and fuels hepatic ketogenesis, a major source of energy for peripheral tissues once glycogen stores become depleted during prolonged fasting and/or periods of higher energy demands (see
Individuals with MCAD deficiency appear normal at birth and historically have presented between age two and 24 months, although presentations in adulthood have also been reported [
Hypoglycemic episodes can be accompanied by seizures.
In a cohort of non-diabetic adults, MCAD deficiency was diagnosed in some individuals presenting with fasting hypoglycemia [
Such instances of metabolic stress lead to vomiting and lethargy, which may quickly progress to coma and death.
The presence of low levels of ketones on urinalysis, urine organic acids, or serum beta-hydroxybutyrate analysis should not be taken as evidence against MCAD deficiency ("hypoketotic" as compared to nonketotic), as ketones can be present during times of acute metabolic decompensation due to long-chain fatty acid oxidation.
Historically, if the diagnosis of MCAD deficiency has not been previously established, between 18% to 25% of affected individuals died during their first metabolic crisis [
The advent of NBS has dramatically decreased the mortality of MCAD deficiency in the neonatal period to 0.6%-2.4% in screened populations [
Early death due to severe hypoglycemia before the return of NBS results still occurs [
Findings at autopsy include cerebral edema and fatty infiltration of the liver, kidneys, and heart.
Prolongation of the QTc interval has been reported in an affected infant and ventricular tachyarrhythmias in another [
A 16-year-old female presented with hepatic, renal, and cardiac failure after an alcoholic binge and subsequent period of starvation [
An adult with MCAD deficiency also developed supraventricular tachycardia, ventricular tachycardia, and ultimately ventricular fibrillation resulting in cardiac arrest after presenting with vomiting and headaches in the setting of hyperammonemia and hypoglycemia [
Often referred to as "asymptomatic" MCAD deficiency, this designation is not entirely accurate. The expansion of NBS programs using tandem mass spectrometry (MS/MS) led to the identification of affected individuals with milder abnormalities in their acylcarnitine profiles (see
Individuals with MCAD deficiency can remain asymptomatic, although whether this is attributable to early awareness of the condition, early initiation of treatment and resulting prevention of symptoms, or to a higher residual MCAD enzymatic activity remains to be determined.
Individuals with a "milder" biochemical phenotype can still develop life-threatening symptoms [
All individuals with MCAD deficiency should be considered at risk of developing clinical manifestations and should receive long-term follow up and management.
A collaborative retrospective analysis of a cohort of 221 affected individuals identified by NBS in the United States showed that C8 level and genotype were significant predictors of neonatal symptoms. Individuals with neonatal symptoms had significantly higher C8 values [
Several other genotype-phenotype correlations have been described:
Individuals homozygous for the common European
Those with less pronounced abnormalities in their acylcarnitine profiles are more likely to be compound heterozygotes either for the common pathogenic variant c.985A>G (p.Lys329Glu) and another pathogenic variant, or for two non-c.985A>G pathogenic variants [
Individuals homozygous for c.985A>G (p.Lys329Glu) had a mean C8 level of 13.8 µmol/L (range: 9-22 µmol/L), and compound heterozygotes had a mean C8 level of 2.6 µmol/L (range: 1.9-3.2 µmol/L) [
Note: Historically, variant nomenclature designated the first amino acid at p.1 of the mature protein, whereas current nomenclature designates the first amino acid at p.1 of the pro-protein.
MCAD deficiency was first described in individuals presenting with a Reye-like phenotype and urine organic acid analysis that revealed overexcretion of medium-chain dicarboxylic acids and hexanoylglycine in the absence of significant ketosis [
The overall prevalence of MCAD deficiency is 5.3 (range: 4.1-6.7; 99% CI) in 100,000 births across a variety of populations [
The number of newborns detected with MCAD deficiency through NBS programs exceeds that expected based on the population frequency of the common c.985A>G pathogenic variant [
The
Based on NBS programs or pilot studies worldwide, the incidence of MCAD deficiency has been determined as follows:
Japan. One in 51,000 live births [
Saudi Arabia. One in 18,000 live births [
Taiwan. One in 263,500 live births [
Historically, MCAD deficiency was considered less common in the Hispanic, African American, and Native American populations in the US. More recent analysis of data from California demonstrated that MCAD deficiency may be as prevalent in Native Americans (1:7,500 live births) as in northern Europeans. Prevalences are similar among newborns of Hispanic, Black, and Middle Eastern origin (1:23,000 live births) [
• Hypoglycemic episodes can be accompanied by seizures.
• In a cohort of non-diabetic adults, MCAD deficiency was diagnosed in some individuals presenting with fasting hypoglycemia [
• Such instances of metabolic stress lead to vomiting and lethargy, which may quickly progress to coma and death.
• The presence of low levels of ketones on urinalysis, urine organic acids, or serum beta-hydroxybutyrate analysis should not be taken as evidence against MCAD deficiency ("hypoketotic" as compared to nonketotic), as ketones can be present during times of acute metabolic decompensation due to long-chain fatty acid oxidation.
• Historically, if the diagnosis of MCAD deficiency has not been previously established, between 18% to 25% of affected individuals died during their first metabolic crisis [
• The advent of NBS has dramatically decreased the mortality of MCAD deficiency in the neonatal period to 0.6%-2.4% in screened populations [
• Early death due to severe hypoglycemia before the return of NBS results still occurs [
• Findings at autopsy include cerebral edema and fatty infiltration of the liver, kidneys, and heart.
• Prolongation of the QTc interval has been reported in an affected infant and ventricular tachyarrhythmias in another [
• A 16-year-old female presented with hepatic, renal, and cardiac failure after an alcoholic binge and subsequent period of starvation [
• An adult with MCAD deficiency also developed supraventricular tachycardia, ventricular tachycardia, and ultimately ventricular fibrillation resulting in cardiac arrest after presenting with vomiting and headaches in the setting of hyperammonemia and hypoglycemia [
• Individuals with MCAD deficiency can remain asymptomatic, although whether this is attributable to early awareness of the condition, early initiation of treatment and resulting prevention of symptoms, or to a higher residual MCAD enzymatic activity remains to be determined.
• Individuals with a "milder" biochemical phenotype can still develop life-threatening symptoms [
• All individuals with MCAD deficiency should be considered at risk of developing clinical manifestations and should receive long-term follow up and management.
• Individuals homozygous for the common European
• Those with less pronounced abnormalities in their acylcarnitine profiles are more likely to be compound heterozygotes either for the common pathogenic variant c.985A>G (p.Lys329Glu) and another pathogenic variant, or for two non-c.985A>G pathogenic variants [
• Individuals homozygous for c.985A>G (p.Lys329Glu) had a mean C8 level of 13.8 µmol/L (range: 9-22 µmol/L), and compound heterozygotes had a mean C8 level of 2.6 µmol/L (range: 1.9-3.2 µmol/L) [
• Individuals homozygous for the common European
• Those with less pronounced abnormalities in their acylcarnitine profiles are more likely to be compound heterozygotes either for the common pathogenic variant c.985A>G (p.Lys329Glu) and another pathogenic variant, or for two non-c.985A>G pathogenic variants [
• Individuals homozygous for c.985A>G (p.Lys329Glu) had a mean C8 level of 13.8 µmol/L (range: 9-22 µmol/L), and compound heterozygotes had a mean C8 level of 2.6 µmol/L (range: 1.9-3.2 µmol/L) [
• Individuals homozygous for the common European
• Those with less pronounced abnormalities in their acylcarnitine profiles are more likely to be compound heterozygotes either for the common pathogenic variant c.985A>G (p.Lys329Glu) and another pathogenic variant, or for two non-c.985A>G pathogenic variants [
• Individuals homozygous for c.985A>G (p.Lys329Glu) had a mean C8 level of 13.8 µmol/L (range: 9-22 µmol/L), and compound heterozygotes had a mean C8 level of 2.6 µmol/L (range: 1.9-3.2 µmol/L) [
•
• Japan. One in 51,000 live births [
• Saudi Arabia. One in 18,000 live births [
• Taiwan. One in 263,500 live births [
• Japan. One in 51,000 live births [
• Saudi Arabia. One in 18,000 live births [
• Taiwan. One in 263,500 live births [
• Japan. One in 51,000 live births [
• Saudi Arabia. One in 18,000 live births [
• Taiwan. One in 263,500 live births [
## Clinical Description
Fatty acid beta-oxidation generates cellular energy in all tissues and fuels hepatic ketogenesis, a major source of energy for peripheral tissues once glycogen stores become depleted during prolonged fasting and/or periods of higher energy demands (see
Individuals with MCAD deficiency appear normal at birth and historically have presented between age two and 24 months, although presentations in adulthood have also been reported [
Hypoglycemic episodes can be accompanied by seizures.
In a cohort of non-diabetic adults, MCAD deficiency was diagnosed in some individuals presenting with fasting hypoglycemia [
Such instances of metabolic stress lead to vomiting and lethargy, which may quickly progress to coma and death.
The presence of low levels of ketones on urinalysis, urine organic acids, or serum beta-hydroxybutyrate analysis should not be taken as evidence against MCAD deficiency ("hypoketotic" as compared to nonketotic), as ketones can be present during times of acute metabolic decompensation due to long-chain fatty acid oxidation.
Historically, if the diagnosis of MCAD deficiency has not been previously established, between 18% to 25% of affected individuals died during their first metabolic crisis [
The advent of NBS has dramatically decreased the mortality of MCAD deficiency in the neonatal period to 0.6%-2.4% in screened populations [
Early death due to severe hypoglycemia before the return of NBS results still occurs [
Findings at autopsy include cerebral edema and fatty infiltration of the liver, kidneys, and heart.
Prolongation of the QTc interval has been reported in an affected infant and ventricular tachyarrhythmias in another [
A 16-year-old female presented with hepatic, renal, and cardiac failure after an alcoholic binge and subsequent period of starvation [
An adult with MCAD deficiency also developed supraventricular tachycardia, ventricular tachycardia, and ultimately ventricular fibrillation resulting in cardiac arrest after presenting with vomiting and headaches in the setting of hyperammonemia and hypoglycemia [
Often referred to as "asymptomatic" MCAD deficiency, this designation is not entirely accurate. The expansion of NBS programs using tandem mass spectrometry (MS/MS) led to the identification of affected individuals with milder abnormalities in their acylcarnitine profiles (see
Individuals with MCAD deficiency can remain asymptomatic, although whether this is attributable to early awareness of the condition, early initiation of treatment and resulting prevention of symptoms, or to a higher residual MCAD enzymatic activity remains to be determined.
Individuals with a "milder" biochemical phenotype can still develop life-threatening symptoms [
All individuals with MCAD deficiency should be considered at risk of developing clinical manifestations and should receive long-term follow up and management.
• Hypoglycemic episodes can be accompanied by seizures.
• In a cohort of non-diabetic adults, MCAD deficiency was diagnosed in some individuals presenting with fasting hypoglycemia [
• Such instances of metabolic stress lead to vomiting and lethargy, which may quickly progress to coma and death.
• The presence of low levels of ketones on urinalysis, urine organic acids, or serum beta-hydroxybutyrate analysis should not be taken as evidence against MCAD deficiency ("hypoketotic" as compared to nonketotic), as ketones can be present during times of acute metabolic decompensation due to long-chain fatty acid oxidation.
• Historically, if the diagnosis of MCAD deficiency has not been previously established, between 18% to 25% of affected individuals died during their first metabolic crisis [
• The advent of NBS has dramatically decreased the mortality of MCAD deficiency in the neonatal period to 0.6%-2.4% in screened populations [
• Early death due to severe hypoglycemia before the return of NBS results still occurs [
• Findings at autopsy include cerebral edema and fatty infiltration of the liver, kidneys, and heart.
• Prolongation of the QTc interval has been reported in an affected infant and ventricular tachyarrhythmias in another [
• A 16-year-old female presented with hepatic, renal, and cardiac failure after an alcoholic binge and subsequent period of starvation [
• An adult with MCAD deficiency also developed supraventricular tachycardia, ventricular tachycardia, and ultimately ventricular fibrillation resulting in cardiac arrest after presenting with vomiting and headaches in the setting of hyperammonemia and hypoglycemia [
• Individuals with MCAD deficiency can remain asymptomatic, although whether this is attributable to early awareness of the condition, early initiation of treatment and resulting prevention of symptoms, or to a higher residual MCAD enzymatic activity remains to be determined.
• Individuals with a "milder" biochemical phenotype can still develop life-threatening symptoms [
• All individuals with MCAD deficiency should be considered at risk of developing clinical manifestations and should receive long-term follow up and management.
## MCAD Deficiency
Individuals with MCAD deficiency appear normal at birth and historically have presented between age two and 24 months, although presentations in adulthood have also been reported [
Hypoglycemic episodes can be accompanied by seizures.
In a cohort of non-diabetic adults, MCAD deficiency was diagnosed in some individuals presenting with fasting hypoglycemia [
Such instances of metabolic stress lead to vomiting and lethargy, which may quickly progress to coma and death.
The presence of low levels of ketones on urinalysis, urine organic acids, or serum beta-hydroxybutyrate analysis should not be taken as evidence against MCAD deficiency ("hypoketotic" as compared to nonketotic), as ketones can be present during times of acute metabolic decompensation due to long-chain fatty acid oxidation.
Historically, if the diagnosis of MCAD deficiency has not been previously established, between 18% to 25% of affected individuals died during their first metabolic crisis [
The advent of NBS has dramatically decreased the mortality of MCAD deficiency in the neonatal period to 0.6%-2.4% in screened populations [
Early death due to severe hypoglycemia before the return of NBS results still occurs [
Findings at autopsy include cerebral edema and fatty infiltration of the liver, kidneys, and heart.
Prolongation of the QTc interval has been reported in an affected infant and ventricular tachyarrhythmias in another [
A 16-year-old female presented with hepatic, renal, and cardiac failure after an alcoholic binge and subsequent period of starvation [
An adult with MCAD deficiency also developed supraventricular tachycardia, ventricular tachycardia, and ultimately ventricular fibrillation resulting in cardiac arrest after presenting with vomiting and headaches in the setting of hyperammonemia and hypoglycemia [
• Hypoglycemic episodes can be accompanied by seizures.
• In a cohort of non-diabetic adults, MCAD deficiency was diagnosed in some individuals presenting with fasting hypoglycemia [
• Such instances of metabolic stress lead to vomiting and lethargy, which may quickly progress to coma and death.
• The presence of low levels of ketones on urinalysis, urine organic acids, or serum beta-hydroxybutyrate analysis should not be taken as evidence against MCAD deficiency ("hypoketotic" as compared to nonketotic), as ketones can be present during times of acute metabolic decompensation due to long-chain fatty acid oxidation.
• Historically, if the diagnosis of MCAD deficiency has not been previously established, between 18% to 25% of affected individuals died during their first metabolic crisis [
• The advent of NBS has dramatically decreased the mortality of MCAD deficiency in the neonatal period to 0.6%-2.4% in screened populations [
• Early death due to severe hypoglycemia before the return of NBS results still occurs [
• Findings at autopsy include cerebral edema and fatty infiltration of the liver, kidneys, and heart.
• Prolongation of the QTc interval has been reported in an affected infant and ventricular tachyarrhythmias in another [
• A 16-year-old female presented with hepatic, renal, and cardiac failure after an alcoholic binge and subsequent period of starvation [
• An adult with MCAD deficiency also developed supraventricular tachycardia, ventricular tachycardia, and ultimately ventricular fibrillation resulting in cardiac arrest after presenting with vomiting and headaches in the setting of hyperammonemia and hypoglycemia [
## "Mild" MCAD Deficiency
Often referred to as "asymptomatic" MCAD deficiency, this designation is not entirely accurate. The expansion of NBS programs using tandem mass spectrometry (MS/MS) led to the identification of affected individuals with milder abnormalities in their acylcarnitine profiles (see
Individuals with MCAD deficiency can remain asymptomatic, although whether this is attributable to early awareness of the condition, early initiation of treatment and resulting prevention of symptoms, or to a higher residual MCAD enzymatic activity remains to be determined.
Individuals with a "milder" biochemical phenotype can still develop life-threatening symptoms [
All individuals with MCAD deficiency should be considered at risk of developing clinical manifestations and should receive long-term follow up and management.
• Individuals with MCAD deficiency can remain asymptomatic, although whether this is attributable to early awareness of the condition, early initiation of treatment and resulting prevention of symptoms, or to a higher residual MCAD enzymatic activity remains to be determined.
• Individuals with a "milder" biochemical phenotype can still develop life-threatening symptoms [
• All individuals with MCAD deficiency should be considered at risk of developing clinical manifestations and should receive long-term follow up and management.
## Genotype-Phenotype Correlations
A collaborative retrospective analysis of a cohort of 221 affected individuals identified by NBS in the United States showed that C8 level and genotype were significant predictors of neonatal symptoms. Individuals with neonatal symptoms had significantly higher C8 values [
Several other genotype-phenotype correlations have been described:
Individuals homozygous for the common European
Those with less pronounced abnormalities in their acylcarnitine profiles are more likely to be compound heterozygotes either for the common pathogenic variant c.985A>G (p.Lys329Glu) and another pathogenic variant, or for two non-c.985A>G pathogenic variants [
Individuals homozygous for c.985A>G (p.Lys329Glu) had a mean C8 level of 13.8 µmol/L (range: 9-22 µmol/L), and compound heterozygotes had a mean C8 level of 2.6 µmol/L (range: 1.9-3.2 µmol/L) [
Note: Historically, variant nomenclature designated the first amino acid at p.1 of the mature protein, whereas current nomenclature designates the first amino acid at p.1 of the pro-protein.
• Individuals homozygous for the common European
• Those with less pronounced abnormalities in their acylcarnitine profiles are more likely to be compound heterozygotes either for the common pathogenic variant c.985A>G (p.Lys329Glu) and another pathogenic variant, or for two non-c.985A>G pathogenic variants [
• Individuals homozygous for c.985A>G (p.Lys329Glu) had a mean C8 level of 13.8 µmol/L (range: 9-22 µmol/L), and compound heterozygotes had a mean C8 level of 2.6 µmol/L (range: 1.9-3.2 µmol/L) [
• Individuals homozygous for the common European
• Those with less pronounced abnormalities in their acylcarnitine profiles are more likely to be compound heterozygotes either for the common pathogenic variant c.985A>G (p.Lys329Glu) and another pathogenic variant, or for two non-c.985A>G pathogenic variants [
• Individuals homozygous for c.985A>G (p.Lys329Glu) had a mean C8 level of 13.8 µmol/L (range: 9-22 µmol/L), and compound heterozygotes had a mean C8 level of 2.6 µmol/L (range: 1.9-3.2 µmol/L) [
• Individuals homozygous for the common European
• Those with less pronounced abnormalities in their acylcarnitine profiles are more likely to be compound heterozygotes either for the common pathogenic variant c.985A>G (p.Lys329Glu) and another pathogenic variant, or for two non-c.985A>G pathogenic variants [
• Individuals homozygous for c.985A>G (p.Lys329Glu) had a mean C8 level of 13.8 µmol/L (range: 9-22 µmol/L), and compound heterozygotes had a mean C8 level of 2.6 µmol/L (range: 1.9-3.2 µmol/L) [
## Nomenclature
MCAD deficiency was first described in individuals presenting with a Reye-like phenotype and urine organic acid analysis that revealed overexcretion of medium-chain dicarboxylic acids and hexanoylglycine in the absence of significant ketosis [
## Prevalence
The overall prevalence of MCAD deficiency is 5.3 (range: 4.1-6.7; 99% CI) in 100,000 births across a variety of populations [
The number of newborns detected with MCAD deficiency through NBS programs exceeds that expected based on the population frequency of the common c.985A>G pathogenic variant [
The
Based on NBS programs or pilot studies worldwide, the incidence of MCAD deficiency has been determined as follows:
Japan. One in 51,000 live births [
Saudi Arabia. One in 18,000 live births [
Taiwan. One in 263,500 live births [
Historically, MCAD deficiency was considered less common in the Hispanic, African American, and Native American populations in the US. More recent analysis of data from California demonstrated that MCAD deficiency may be as prevalent in Native Americans (1:7,500 live births) as in northern Europeans. Prevalences are similar among newborns of Hispanic, Black, and Middle Eastern origin (1:23,000 live births) [
•
• Japan. One in 51,000 live births [
• Saudi Arabia. One in 18,000 live births [
• Taiwan. One in 263,500 live births [
• Japan. One in 51,000 live births [
• Saudi Arabia. One in 18,000 live births [
• Taiwan. One in 263,500 live births [
• Japan. One in 51,000 live births [
• Saudi Arabia. One in 18,000 live births [
• Taiwan. One in 263,500 live births [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
All causes of a Reye-like syndrome (i.e., acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver) need to be considered in the differential diagnosis of medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency, including other disorders of fatty acid beta-oxidation, defects in ketogenesis,
Genes of interest in the differential diagnosis of MCAD deficiency are listed in
Genes of Interest in the Differential Diagnosis of Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency
Acylcarnitines demonstrate variable ↑ of C4-, C5-, C5DC-, C6-, C8-, C10:1-, C12-, C14-, C14:1-, C16-, C16:1-, C16-OH-, C16:1-OH-, C18-, C18:1-, C18-OH-, & C18:1-OH-acylcarnitines.
↑ of diagnostic biochemical markers may incl glutaric acid, 3-hydroxyisovaleric acid, lactic acid, medium- & long-chain dicarboxylic acids, & glycine species such as isovalerylglycine, isobutyrylglycine, & 2-methylbutyrylglycine.
Ketone bodies incl acetoacetic acid & 3-hydroxybutyric acids are minimal or undetectable, distinguishing this disorder from MCAD deficiency.
AR = autosomal recessive; ARG1 = arginase; ASL deficiency = argininosuccinic aciduria; ASS1 deficiency = citrullinemia type I deficiency; CPS1 = carbamoylphosphate synthetase I; MCAD = medium-chain acyl-coenzyme A dehydrogenase; MOI = mode of inheritance; NAGS = N-acetylglutamate synthase; ORNT1 = ornithine translocase; OTC = ornithine transcarbamylase; XL = X-linked
Most infants with SCAD deficiency identified through newborn screening have remained well, and asymptomatic relatives who meet diagnostic criteria have been reported. Thus, SCAD deficiency is now viewed as a clinically benign biochemical phenotype rather than a disease.
OTC deficiency is inherited in an X-linked manner; deficiencies of NAGS, CPS1, ASS1, ASL, ARG1, ORNT1, and citrin are inherited in an autosomal recessive manner.
• Acylcarnitines demonstrate variable ↑ of C4-, C5-, C5DC-, C6-, C8-, C10:1-, C12-, C14-, C14:1-, C16-, C16:1-, C16-OH-, C16:1-OH-, C18-, C18:1-, C18-OH-, & C18:1-OH-acylcarnitines.
• ↑ of diagnostic biochemical markers may incl glutaric acid, 3-hydroxyisovaleric acid, lactic acid, medium- & long-chain dicarboxylic acids, & glycine species such as isovalerylglycine, isobutyrylglycine, & 2-methylbutyrylglycine.
• Ketone bodies incl acetoacetic acid & 3-hydroxybutyric acids are minimal or undetectable, distinguishing this disorder from MCAD deficiency.
## Management
Management guidelines for acute illness in individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency have been published [
When MCAD deficiency is suspected during the diagnostic evaluation, including on newborn screening (i.e., due to highly elevated C8-, C6-, C10-, and C10:1-acylcarnitines, elevated C8/C10 ratio, and urine hexanoylglycine elevation), metabolic treatment should be initiated immediately.
Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (e.g., childhood obesity due to frequent feeding) require a multidisciplinary approach with oversight and expertise from a specialized metabolic center.
To establish the extent of disease and needs in an individual diagnosed with MCAD deficiency, the evaluations summarized in
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Recommended Evaluations Following Initial Diagnosis
Blood glucose concentration
Liver function tests (i.e., AST, ALT, alkaline phosphatase, prothrombin time, partial thromboplastin time, total bilirubin, albumin)
Blood gas analysis
Ammonia concentration (collected in a sodium-heparin tube, placed on ice immediately, & sent STAT to lab on ice)
Lactic acid concentration
CBC w/differential
Electrolytes
Blood culture (in case of fever)
Laboratory testing or imaging is obtained as clinically indicated.
Free and total carnitine level are checked routinely in some but not all practices.
Consider referral to developmental pediatrician, depending on age & current developmental achievement.
For persons age >12 mos: screening for concerns incl ADHD if there is history of recurrent metabolic decompensations or severe hypoglycemic episodes
ADHD = attention-deficit/hyperactivity disorder; ALT = alanine transaminase; AST = aspartate transaminase; CBC = complete blood count; MCAD = medium-chain acyl-coenzyme A dehydrogenase; MOI = mode of inheritance; PT = physical therapy; STAT = short turnaround time
After a new diagnosis of MCAD deficiency in an infant or child, the closest hospital and local pediatrician should also be informed.
Clinical geneticist and/or clinical biochemical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for MCAD deficiency. However, routine dietary therapy (see
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Routine Daily Treatment
In infants, frequent feeding (every 2-3 hrs). Breastmilk or standard infant formulas typically meet nutritional needs during infancy.
Overnight feeding, a bedtime snack, or 2 g/kg of uncooked cornstarch
Normal, healthy diet containing no more than 30% of total energy from fat
Extra calories are not needed, & overfeeding can lead to obesity.
All persons w/MCAD deficiency should avoid skipping meals & weight loss diets that recommend fasting.
Prolonged or intense exercise should be covered by adequate carbohydrate intake & hydration.
IV glucose is recommended for surgical procedures that require several hours of fasting.
Birth to age 4 mos: no more than 4 hrs of fasting during day or night
Age 5-12 mos: an additional hr of fasting for each month of life up to age 12 mos (i.e., 5 hrs fasting at age 5 mos, 6 hrs fasting at age 6 mos, etc., until max of 12 hrs at age 1 yr)
Age >1 yr: no fasting longer than 12 hrs for life,
To eliminate toxic metabolites
Persons who are homozygous for c.985A>G may need higher doses of L-carnitine supplementation.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
ADHD = attention-deficit/hyperactivity disorder; IV = intravenous; MCAD = medium-chain acyl-coenzyme A dehydrogenase; OT = occupational therapy; PT = physical therapy
As a source of complex carbohydrates at bedtime to ensure sufficient glucose supply overnight
If an individual does not have an illness, this supplementary feeding may not be necessary.
See
Some centers liberalize fasting requirements after age two to three years.
Controversy exists whether L-carnitine supplementation is necessary in MCAD deficiency, even in those with low free carnitine levels [
Two exercise studies of individuals with MCAD deficiency before and after L-carnitine supplementation suggested improved exercise tolerance with supplementation of 100 mg/kg/day [
Prepubertal children may become overweight given the frequent feeding as part of treatment, especially with the increasing incidence of obesity in pediatric and general populations worldwide.
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Emergency Outpatient Treatment
Carbohydrate supplementation orally or via enteral feed
↑ of carnitine supplementation
Trial of outpatient treatment at home for up to 12 hrs
Reassessment (~every 2 hrs) for clinical changes
Fever <38.5 °C (101 °F); enteral or gastrostomy tube feeding is tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability, hypotonia, dystonia)
Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide nutritional arrangements in the outpatient setting, with some centers recommending frequent provision of carbohydrate-rich, protein-free beverages every two hours, with frequent reassessment.
Controversy exists whether L-carnitine supplementation is necessary in MCAD deficiency.
Alterations in mentation/alertness, fever, enteral feeding tolerance, and/or any new or evolving clinical features should be discussed with the designated center of expertise for inherited metabolic diseases.
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
An acute illness places the infant with MCAD deficiency at high risk for metabolic crisis. Metabolic crisis should be considered a medical emergency and implementation of treatment is essential (see
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Acute Inpatient Treatment
Administration of simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or IV fluids
IV administration of glucose should be initiated immediately w/10% dextrose w/appropriate electrolytes at rate of 1.5x maintenance rate or 10-12 mg glucose/kg/min to achieve & maintain blood glucose level >5 mmol/L, or between 120 & 170 mg/dL.
Address electrolytes & pH imbalances w/IV fluid mgmt.
IV = intravenous
See
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with MCAD deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.
As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
Avoidance of fasting remains the cornerstone of MCAD deficiency treatment. Although management of any given affected individual is nuanced and managed on a case-by-case basis, minor illnesses, where caloric needs are increased or provision of adequate calories is compromised, should be observed closely and promptly treated with a low threshold for hospital admission. An emergency management protocol should be in place and parents or caregivers should be given an emergency letter.
A clinical geneticist or clinical biochemical geneticist or similarly qualified metabolic specialist should be consulted immediately during concurrent illness, especially when it involves fever and/or poor caloric intake.
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see also
Individuals with MCAD deficiency are at risk for a secondary free carnitine deficiency, as accumulated acylcarnitine species cause depletion of carnitine stores by renal excretion. Accumulated acylcarnitine species are also thought to inhibit organic cation/carnitine transporter 2 (OCTN2), which lowers the renal excretion threshold for free carnitine and further depletes carnitine stores in the body [
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Prevention of Secondary Manifestations
Intense & ongoing education of affected persons & caregivers re natural history, maintenance, & emergency treatment
Treatment protocols & provision of emergency letters
Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); Lys-free, Trp-reduced amino acid formula; and medication required for maintenance & emergency treatment (carnitine, antipyretics) should always be maintained at home.
Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers / pediatricians, & to teachers & school staff.
Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for MCAD deficiency & containing contact information for primary treating metabolic center.
For any planned travel or vacations, consider contacting center of expertise near destination prior to travel dates.
Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
IV = intravenous; MCAD = medium-chain acyl-coenzyme A dehydrogenase
The New England Metabolic Consortium of Metabolic Programs website provides an example of a post-emergency management letter for MCAD deficiency (see
Essential information including written treatment protocols should be provided before inpatient emergency treatment might be necessary.
Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5 °C; (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur.
Infants should establish care with a biochemical genetics clinic including a metabolic dietitian as soon as possible following a positive newborn screen. A metabolic dietician (see
The frequency of routine follow-up visits is individualized based on comfort level of the affected persons, their families, and health care providers.
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Recommended Surveillance
Neuropsychological testing using age-appropriate standardized assessment batteries
Standardized quality-of-life assessment tools for affected persons & parents/caregivers
ADHD = attention-deficit/hyperactivity disorder
Prepubertal children may become overweight given the frequent feeding as part of treatment, especially with the increasing incidence of obesity in pediatric and general populations worldwide.
Although development is typically normal for individuals treated prospectively, those who experience metabolic decompensations requiring hospitalization often demonstrate developmental and neurologic disabilities.
Not routinely checked at all metabolic centers
Hypoglycemia must be avoided by frequent feedings early in life to avoid catabolism – if necessary, by intravenous administration of glucose.
Infant formulas, coconut oil, and other manufactured foods containing medium-chain triglycerides as the primary source of fat are not recommended in MCAD deficiency; however, ingesting small amounts is not contraindicated.
Popular high-fat/low-carbohydrate diets are not appropriate for individuals with MCAD deficiency.
Alcohol consumption, in particular acute alcohol intoxication (e.g., binge drinking), often elicits metabolic decompensation in individuals with MCAD deficiency [
Aspirin has been demonstrated to exacerbate MCAD deficiency by increasing mitochondrial fatty acid oxidation and long-chain fatty acid flux and inhibiting peroxisomal fatty acid oxidation, which normally serves as a lipitoxic buffer [
It is appropriate to evaluate the older and younger sibs and offspring of a proband in order to identify as early as possible those who would benefit from treatment and preventive measures.
If the
If the
See
Pregnant women who have MCAD deficiency must avoid catabolism. This is supported by several case reports describing carnitine deficiency, acute liver failure, and HELLP syndrome (
A Phase II dose-escalating clinical trial examining the use of glycerol phenylbutyrate (Ravicti
A previous Phase I clinical trial for the use of glycerol phenylbutyrate at 2, 4, and 6 g/m
A Phase II, open-label, fixed-dose study evaluating the use of sodium phenylbutyrate (ACER-001) in the treatment of adult and pediatric patients with MCAD deficiency due to the common
A Phase II, escalating-dose, open-label study of triheptanoin to prevent hypoglycemia in individuals with MCAD deficiency is ongoing as of June 2024 (
Search
• Blood glucose concentration
• Liver function tests (i.e., AST, ALT, alkaline phosphatase, prothrombin time, partial thromboplastin time, total bilirubin, albumin)
• Blood gas analysis
• Ammonia concentration (collected in a sodium-heparin tube, placed on ice immediately, & sent STAT to lab on ice)
• Lactic acid concentration
• CBC w/differential
• Electrolytes
• Blood culture (in case of fever)
• Laboratory testing or imaging is obtained as clinically indicated.
• Free and total carnitine level are checked routinely in some but not all practices.
• Consider referral to developmental pediatrician, depending on age & current developmental achievement.
• For persons age >12 mos: screening for concerns incl ADHD if there is history of recurrent metabolic decompensations or severe hypoglycemic episodes
• In infants, frequent feeding (every 2-3 hrs). Breastmilk or standard infant formulas typically meet nutritional needs during infancy.
• Overnight feeding, a bedtime snack, or 2 g/kg of uncooked cornstarch
• Normal, healthy diet containing no more than 30% of total energy from fat
• Extra calories are not needed, & overfeeding can lead to obesity.
• All persons w/MCAD deficiency should avoid skipping meals & weight loss diets that recommend fasting.
• Prolonged or intense exercise should be covered by adequate carbohydrate intake & hydration.
• IV glucose is recommended for surgical procedures that require several hours of fasting.
• Birth to age 4 mos: no more than 4 hrs of fasting during day or night
• Age 5-12 mos: an additional hr of fasting for each month of life up to age 12 mos (i.e., 5 hrs fasting at age 5 mos, 6 hrs fasting at age 6 mos, etc., until max of 12 hrs at age 1 yr)
• Age >1 yr: no fasting longer than 12 hrs for life,
• To eliminate toxic metabolites
• Persons who are homozygous for c.985A>G may need higher doses of L-carnitine supplementation.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Carbohydrate supplementation orally or via enteral feed
• ↑ of carnitine supplementation
• Trial of outpatient treatment at home for up to 12 hrs
• Reassessment (~every 2 hrs) for clinical changes
• Administration of simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or IV fluids
• IV administration of glucose should be initiated immediately w/10% dextrose w/appropriate electrolytes at rate of 1.5x maintenance rate or 10-12 mg glucose/kg/min to achieve & maintain blood glucose level >5 mmol/L, or between 120 & 170 mg/dL.
• Address electrolytes & pH imbalances w/IV fluid mgmt.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with MCAD deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
• Intense & ongoing education of affected persons & caregivers re natural history, maintenance, & emergency treatment
• Treatment protocols & provision of emergency letters
• Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); Lys-free, Trp-reduced amino acid formula; and medication required for maintenance & emergency treatment (carnitine, antipyretics) should always be maintained at home.
• Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers / pediatricians, & to teachers & school staff.
• Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for MCAD deficiency & containing contact information for primary treating metabolic center.
• For any planned travel or vacations, consider contacting center of expertise near destination prior to travel dates.
• Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
• Neuropsychological testing using age-appropriate standardized assessment batteries
• Standardized quality-of-life assessment tools for affected persons & parents/caregivers
• If the
• If the
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MCAD deficiency, the evaluations summarized in
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Recommended Evaluations Following Initial Diagnosis
Blood glucose concentration
Liver function tests (i.e., AST, ALT, alkaline phosphatase, prothrombin time, partial thromboplastin time, total bilirubin, albumin)
Blood gas analysis
Ammonia concentration (collected in a sodium-heparin tube, placed on ice immediately, & sent STAT to lab on ice)
Lactic acid concentration
CBC w/differential
Electrolytes
Blood culture (in case of fever)
Laboratory testing or imaging is obtained as clinically indicated.
Free and total carnitine level are checked routinely in some but not all practices.
Consider referral to developmental pediatrician, depending on age & current developmental achievement.
For persons age >12 mos: screening for concerns incl ADHD if there is history of recurrent metabolic decompensations or severe hypoglycemic episodes
ADHD = attention-deficit/hyperactivity disorder; ALT = alanine transaminase; AST = aspartate transaminase; CBC = complete blood count; MCAD = medium-chain acyl-coenzyme A dehydrogenase; MOI = mode of inheritance; PT = physical therapy; STAT = short turnaround time
After a new diagnosis of MCAD deficiency in an infant or child, the closest hospital and local pediatrician should also be informed.
Clinical geneticist and/or clinical biochemical geneticist, certified genetic counselor, certified advanced genetic nurse
• Blood glucose concentration
• Liver function tests (i.e., AST, ALT, alkaline phosphatase, prothrombin time, partial thromboplastin time, total bilirubin, albumin)
• Blood gas analysis
• Ammonia concentration (collected in a sodium-heparin tube, placed on ice immediately, & sent STAT to lab on ice)
• Lactic acid concentration
• CBC w/differential
• Electrolytes
• Blood culture (in case of fever)
• Laboratory testing or imaging is obtained as clinically indicated.
• Free and total carnitine level are checked routinely in some but not all practices.
• Consider referral to developmental pediatrician, depending on age & current developmental achievement.
• For persons age >12 mos: screening for concerns incl ADHD if there is history of recurrent metabolic decompensations or severe hypoglycemic episodes
## Treatment of Manifestations
There is no cure for MCAD deficiency. However, routine dietary therapy (see
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Routine Daily Treatment
In infants, frequent feeding (every 2-3 hrs). Breastmilk or standard infant formulas typically meet nutritional needs during infancy.
Overnight feeding, a bedtime snack, or 2 g/kg of uncooked cornstarch
Normal, healthy diet containing no more than 30% of total energy from fat
Extra calories are not needed, & overfeeding can lead to obesity.
All persons w/MCAD deficiency should avoid skipping meals & weight loss diets that recommend fasting.
Prolonged or intense exercise should be covered by adequate carbohydrate intake & hydration.
IV glucose is recommended for surgical procedures that require several hours of fasting.
Birth to age 4 mos: no more than 4 hrs of fasting during day or night
Age 5-12 mos: an additional hr of fasting for each month of life up to age 12 mos (i.e., 5 hrs fasting at age 5 mos, 6 hrs fasting at age 6 mos, etc., until max of 12 hrs at age 1 yr)
Age >1 yr: no fasting longer than 12 hrs for life,
To eliminate toxic metabolites
Persons who are homozygous for c.985A>G may need higher doses of L-carnitine supplementation.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
ADHD = attention-deficit/hyperactivity disorder; IV = intravenous; MCAD = medium-chain acyl-coenzyme A dehydrogenase; OT = occupational therapy; PT = physical therapy
As a source of complex carbohydrates at bedtime to ensure sufficient glucose supply overnight
If an individual does not have an illness, this supplementary feeding may not be necessary.
See
Some centers liberalize fasting requirements after age two to three years.
Controversy exists whether L-carnitine supplementation is necessary in MCAD deficiency, even in those with low free carnitine levels [
Two exercise studies of individuals with MCAD deficiency before and after L-carnitine supplementation suggested improved exercise tolerance with supplementation of 100 mg/kg/day [
Prepubertal children may become overweight given the frequent feeding as part of treatment, especially with the increasing incidence of obesity in pediatric and general populations worldwide.
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Emergency Outpatient Treatment
Carbohydrate supplementation orally or via enteral feed
↑ of carnitine supplementation
Trial of outpatient treatment at home for up to 12 hrs
Reassessment (~every 2 hrs) for clinical changes
Fever <38.5 °C (101 °F); enteral or gastrostomy tube feeding is tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability, hypotonia, dystonia)
Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide nutritional arrangements in the outpatient setting, with some centers recommending frequent provision of carbohydrate-rich, protein-free beverages every two hours, with frequent reassessment.
Controversy exists whether L-carnitine supplementation is necessary in MCAD deficiency.
Alterations in mentation/alertness, fever, enteral feeding tolerance, and/or any new or evolving clinical features should be discussed with the designated center of expertise for inherited metabolic diseases.
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
An acute illness places the infant with MCAD deficiency at high risk for metabolic crisis. Metabolic crisis should be considered a medical emergency and implementation of treatment is essential (see
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Acute Inpatient Treatment
Administration of simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or IV fluids
IV administration of glucose should be initiated immediately w/10% dextrose w/appropriate electrolytes at rate of 1.5x maintenance rate or 10-12 mg glucose/kg/min to achieve & maintain blood glucose level >5 mmol/L, or between 120 & 170 mg/dL.
Address electrolytes & pH imbalances w/IV fluid mgmt.
IV = intravenous
See
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with MCAD deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.
As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
• In infants, frequent feeding (every 2-3 hrs). Breastmilk or standard infant formulas typically meet nutritional needs during infancy.
• Overnight feeding, a bedtime snack, or 2 g/kg of uncooked cornstarch
• Normal, healthy diet containing no more than 30% of total energy from fat
• Extra calories are not needed, & overfeeding can lead to obesity.
• All persons w/MCAD deficiency should avoid skipping meals & weight loss diets that recommend fasting.
• Prolonged or intense exercise should be covered by adequate carbohydrate intake & hydration.
• IV glucose is recommended for surgical procedures that require several hours of fasting.
• Birth to age 4 mos: no more than 4 hrs of fasting during day or night
• Age 5-12 mos: an additional hr of fasting for each month of life up to age 12 mos (i.e., 5 hrs fasting at age 5 mos, 6 hrs fasting at age 6 mos, etc., until max of 12 hrs at age 1 yr)
• Age >1 yr: no fasting longer than 12 hrs for life,
• To eliminate toxic metabolites
• Persons who are homozygous for c.985A>G may need higher doses of L-carnitine supplementation.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Carbohydrate supplementation orally or via enteral feed
• ↑ of carnitine supplementation
• Trial of outpatient treatment at home for up to 12 hrs
• Reassessment (~every 2 hrs) for clinical changes
• Administration of simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or IV fluids
• IV administration of glucose should be initiated immediately w/10% dextrose w/appropriate electrolytes at rate of 1.5x maintenance rate or 10-12 mg glucose/kg/min to achieve & maintain blood glucose level >5 mmol/L, or between 120 & 170 mg/dL.
• Address electrolytes & pH imbalances w/IV fluid mgmt.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with MCAD deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
## Prevention of Primary Manifestations
Avoidance of fasting remains the cornerstone of MCAD deficiency treatment. Although management of any given affected individual is nuanced and managed on a case-by-case basis, minor illnesses, where caloric needs are increased or provision of adequate calories is compromised, should be observed closely and promptly treated with a low threshold for hospital admission. An emergency management protocol should be in place and parents or caregivers should be given an emergency letter.
A clinical geneticist or clinical biochemical geneticist or similarly qualified metabolic specialist should be consulted immediately during concurrent illness, especially when it involves fever and/or poor caloric intake.
## Prevention of Secondary Complications
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see also
Individuals with MCAD deficiency are at risk for a secondary free carnitine deficiency, as accumulated acylcarnitine species cause depletion of carnitine stores by renal excretion. Accumulated acylcarnitine species are also thought to inhibit organic cation/carnitine transporter 2 (OCTN2), which lowers the renal excretion threshold for free carnitine and further depletes carnitine stores in the body [
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Prevention of Secondary Manifestations
Intense & ongoing education of affected persons & caregivers re natural history, maintenance, & emergency treatment
Treatment protocols & provision of emergency letters
Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); Lys-free, Trp-reduced amino acid formula; and medication required for maintenance & emergency treatment (carnitine, antipyretics) should always be maintained at home.
Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers / pediatricians, & to teachers & school staff.
Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for MCAD deficiency & containing contact information for primary treating metabolic center.
For any planned travel or vacations, consider contacting center of expertise near destination prior to travel dates.
Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
IV = intravenous; MCAD = medium-chain acyl-coenzyme A dehydrogenase
The New England Metabolic Consortium of Metabolic Programs website provides an example of a post-emergency management letter for MCAD deficiency (see
Essential information including written treatment protocols should be provided before inpatient emergency treatment might be necessary.
Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5 °C; (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur.
• Intense & ongoing education of affected persons & caregivers re natural history, maintenance, & emergency treatment
• Treatment protocols & provision of emergency letters
• Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); Lys-free, Trp-reduced amino acid formula; and medication required for maintenance & emergency treatment (carnitine, antipyretics) should always be maintained at home.
• Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers / pediatricians, & to teachers & school staff.
• Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for MCAD deficiency & containing contact information for primary treating metabolic center.
• For any planned travel or vacations, consider contacting center of expertise near destination prior to travel dates.
• Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
## Surveillance
Infants should establish care with a biochemical genetics clinic including a metabolic dietitian as soon as possible following a positive newborn screen. A metabolic dietician (see
The frequency of routine follow-up visits is individualized based on comfort level of the affected persons, their families, and health care providers.
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in
Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Recommended Surveillance
Neuropsychological testing using age-appropriate standardized assessment batteries
Standardized quality-of-life assessment tools for affected persons & parents/caregivers
ADHD = attention-deficit/hyperactivity disorder
Prepubertal children may become overweight given the frequent feeding as part of treatment, especially with the increasing incidence of obesity in pediatric and general populations worldwide.
Although development is typically normal for individuals treated prospectively, those who experience metabolic decompensations requiring hospitalization often demonstrate developmental and neurologic disabilities.
Not routinely checked at all metabolic centers
• Neuropsychological testing using age-appropriate standardized assessment batteries
• Standardized quality-of-life assessment tools for affected persons & parents/caregivers
## Agents/Circumstances to Avoid
Hypoglycemia must be avoided by frequent feedings early in life to avoid catabolism – if necessary, by intravenous administration of glucose.
Infant formulas, coconut oil, and other manufactured foods containing medium-chain triglycerides as the primary source of fat are not recommended in MCAD deficiency; however, ingesting small amounts is not contraindicated.
Popular high-fat/low-carbohydrate diets are not appropriate for individuals with MCAD deficiency.
Alcohol consumption, in particular acute alcohol intoxication (e.g., binge drinking), often elicits metabolic decompensation in individuals with MCAD deficiency [
Aspirin has been demonstrated to exacerbate MCAD deficiency by increasing mitochondrial fatty acid oxidation and long-chain fatty acid flux and inhibiting peroxisomal fatty acid oxidation, which normally serves as a lipitoxic buffer [
## Evaluation of Relatives at Risk
It is appropriate to evaluate the older and younger sibs and offspring of a proband in order to identify as early as possible those who would benefit from treatment and preventive measures.
If the
If the
See
• If the
• If the
## Pregnancy Management
Pregnant women who have MCAD deficiency must avoid catabolism. This is supported by several case reports describing carnitine deficiency, acute liver failure, and HELLP syndrome (
## Therapies Under Investigation
A Phase II dose-escalating clinical trial examining the use of glycerol phenylbutyrate (Ravicti
A previous Phase I clinical trial for the use of glycerol phenylbutyrate at 2, 4, and 6 g/m
A Phase II, open-label, fixed-dose study evaluating the use of sodium phenylbutyrate (ACER-001) in the treatment of adult and pediatric patients with MCAD deficiency due to the common
A Phase II, escalating-dose, open-label study of triheptanoin to prevent hypoglycemia in individuals with MCAD deficiency is ongoing as of June 2024 (
Search
## Genetic Counseling
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Given that a clear genotype-phenotype correlation does not exist for MCAD deficiency and that individuals with biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has MCAD deficiency or is a carrier (see Clinical Characteristics,
Given the high carrier frequency in the general population, it is appropriate to test the offspring of an individual with MCAD deficiency for the disorder (see Management,
Molecular genetic testing to determine genetic status is possible if both
Note: Biochemical screening tests such as acylcarnitine, organic acid, or acylglycine analyses are not useful in determining carrier status.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
The carrier frequency for the
The ACMG includes MCAD deficiency among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
Note: States store leftover dried blood spot samples for variable lengths of time following newborn screening (NBS) testing. These samples may be retrievable with parent/patient consent for retrospective biochemical or molecular genetic testing.
Once both
Prompt postnatal testing by NBS, plasma acylcarnitines, and urine acylglycines and consultation with a biochemical geneticist are indicated.
Differences in perspective may exist among medical professionals and in families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Given that a clear genotype-phenotype correlation does not exist for MCAD deficiency and that individuals with biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has MCAD deficiency or is a carrier (see Clinical Characteristics,
• Given the high carrier frequency in the general population, it is appropriate to test the offspring of an individual with MCAD deficiency for the disorder (see Management,
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The carrier frequency for the
• The ACMG includes MCAD deficiency among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
## Mode of Inheritance
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Given that a clear genotype-phenotype correlation does not exist for MCAD deficiency and that individuals with biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has MCAD deficiency or is a carrier (see Clinical Characteristics,
Given the high carrier frequency in the general population, it is appropriate to test the offspring of an individual with MCAD deficiency for the disorder (see Management,
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Given that a clear genotype-phenotype correlation does not exist for MCAD deficiency and that individuals with biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has MCAD deficiency or is a carrier (see Clinical Characteristics,
• Given the high carrier frequency in the general population, it is appropriate to test the offspring of an individual with MCAD deficiency for the disorder (see Management,
## Carrier Detection
Molecular genetic testing to determine genetic status is possible if both
Note: Biochemical screening tests such as acylcarnitine, organic acid, or acylglycine analyses are not useful in determining carrier status.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
The carrier frequency for the
The ACMG includes MCAD deficiency among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
Note: States store leftover dried blood spot samples for variable lengths of time following newborn screening (NBS) testing. These samples may be retrievable with parent/patient consent for retrospective biochemical or molecular genetic testing.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The carrier frequency for the
• The ACMG includes MCAD deficiency among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
## Prenatal Testing and Preimplantation Genetic Testing
Once both
Prompt postnatal testing by NBS, plasma acylcarnitines, and urine acylglycines and consultation with a biochemical geneticist are indicated.
Differences in perspective may exist among medical professionals and in families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
TEMPLE (Tools Enabling Metabolic Parents LEarning)
United Kingdom
International Network for Fatty Acid Oxidation Research and Management
United Kingdom
Health Resources & Services Administration
•
• TEMPLE (Tools Enabling Metabolic Parents LEarning)
• United Kingdom
•
•
•
•
•
•
•
•
•
•
•
•
•
•
• International Network for Fatty Acid Oxidation Research and Management
•
•
• United Kingdom
•
•
•
•
• Health Resources & Services Administration
•
## Molecular Genetics
Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency (
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH
The mature MCAD protein is a homotetramer encoded by a nuclear gene; it is active within the mitochondria. The leading 25 amino acids of the precursor protein are cleaved off once the MCAD protein has reached the mitochondria. Heat shock protein 60 (HSP60) then aids in the folding of the monomer (42.5 kd). The assembled, mature homotetramer is flavin dependent, with each subunit containing one flavin adenine dinucleotide (FAD) molecule. Electron transfer flavoprotein (ETF) functions as the enzyme's electron acceptor, which explains why MCAD metabolites are also present in individuals with glutaric acidemia type II.
Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage [
Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency [
NBS = newborn screening
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Historically, variant nomenclature designated the first amino acid at p.1 of the mature protein, whereas current nomenclature designates the first amino acid at p.1 of the pro-protein.
Affected individuals who are compound heterozygous for c.199T>C (p.Tyr67His) and a second pathogenic variant are at risk for developing clinical symptoms [
This pathogenic variant has been shown to destabilize the quaternary structure of the enzyme due to misfolding, resulting in loss of function with rapid degradation of the mutated protein [
## Molecular Pathogenesis
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH
The mature MCAD protein is a homotetramer encoded by a nuclear gene; it is active within the mitochondria. The leading 25 amino acids of the precursor protein are cleaved off once the MCAD protein has reached the mitochondria. Heat shock protein 60 (HSP60) then aids in the folding of the monomer (42.5 kd). The assembled, mature homotetramer is flavin dependent, with each subunit containing one flavin adenine dinucleotide (FAD) molecule. Electron transfer flavoprotein (ETF) functions as the enzyme's electron acceptor, which explains why MCAD metabolites are also present in individuals with glutaric acidemia type II.
Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage [
Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency [
NBS = newborn screening
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Historically, variant nomenclature designated the first amino acid at p.1 of the mature protein, whereas current nomenclature designates the first amino acid at p.1 of the pro-protein.
Affected individuals who are compound heterozygous for c.199T>C (p.Tyr67His) and a second pathogenic variant are at risk for developing clinical symptoms [
This pathogenic variant has been shown to destabilize the quaternary structure of the enzyme due to misfolding, resulting in loss of function with rapid degradation of the mutated protein [
## Chapter Notes
Dr Jerry Vockley (
Irene J Chang, MD (2019-present)Christina Lam, MD (2024-present)Dietrich Matern, MD, PhD; Mayo Clinic College of Medicine (1999-2019)J Lawrence Merritt 2nd, MD; University of Washington (2019-2024)Piero Rinaldo, MD, PhD; Mayo Clinic College of Medicine (1999-2019)Jerry Vockley, MD, PhD (2024-present)
26 September 2024 (ma) Comprehensive update posted live
27 June 2019 (ha) Comprehensive update posted live
5 March 2015 (me) Comprehensive update posted live
19 January 2012 (me) Comprehensive update posted live
3 February 2005 (me) Comprehensive update posted live
27 January 2003 (me) Comprehensive update posted live
20 April 2000 (me) Review posted live
16 December 1999 (dm) Original submission
• 26 September 2024 (ma) Comprehensive update posted live
• 27 June 2019 (ha) Comprehensive update posted live
• 5 March 2015 (me) Comprehensive update posted live
• 19 January 2012 (me) Comprehensive update posted live
• 3 February 2005 (me) Comprehensive update posted live
• 27 January 2003 (me) Comprehensive update posted live
• 20 April 2000 (me) Review posted live
• 16 December 1999 (dm) Original submission
## Author Notes
Dr Jerry Vockley (
## Author History
Irene J Chang, MD (2019-present)Christina Lam, MD (2024-present)Dietrich Matern, MD, PhD; Mayo Clinic College of Medicine (1999-2019)J Lawrence Merritt 2nd, MD; University of Washington (2019-2024)Piero Rinaldo, MD, PhD; Mayo Clinic College of Medicine (1999-2019)Jerry Vockley, MD, PhD (2024-present)
## Revision History
26 September 2024 (ma) Comprehensive update posted live
27 June 2019 (ha) Comprehensive update posted live
5 March 2015 (me) Comprehensive update posted live
19 January 2012 (me) Comprehensive update posted live
3 February 2005 (me) Comprehensive update posted live
27 January 2003 (me) Comprehensive update posted live
20 April 2000 (me) Review posted live
16 December 1999 (dm) Original submission
• 26 September 2024 (ma) Comprehensive update posted live
• 27 June 2019 (ha) Comprehensive update posted live
• 5 March 2015 (me) Comprehensive update posted live
• 19 January 2012 (me) Comprehensive update posted live
• 3 February 2005 (me) Comprehensive update posted live
• 27 January 2003 (me) Comprehensive update posted live
• 20 April 2000 (me) Review posted live
• 16 December 1999 (dm) Original submission
## References
## Literature Cited
|
[] |
20/4/2000
|
26/9/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mccune-albright
|
mccune-albright
|
[
"FD/MAS",
"FD/MAS",
"Guanine nucleotide-binding protein G(s) subunit alpha isoforms short",
"GNAS",
"Fibrous Dysplasia / McCune-Albright Syndrome"
] |
Fibrous Dysplasia / McCune-Albright Syndrome
|
Vivian Szymczuk, Pablo Florenzano, Luis F de Castro, Michael T Collins, Alison M Boyce
|
Summary Fibrous dysplasia / McCune-Albright syndrome (FD/MAS), the result of an early embryonic postzygotic somatic activating pathogenic variant in Hyperpigmented skin macules are common and are usually the first manifestation of the disease, apparent at or shortly after birth. Fibrous dysplasia (FD), which can involve any part and combination of the craniofacial, axial, and/or appendicular skeleton, can range from an isolated, asymptomatic monostotic lesion discovered incidentally to severe, disabling polyostotic disease involving practically the entire skeleton and leading to progressive scoliosis, facial deformity, and loss of mobility, vision, and/or hearing. Endocrinopathies include gonadotropin-independent precocious puberty resulting from recurrent ovarian cysts in girls and autonomous testosterone production in boys; testicular lesions with or without associated gonadotropin-independent precocious puberty; thyroid lesions with or without non-autoimmune hyperthyroidism; growth hormone excess; FGF23-mediated phosphate wasting with or without hypophosphatemia in association with fibrous dysplasia; and neonatal hypercortisolism. In most individuals, the diagnosis of FD/MAS is based on the finding of two or more typical clinical features. In individuals whose only clinical finding is monostotic FD, identification of a somatic activating pathogenic variant in FD/MAS is not inherited. No parent of a child with FD/MAS has been demonstrated to have any significant, distinctive manifestations of the disorder. The risk to sibs is expected to be the same as in the general population. There are no verified instances of vertical transmission of FD/MAS.
|
## Diagnosis
Fibrous dysplasia / McCune-Albright syndrome (FD/MAS) is usually diagnosed based on characteristic clinical, radiographic, and laboratory manifestations, although formal diagnostic criteria have not been published.
FD/MAS
Borders are jagged and irregular, often referred to as resembling the "coast of Maine" (in contrast to the smooth-bordered "coast of California" lesions seen in
Distribution shows an association with ("respecting") the midline of the body and following the developmental lines of Blaschko, which reflect patterns of embryonic cell migration (see
FD can be monostotic (i.e., involvement of one bone) or polyostotic (i.e., involvement of >1 bone).
FD can involve any part and combination of the craniofacial, axial, and/or appendicular skeleton (see
The initial radiologic evaluation for FD should include a
Gonadotropin-independent precocious puberty
Testicular lesions including Leydig and/or Sertoli cell hyperplasia with characteristic ultrasonographic features, with or without associated gonadotropin-independent precocious puberty (See
Thyroid lesions with characteristic ultrasonographic features, with or without non-autoimmune hyperthyroidism (See
Growth hormone excess
Fibroblast growth factor 23 (FGF23)-mediated phosphate wasting with or without hypophosphatemia
Neonatal hypercortisolism
The clinical diagnosis of FD/MAS
Molecular genetic testing approaches include
~80% in lesional tissue
~20%-30% in peripheral blood leukocytes
Note: (1) Variant detection depends on the level of mosaicism in the tissue and the sensitivity of the technique. Detection frequency of a variant at p.Arg201 using standard PCR was highest in endocrine organs and lowest in affected skin specimens [
Molecular Genetic Testing Used in Fibrous Dysplasia / McCune-Albright Syndrome
8%-90%
75%-100%
See
See
Targeted analysis may be performed by sequence analysis
Testing tissue from a lesion biopsy has a higher clinical yield than testing a blood sample. The detection rate for a blood sample is ~20%-30% [
Somatic
Rarely, other amino acid substitutions at p.Arg201 and at p.Gln227 have been detected (see
Variant detection depends on the level of mosaicism in the tissue and the sensitivity of the technique. Variant detection at p.Arg201 using standard PCR was highest in endocrine organs and lowest in affected skin specimens [
When modified primers (peptide nucleic acid) [
• Borders are jagged and irregular, often referred to as resembling the "coast of Maine" (in contrast to the smooth-bordered "coast of California" lesions seen in
• Distribution shows an association with ("respecting") the midline of the body and following the developmental lines of Blaschko, which reflect patterns of embryonic cell migration (see
• FD can be monostotic (i.e., involvement of one bone) or polyostotic (i.e., involvement of >1 bone).
• FD can involve any part and combination of the craniofacial, axial, and/or appendicular skeleton (see
• The initial radiologic evaluation for FD should include a
• Gonadotropin-independent precocious puberty
• Testicular lesions including Leydig and/or Sertoli cell hyperplasia with characteristic ultrasonographic features, with or without associated gonadotropin-independent precocious puberty (See
• Thyroid lesions with characteristic ultrasonographic features, with or without non-autoimmune hyperthyroidism (See
• Growth hormone excess
• Fibroblast growth factor 23 (FGF23)-mediated phosphate wasting with or without hypophosphatemia
• Neonatal hypercortisolism
• ~80% in lesional tissue
• ~20%-30% in peripheral blood leukocytes
• 8%-90%
• 75%-100%
## Suggestive Findings
FD/MAS
Borders are jagged and irregular, often referred to as resembling the "coast of Maine" (in contrast to the smooth-bordered "coast of California" lesions seen in
Distribution shows an association with ("respecting") the midline of the body and following the developmental lines of Blaschko, which reflect patterns of embryonic cell migration (see
FD can be monostotic (i.e., involvement of one bone) or polyostotic (i.e., involvement of >1 bone).
FD can involve any part and combination of the craniofacial, axial, and/or appendicular skeleton (see
The initial radiologic evaluation for FD should include a
Gonadotropin-independent precocious puberty
Testicular lesions including Leydig and/or Sertoli cell hyperplasia with characteristic ultrasonographic features, with or without associated gonadotropin-independent precocious puberty (See
Thyroid lesions with characteristic ultrasonographic features, with or without non-autoimmune hyperthyroidism (See
Growth hormone excess
Fibroblast growth factor 23 (FGF23)-mediated phosphate wasting with or without hypophosphatemia
Neonatal hypercortisolism
• Borders are jagged and irregular, often referred to as resembling the "coast of Maine" (in contrast to the smooth-bordered "coast of California" lesions seen in
• Distribution shows an association with ("respecting") the midline of the body and following the developmental lines of Blaschko, which reflect patterns of embryonic cell migration (see
• FD can be monostotic (i.e., involvement of one bone) or polyostotic (i.e., involvement of >1 bone).
• FD can involve any part and combination of the craniofacial, axial, and/or appendicular skeleton (see
• The initial radiologic evaluation for FD should include a
• Gonadotropin-independent precocious puberty
• Testicular lesions including Leydig and/or Sertoli cell hyperplasia with characteristic ultrasonographic features, with or without associated gonadotropin-independent precocious puberty (See
• Thyroid lesions with characteristic ultrasonographic features, with or without non-autoimmune hyperthyroidism (See
• Growth hormone excess
• Fibroblast growth factor 23 (FGF23)-mediated phosphate wasting with or without hypophosphatemia
• Neonatal hypercortisolism
## Establishing the Diagnosis
The clinical diagnosis of FD/MAS
Molecular genetic testing approaches include
~80% in lesional tissue
~20%-30% in peripheral blood leukocytes
Note: (1) Variant detection depends on the level of mosaicism in the tissue and the sensitivity of the technique. Detection frequency of a variant at p.Arg201 using standard PCR was highest in endocrine organs and lowest in affected skin specimens [
Molecular Genetic Testing Used in Fibrous Dysplasia / McCune-Albright Syndrome
8%-90%
75%-100%
See
See
Targeted analysis may be performed by sequence analysis
Testing tissue from a lesion biopsy has a higher clinical yield than testing a blood sample. The detection rate for a blood sample is ~20%-30% [
Somatic
Rarely, other amino acid substitutions at p.Arg201 and at p.Gln227 have been detected (see
Variant detection depends on the level of mosaicism in the tissue and the sensitivity of the technique. Variant detection at p.Arg201 using standard PCR was highest in endocrine organs and lowest in affected skin specimens [
When modified primers (peptide nucleic acid) [
• ~80% in lesional tissue
• ~20%-30% in peripheral blood leukocytes
• 8%-90%
• 75%-100%
## Clinical Characteristics
Fibrous dysplasia / McCune-Albright syndrome (FD/MAS) results from mosaic somatic activating pathogenic variants in
The phenotypic spectrum of FD/MAS ranges from asymptomatic incidental findings to neonatal lethality. There is a high degree of variability between individuals, both in the number of affected tissues and the degree to which they are affected. Disease manifestations depend on the time during embryogenesis that the somatic pathogenic variant occurred, the tissue involved, and the role of Gα
Individual bone lesions typically manifest during the first few years of life and expand during childhood. The vast majority of clinically significant bone lesions are detectable by age ten years, with few new and almost no clinically significant bone lesions appearing after age 15 years [
The clinical presentation and course of FD depends on the location and extent of the affected skeleton:
Radiographs of the appendicular skeleton show expansive lesions with endosteal scalloping, thinning of the cortex, and a "ground-glass" appearance (see
FD in the craniofacial skeleton is typically expansile and appears sclerotic on radiographs, but demonstrates a typical "ground-glass" appearance on CT (see
With aging, FD lesions in the appendicular skeleton tend to become sclerotic on radiographs, and craniofacial FD lesions develop a "cystic" appearance (see
Precocious puberty is less common in boys with FD/MAS (~10%-15%), and is due to autonomous testosterone production [
In both girls and boys, prolonged autonomous sex steroid production typically leads to activation of the hypothalamic-pituitary axis and the development of central precocious puberty.
The potential for malignant transformation of testicular lesions is unknown, but appears to be low [
Hyperthyroidism is present in 10%-30% of individuals with FD/MAS, and results from both increased hormone production and increased conversion of thyroxine (T
Malignant transformation of affected thyroid tissue has rarely been reported [
Affected individuals typically present with linear growth acceleration, and may develop features of acromegaly. Clinically, growth hormone excess must be distinguished from precocious puberty and hyperthyroidism, which also present with growth acceleration.
Untreated growth hormone excess is associated with expansion of craniofacial FD, leading to macrocephaly and increased risk of vision and hearing loss [
In contrast to most other features of FD/MAS, hypophosphatemia may wax and wane over the course of a person's lifetime and become more severe during periods of rapid skeletal growth. Hypophosphatemia may resolve as persons with FD become older, likely reflecting the intrinsic changes in FD that occur with age [
Affected individuals with frank hypophosphatemia may develop rickets/osteomalacia, increased fractures, skeletal deformities, and bone pain [
Hepatitis and neonatal cholestasis may be pronounced in infants, and generally wane with age to a mild persistent form [
Hepatic adenomas and hepatoblastoma have also been reported [
Liver failure in adults with FD/MAS has not been described.
Gastroesophageal reflux manifests in childhood and may be severe.
Upper gastrointestinal polyps have been described as a common finding in individuals with FD/MAS [
Pancreatitis
Intraductal papillary mucinous neoplasms (IPMN) have been reported, which may present with variable grades of dysplasia [
To date, only activating
The association of intramuscular myxomas with FD/MAS has been termed "Mazabraud syndrome." However, myxomas are more accurately categorized as an established feature of McCune-Albright syndrome (MAS).
FD/MAS is rare. While reliable data of prevalence are not available, estimates range between 1:100,000 and 1:1,000,000.
In contrast, FD (particularly the monostotic form) is not rare, and has been estimated to account for as much as 7% of all benign bone tumors.
• Radiographs of the appendicular skeleton show expansive lesions with endosteal scalloping, thinning of the cortex, and a "ground-glass" appearance (see
• FD in the craniofacial skeleton is typically expansile and appears sclerotic on radiographs, but demonstrates a typical "ground-glass" appearance on CT (see
• With aging, FD lesions in the appendicular skeleton tend to become sclerotic on radiographs, and craniofacial FD lesions develop a "cystic" appearance (see
• Precocious puberty is less common in boys with FD/MAS (~10%-15%), and is due to autonomous testosterone production [
• In both girls and boys, prolonged autonomous sex steroid production typically leads to activation of the hypothalamic-pituitary axis and the development of central precocious puberty.
• The potential for malignant transformation of testicular lesions is unknown, but appears to be low [
• Hyperthyroidism is present in 10%-30% of individuals with FD/MAS, and results from both increased hormone production and increased conversion of thyroxine (T
• Malignant transformation of affected thyroid tissue has rarely been reported [
• Affected individuals typically present with linear growth acceleration, and may develop features of acromegaly. Clinically, growth hormone excess must be distinguished from precocious puberty and hyperthyroidism, which also present with growth acceleration.
• Untreated growth hormone excess is associated with expansion of craniofacial FD, leading to macrocephaly and increased risk of vision and hearing loss [
• In contrast to most other features of FD/MAS, hypophosphatemia may wax and wane over the course of a person's lifetime and become more severe during periods of rapid skeletal growth. Hypophosphatemia may resolve as persons with FD become older, likely reflecting the intrinsic changes in FD that occur with age [
• Affected individuals with frank hypophosphatemia may develop rickets/osteomalacia, increased fractures, skeletal deformities, and bone pain [
• Hepatitis and neonatal cholestasis may be pronounced in infants, and generally wane with age to a mild persistent form [
• Hepatic adenomas and hepatoblastoma have also been reported [
• Liver failure in adults with FD/MAS has not been described.
• Gastroesophageal reflux manifests in childhood and may be severe.
• Upper gastrointestinal polyps have been described as a common finding in individuals with FD/MAS [
• Pancreatitis
• Intraductal papillary mucinous neoplasms (IPMN) have been reported, which may present with variable grades of dysplasia [
## Clinical Description
Fibrous dysplasia / McCune-Albright syndrome (FD/MAS) results from mosaic somatic activating pathogenic variants in
The phenotypic spectrum of FD/MAS ranges from asymptomatic incidental findings to neonatal lethality. There is a high degree of variability between individuals, both in the number of affected tissues and the degree to which they are affected. Disease manifestations depend on the time during embryogenesis that the somatic pathogenic variant occurred, the tissue involved, and the role of Gα
Individual bone lesions typically manifest during the first few years of life and expand during childhood. The vast majority of clinically significant bone lesions are detectable by age ten years, with few new and almost no clinically significant bone lesions appearing after age 15 years [
The clinical presentation and course of FD depends on the location and extent of the affected skeleton:
Radiographs of the appendicular skeleton show expansive lesions with endosteal scalloping, thinning of the cortex, and a "ground-glass" appearance (see
FD in the craniofacial skeleton is typically expansile and appears sclerotic on radiographs, but demonstrates a typical "ground-glass" appearance on CT (see
With aging, FD lesions in the appendicular skeleton tend to become sclerotic on radiographs, and craniofacial FD lesions develop a "cystic" appearance (see
Precocious puberty is less common in boys with FD/MAS (~10%-15%), and is due to autonomous testosterone production [
In both girls and boys, prolonged autonomous sex steroid production typically leads to activation of the hypothalamic-pituitary axis and the development of central precocious puberty.
The potential for malignant transformation of testicular lesions is unknown, but appears to be low [
Hyperthyroidism is present in 10%-30% of individuals with FD/MAS, and results from both increased hormone production and increased conversion of thyroxine (T
Malignant transformation of affected thyroid tissue has rarely been reported [
Affected individuals typically present with linear growth acceleration, and may develop features of acromegaly. Clinically, growth hormone excess must be distinguished from precocious puberty and hyperthyroidism, which also present with growth acceleration.
Untreated growth hormone excess is associated with expansion of craniofacial FD, leading to macrocephaly and increased risk of vision and hearing loss [
In contrast to most other features of FD/MAS, hypophosphatemia may wax and wane over the course of a person's lifetime and become more severe during periods of rapid skeletal growth. Hypophosphatemia may resolve as persons with FD become older, likely reflecting the intrinsic changes in FD that occur with age [
Affected individuals with frank hypophosphatemia may develop rickets/osteomalacia, increased fractures, skeletal deformities, and bone pain [
Hepatitis and neonatal cholestasis may be pronounced in infants, and generally wane with age to a mild persistent form [
Hepatic adenomas and hepatoblastoma have also been reported [
Liver failure in adults with FD/MAS has not been described.
Gastroesophageal reflux manifests in childhood and may be severe.
Upper gastrointestinal polyps have been described as a common finding in individuals with FD/MAS [
Pancreatitis
Intraductal papillary mucinous neoplasms (IPMN) have been reported, which may present with variable grades of dysplasia [
• Radiographs of the appendicular skeleton show expansive lesions with endosteal scalloping, thinning of the cortex, and a "ground-glass" appearance (see
• FD in the craniofacial skeleton is typically expansile and appears sclerotic on radiographs, but demonstrates a typical "ground-glass" appearance on CT (see
• With aging, FD lesions in the appendicular skeleton tend to become sclerotic on radiographs, and craniofacial FD lesions develop a "cystic" appearance (see
• Precocious puberty is less common in boys with FD/MAS (~10%-15%), and is due to autonomous testosterone production [
• In both girls and boys, prolonged autonomous sex steroid production typically leads to activation of the hypothalamic-pituitary axis and the development of central precocious puberty.
• The potential for malignant transformation of testicular lesions is unknown, but appears to be low [
• Hyperthyroidism is present in 10%-30% of individuals with FD/MAS, and results from both increased hormone production and increased conversion of thyroxine (T
• Malignant transformation of affected thyroid tissue has rarely been reported [
• Affected individuals typically present with linear growth acceleration, and may develop features of acromegaly. Clinically, growth hormone excess must be distinguished from precocious puberty and hyperthyroidism, which also present with growth acceleration.
• Untreated growth hormone excess is associated with expansion of craniofacial FD, leading to macrocephaly and increased risk of vision and hearing loss [
• In contrast to most other features of FD/MAS, hypophosphatemia may wax and wane over the course of a person's lifetime and become more severe during periods of rapid skeletal growth. Hypophosphatemia may resolve as persons with FD become older, likely reflecting the intrinsic changes in FD that occur with age [
• Affected individuals with frank hypophosphatemia may develop rickets/osteomalacia, increased fractures, skeletal deformities, and bone pain [
• Hepatitis and neonatal cholestasis may be pronounced in infants, and generally wane with age to a mild persistent form [
• Hepatic adenomas and hepatoblastoma have also been reported [
• Liver failure in adults with FD/MAS has not been described.
• Gastroesophageal reflux manifests in childhood and may be severe.
• Upper gastrointestinal polyps have been described as a common finding in individuals with FD/MAS [
• Pancreatitis
• Intraductal papillary mucinous neoplasms (IPMN) have been reported, which may present with variable grades of dysplasia [
## Genotype-Phenotype Correlations
To date, only activating
## Nomenclature
The association of intramuscular myxomas with FD/MAS has been termed "Mazabraud syndrome." However, myxomas are more accurately categorized as an established feature of McCune-Albright syndrome (MAS).
## Prevalence
FD/MAS is rare. While reliable data of prevalence are not available, estimates range between 1:100,000 and 1:1,000,000.
In contrast, FD (particularly the monostotic form) is not rare, and has been estimated to account for as much as 7% of all benign bone tumors.
## Genetically Related (Allelic) Disorders
In contrast to somatic activating (gain-of-function) pathogenic variants at specific
Allelic Disorders Caused by Germline Inactivating (Loss-of-Function)
See
Pseudohypoparathyroidism Ib can also be caused by heterozygous deletion of
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Fibrous Dysplasia / McCune-Albright Syndrome
FGF23-mediated hypophosphatemia
Hyperpigmented macules that follow developmental lines of Blaschko
Skeletal features (e.g., skeletal deformities, dysplastic bone lesions, scoliosis, craniofacial involvement ranging from calvarial thinning & maxillary hypoplasia to severe osteolysis w/large calvarial defects)
Epidermal & congenital melanocytic nevi
Neurologic abnormalities
Endocrinopathies are not a common feature, but central precocious puberty, thyroid nodules, & pheochromocytoma have been reported.
Ophthalmologic disorders (colobomas, limbal dermoids, strabismus, corneal opacities)
≥6 café au lait macules that are generally smooth bordered ("coast of California") as opposed to the irregularly bordered ("coast of Maine") lesions seen in FD/MAS
Skeletal features (e.g., kyphoscoliosis, sphenoid dysplasia, cortical thinning of long bones, & bowing & dysplasia, particularly of the tibia, which may result in pseudarthroses)
Tumors of the nervous system (e.g., neurofibromas & optic gliomas)
Pigmented iris hamartomas
Axillary freckling
Symmetric fibro-osseous lesions are generally limited to the maxilla & mandible.
No extraskeletal manifestations
AD = autosomal dominant; FD/MAS = fibrous dysplasia / McCune-Albright syndrome; MOI = mode of inheritance
CSHS is a mosaic disorder resulting from postzygotic somatic activating pathogenic variants in
In approximately 80% of affected individuals, cherubism arises from a heterozygous pathogenic variant in
Fibro-osseous Skeletal Lesions in the Differential Diagnosis of Fibrous Dysplasia / McCune-Albright Syndrome
Acquired lesions w/histopathologic features similar to FD, incl proliferation of bone marrow stromal cells & the presence of multiple multinucleated giant cells
Typically benign, but may result in localized bone destruction & (rarely) metastases
Benign lesions typically affecting the mandible & maxillae & presenting w/local expansion of a firm, painless mass
Ossifying fibromas are generally more aggressive than craniofacial FD lesions & are treated w/surgical excision.
Typically occur in children age <10 yrs & most commonly affect the anterior tibia
Children present w/painless localized swelling &, in rare instances, w/fracture or progressive deformity.
Radiographs show a well-circumscribed radiolucent lesion w/characteristic sclerotic rim along the intracortical surface.
Radiographic manifestations typically incl bilateral, multilocular, radiolucent areas w/in the mandible, usually located at the angles & rami. The coronoid processes are commonly involved, whereas the condyles are rarely affected.
Histologic manifestations of lesions in the mandible &/or maxilla: non-neoplastic fibrotic lesions that contain numerous multinuclear giant cells & occasionally cysts. Increase in osteoid & newly formed bone matrix is observed in the periphery.
FD = fibrous dysplasia
• FGF23-mediated hypophosphatemia
• Hyperpigmented macules that follow developmental lines of Blaschko
• Skeletal features (e.g., skeletal deformities, dysplastic bone lesions, scoliosis, craniofacial involvement ranging from calvarial thinning & maxillary hypoplasia to severe osteolysis w/large calvarial defects)
• Epidermal & congenital melanocytic nevi
• Neurologic abnormalities
• Endocrinopathies are not a common feature, but central precocious puberty, thyroid nodules, & pheochromocytoma have been reported.
• Ophthalmologic disorders (colobomas, limbal dermoids, strabismus, corneal opacities)
• ≥6 café au lait macules that are generally smooth bordered ("coast of California") as opposed to the irregularly bordered ("coast of Maine") lesions seen in FD/MAS
• Skeletal features (e.g., kyphoscoliosis, sphenoid dysplasia, cortical thinning of long bones, & bowing & dysplasia, particularly of the tibia, which may result in pseudarthroses)
• Tumors of the nervous system (e.g., neurofibromas & optic gliomas)
• Pigmented iris hamartomas
• Axillary freckling
• Symmetric fibro-osseous lesions are generally limited to the maxilla & mandible.
• No extraskeletal manifestations
• Acquired lesions w/histopathologic features similar to FD, incl proliferation of bone marrow stromal cells & the presence of multiple multinucleated giant cells
• Typically benign, but may result in localized bone destruction & (rarely) metastases
• Benign lesions typically affecting the mandible & maxillae & presenting w/local expansion of a firm, painless mass
• Ossifying fibromas are generally more aggressive than craniofacial FD lesions & are treated w/surgical excision.
• Typically occur in children age <10 yrs & most commonly affect the anterior tibia
• Children present w/painless localized swelling &, in rare instances, w/fracture or progressive deformity.
• Radiographs show a well-circumscribed radiolucent lesion w/characteristic sclerotic rim along the intracortical surface.
• Radiographic manifestations typically incl bilateral, multilocular, radiolucent areas w/in the mandible, usually located at the angles & rami. The coronoid processes are commonly involved, whereas the condyles are rarely affected.
• Histologic manifestations of lesions in the mandible &/or maxilla: non-neoplastic fibrotic lesions that contain numerous multinuclear giant cells & occasionally cysts. Increase in osteoid & newly formed bone matrix is observed in the periphery.
## Management
After the initial diagnosis, all individuals with fibrous dysplasia / McCune-Albright syndrome (FD/MAS) should be evaluated to determine the extent of disease. The presence of any features of FD/MAS should prompt more detailed clinical evaluation for additional manifestations. The authors recommend the following studies, if they have not already been completed.
Total body bone scintigraphy to identify and determine the extent of fibrous dysplasia (FD). The majority of clinically significant skeletal lesions are apparent on bone scan by age five years.
Imaging of identified areas of FD with radiographs (axial and appendicular FD) and/or CT (craniofacial FD) to more clearly evaluate the extent and anatomy of the lesions
Baseline ophthalmologic, otolaryngologic, and audiologic evaluations in persons with craniofacial FD
Skeletal evaluation (See
Biochemical screening for hyperthyroidism, growth hormone excess (insulin-like growth factor 1 [IGF-1] level), and fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia (See
In individuals with clinical signs or a previous history of precocious puberty: biochemical screening, pelvic ultrasound examination (in females), and bone age examination (See
Ultrasound examination of the thyroid gland and testes (in all males) to evaluate for subclinical disease (See
Testing for hypercortisolism in infants with clinical evidence of Cushing syndrome (hypertension, facial plethora, abdominal obesity, developmental delay, poor weight gain, decreased linear growth, small size for gestational age) (See
Recommended evaluations for growth hormone excess in individuals with fibrous dysplasia / McCune-Albright syndrome
GH = growth hormone; H&P = history and physical examination; IGF-1 = insulin-like growth factor 1; MAS = McCune-Albright syndrome; OGTT = oral glucose tolerance test; PP = precocious puberty; PRL = prolactin
1. To be performed at initial presentation in all individuals with MAS, regardless of clinical symptoms.
2. The majority of individuals with MAS-associated GH excess will have increased prolactin secretion [
3. Practitioners may consider pituitary MRI in individuals suspected of having MAS-associated GH excess; however, findings may be nonspecific and rarely change management [
4. There are a variety of techniques for frequent GH sampling. Collecting GH samples every 20 minutes for 12 hours from 8 PM to 8 AM, with a lack of nadir below 1.0 ng/mL, is considered consistent with GH excess.
5. In those with craniofacial FD it is prudent to have a low threshold for initiating treatment, as uncontrolled GH excess is associated with increased craniofacial morbidity [
6. MAS-associated GH excess may rarely present as late as young adulthood; therefore, ongoing monitoring with periodic IGF-1 levels is prudent in those with significant craniofacial FD.
Recommended evaluations for gonadal abnormalities in females with fibrous dysplasia / McCune-Albright syndrome
FSH = follicle-stimulating hormone; GH = growth hormone; H&P = history and physical examination; LH = luteinizing hormone; MAS = McCune-Albright syndrome; PP = precocious puberty; US = ultrasound
1. To be performed at initial presentation in all girls with MAS, regardless of clinical symptoms.
2. Gonadotropins should be suppressed in those with precocious puberty, unless autonomous estrogen production has induced central precocious puberty [
3. Estrogen production in MAS-associated precocious puberty is intermittent, and undetectable levels do not eliminate the possibility of disease.
4. Ovarian cysts are suggestive of MAS-associated precocious puberty; however, absence of cysts does not eliminate the possibility of disease [Authors, personal observation].
5. In isolated peripheral precocious puberty, the differential diagnosis includes estrogen-producing tumor. Evaluation for additional features of MAS may establish the diagnosis.
6. Unlike other features of MAS, autonomous ovarian activity may present at any time during infancy or childhood. Girls should continue to be monitored clinically for signs of peripheral precocious puberty; however, routine laboratory testing and imaging is not recommended.
7. Affected females may rarely present with intermittent ovarian activity with only subtle signs of estrogenization (mild intermittent breast development without vaginal bleeding).
8. Hyperthyroidism and GH excess may present with an advanced bone age compared to chronologic age.
Recommended evaluations for gonadal abnormalities in males with fibrous dysplasia / McCune-Albright syndrome
FSH = follicle-stimulating hormone; GH = growth hormone; H&P = history and physical examination; LH = luteinizing hormone; MAS = McCune-Albright syndrome; PP = precocious puberty; US = ultrasound
1. Performed at initial presentation in all boys with MAS, regardless of clinical symptoms.
2. Typical MAS-associated macro-orchidism presents with uniform, unilateral, or bilateral testicular enlargement without discrete palpable masses.
3. Precocious puberty is less likely to occur in males who do not have evidence of testicular involvement on ultrasound. The presence of macro-orchidism is typically associated with US abnormalities.
4. Hyperthyroidism and GH excess may present with an advanced bone age compared to chronologic age.
5. Autonomous testicular activity may present at any time during childhood. Boys should continue to be monitored clinically for signs of peripheral precocious puberty; however, routine laboratory testing and imaging is not recommended [
Recommended evaluations for thyroid abnormalities in individuals with fibrous dysplasia / McCune-Albright syndrome
H&P = history and physical examination; MAS = McCune-Albright syndrome; T3 = triiodothyronine; T4 = thyroxine; TFTs = thyroid function tests; TSH = thyroid-stimulating hormone; US = ultrasound
1. To be performed at initial presentation in all individuals with MAS, regardless of clinical symptoms.
2. An elevated T3:T4 ratio is suggestive of autonomous T3 production in individuals with MAS [
3. A small percentage of affected individuals with radiologic thyroid abnormalities and normal TFTs will develop hyperthyroidism at some point during childhood.
4. The absence of biochemical or radiologic thyroid abnormalities after age five years likely eliminates the possibility of MAS-associated thyroid disease, and no further routine monitoring is required.
5. MAS-associated thyroid disease is correlated with a slightly increased risk of thyroid cancer (see
Recommended evaluations for adrenal gland dysfunction in individuals with fibrous dysplasia / McCune-Albright syndrome
CT = computerized tomography; H&P = history and physical examination; SGA = small for gestational age; US = ultrasound
1. To be performed at initial presentation in all individuals with MAS, regardless of clinical symptoms.
2. Liver disease is highly correlated with MAS-associated hypercortisolism.
3. Prognosis of hypercortisolism is negatively correlated with the presence of comorbid heart disease [
4. Hypercortisolism in MAS results from autonomous activity of the adrenal fetal zone, which involutes rapidly after birth and is typically gone by age one year [
Recommended evaluations for gastrointestinal issues in individuals with fibrous dysplasia / McCune-Albright syndrome
GERD = gastroesophageal reflux disease; GI = gastrointestinal; H&P = history and physical examination; MAS = McCune-Albright syndrome; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging
1. To be performed at initial presentation in all individuals with MAS, regardless of clinical symptoms.
2. Age is not based upon clinical evidence, but on age at which affected individuals may undergo MRI/MRCP without requiring sedation, and should be individualized based on clinical judgment.
3. Age of onset of pancreatic cyst development is not established; therefore, clinical monitoring for gastrointestinal symptoms in these affected individuals is indicated.
4. Affected individuals should continue to be monitored clinically for new signs of gastrointestinal/pancreatic involvement, including pancreatitis and diabetes [
Management is most effectively accomplished through the input of a multidisciplinary team of specialists, including an endocrinologist, orthopedic surgeon, physiatrist, ophthalmologist, audiologist, endocrine surgeon, craniofacial surgeon, and clinical geneticist. A consensus statement from the FD/MAS international consortium on best practice management guidelines was published in 2019 [
There are no established medical therapies capable of altering the disease course in FD. Current management is focused on optimizing function and minimizing morbidity related to fractures and deformity. The primary elements of management include the following (see also
Orthopedic surgery to repair fractures and to prevent and correct deformities. A surgeon experienced in FD should be consulted, as approaches previously considered standard (e.g., curettage, grafting, external fixation) are frequently ineffective [
Diagnosis and treatment of scoliosis is of particular importance, as it may be rapidly progressive and in rare instances may lead to fatal respiratory compromise. For this reason, all individuals with spinal FD should be monitored closely by an orthopedic surgeon or physiatrist for possible progression. Surgical fusion has been shown to be effective at stabilizing the spine [
Aneurysmal bone cysts, best detected by MRI, are rapidly expanding fluid-filled lesions that form within preexisting areas of FD. Affected individuals experience acute onset of severe pain, rapidly expanding localized deformity, and rarely – when cysts compress the optic nerve – rapid loss of vision. Aneurysmal bone cysts thus carry a high risk of morbidity and should be evaluated urgently by a surgeon [
Optical coherence tomography (OCT) can be used to more accurately assess for developing optic neuropathy in individuals with FD, as retinal nerve fiber layer thickness has been shown to be a better indicator of optic neuropathy than conventional CT assessment of optic canal stenosis and optic nerve stretch [
Prophylactic optic nerve decompression to reduce the risk of vision loss can in fact increase the risk of vision loss and is thus contraindicated [
Physical therapy to optimize function and attenuate loss of mobility is appropriate. Affected individuals with lower-extremity FD in particular may benefit from therapies to address hip girdle weakness, range of motion, and leg length discrepancies [
Intravenous bisphosphonates such as zoledronic acid and pamidronate are usually effective at relieving bone pain. Dosing should be based on symptoms, not on a fixed interval or bone turnover markers. The oral bisphosphonate alendronate has been shown to be ineffective for treatment of bone pain [
Denosumab, a human monoclonal antibody to receptor activator of nuclear kappa-B ligand (RANKL), has been used in several individuals with FD, with an apparent significant reduction in bone turnover markers and lesion activity, and has demonstrated improvement in osteogenic cell maturation and bone formation [
Burosumab, a human monoclonal antibody to FGF23, has been used in an individual with FD who demonstrated sustained normalization of serum phosphate and improvement in alkaline phosphatase levels along with clinical improvement in bone pain [
Malignancy should remain a consideration for individuals with acute or rapidly expanding FD lesions, or with atypical radiographic features such as compromise of the bony cortex with an associated soft tissue mass.
Recommended management for fibrous dysplasia in individuals with fibrous dysplasia / McCune-Albright syndrome
b.i.d. = twice daily; CT = computerized tomography; FD = fibrous dysplasia; GI = gastrointestinal; NSAIDs = nonsteroidal anti-inflammatory drugs
1. Affected individuals should be evaluated yearly by a neuro-ophthalmologist; less frequently once stability is demonstrated. Those with evidence of optic neuropathy should be referred to an experienced craniofacial surgical team.
2. Repeat head CT approximately every five years, potentially sooner in younger individuals, those with severe disease, or if vision or hearing deficits develop [
3. Optic nerve encasement is common and usually asymptomatic. Prophylactic optic nerve decompression in the absence of optic neuropathy is contraindicated [
4. Scoliosis may be progressive and potentially fatal in severe cases. All affected individuals with scoliosis should be followed regularly by an orthopedic surgeon [
5. Inadequately treated hypophosphatemia may significantly worsen bone pain and must be addressed before considering bisphosphonates [
6. Bisphosphonates have not been shown to affect disease progression and use should be limited to treatment of FD-related bone pain [
7. Doses should be repeated as needed when pain returns rather than on a set dosing schedule. In absence of significant decrease in bone pain, bisphosphonate treatment should be discontinued.
Children of both sexes frequently enter central precocious puberty due to premature sex steroid exposure (see
Recommended management for precocious puberty in girls with fibrous dysplasia / McCune-Albright syndrome
H&P = history and physical examination; PP = precocious puberty; US = ultrasound
1. The primary indication for treatment is to prevent impairment of adult height. Vaginal bleeding in the absence of bone age advancement does not typically warrant treatment. Exceptions may be made for very young children with frequent bleeding episodes deemed likely to lead to bone age advancement, or those who experience significant psychosocial distress related to pubertal episodes [
2. The primary end point for treatment efficacy is prevention of bone age advancement, which is assessed by growth velocity and bone age examination. Routine laboratory testing and US are unlikely to change management, and are not recommended.
Recommended management for gonadal involvement in boys with fibrous dysplasia / McCune-Albright syndrome
H&P = history and physical examination; b.i.d. = twice daily; PP = precocious puberty; US = ultrasound
1. The primary indication for treatment is to prevent impairment of adult height. Elevated testosterone levels in the absence of bone age advancement does not warrant treatment. Exceptions may be made for boys with testosterone-induced behavioral changes or progressive masculinization of the genitalia.
2. Routine laboratory testing is unlikely to change management and is not recommended.
3. Routine biopsy of affected testes is not recommended. Lesions should be followed with serial exam and US. Consider biopsy for lesions with atypical features such as a palpable mass, or for lesions that are large and/or progressive [
Radioablation is typically avoided due to potential preferential uptake by tissues bearing a somatic activating
Recommended management for hyperthyroidism in individuals with fibrous dysplasia / McCune-Albright syndrome
1. Total thyroidectomy is preferred over subtotal as any remaining abnormal tissue has the potential to regrow, with recurrence of hyperthyroidism. Accordingly, radioactive iodine uptake scan will not alter management and is not part of routine preoperative care.
2. After thyroidectomy affected individuals should continue to be monitored with yearly physical exam and thyroid ultrasound.
3. Preferential uptake of radioactive iodine by diseased tissue may lead to a theoretic risk of thyroid cancer in the remaining unaffected tissue.
4. Both thyroid and non-thyroidal tissues with an activating pathogenic
In growing children, the therapeutic goal is to maintain the insulin-like growth factor 1 (IGF-1) level in the middle of the normal range with an IGF-1 z score below zero.
In skeletally mature individuals, the goal is to decrease the IGF-1 level to as low as possible.
Medical therapy is typically continued indefinitely, as options for definitive treatment are associated with significant morbidity. Surgery may be technically difficult or precluded due to craniofacial FD. Additionally, given the diffuse pituitary infiltration of GH-producing cells, affected individuals treated surgically require total hypophysectomy with resulting total hypopituitarism [
The hyperprolactinemia that frequently accompanies GH excess is generally responsive to treatment with dopamine agonists, including cabergoline and bromocriptine. This class of drugs could also have an effect on GH excess treatment in those with modest elevations of GH and IGF-1 levels, with or without concomitant hyperprolactinemia [
Recommended management for growth hormone excess in individuals with fibrous dysplasia / McCune-Albright syndrome
FD = fibrous dysplasia; GH = growth hormone; IGF-1 = insulin-like growth factor 1; SD = standard deviation
1. Hyperprolactinemia accompanies GH excess in approximately 80% of individuals with MAS. It usually only requires treatment if levels are very high and/or it is interfering with pubertal progression, menses, or sexual function [
2. The authors' practice is to add pegvisomant after reaching a maximal dose of somatostatin analogs.
3. Effective for treatment of modest elevations of GH and IGF-1 levels, with or without concomitant hyperprolactinemia.
4. Due to characteristic diffuse somatolactotroph hyperplasia of the pituitary, total hypophysectomy is required for successful surgical treatment [
5. FD of the skull base is nearly universal in individuals with MAS-associated GH excess. There are reports of fatal skull base osteosarcomas arising after pituitary irradiation for treatment of MAS-associated GH excess [
Definitive treatment includes surgical removal of the diseased adrenal glands.
For medical treatment, metyrapone is frequently effective and is preferred over ketoconazole in children with liver abnormalities.
Spontaneous remission has been clearly documented in some affected individuals [
Recommended management for hypercortisolism in individuals with fibrous dysplasia / McCune-Albright syndrome
b.i.d. = twice daily; MAS = McCune-Albright syndrome; m
1. Affected individuals are often critically ill at presentation, which may impact treatment options.
2. Hepatotoxicity is an important consideration due to frequent comorbid liver disease [
3. Spontaneous resolution may occur due to involution of the adrenal fetal zone, which is the source of hypercortisolism in MAS [
4. Children with a current or remote history of MAS-associated hypercortisolism are at increased risk for neurodevelopmental delays, and should be considered for early interventional services [
Recommended management for pancreatic involvement in individuals with fibrous dysplasia / McCune-Albright syndrome
EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging
1. Based on the 2012 International Consensus Guidelines for the management of intraductal papillary mucinous neoplasm (IPMNs) [
2. The interval for repeat MRI/MRCP is not established [
Due to the mosaic nature of FD/MAS, the clinical findings in affected individuals can vary significantly, with some individuals having involvement of only one organ system and others having more widespread involvement. Additionally, some features are age dependent and are either not likely to develop after a certain age or are more likely to affect older individuals. The following information on surveillance applies to individuals who have already been evaluated for signs and symptoms of the condition and in whom the extent of disease has been assessed; surveillance will need to be tailored to the individual's age and known affected organ systems (see
Fibrous Dysplasia / McCune Albright Syndrome: Surveillance to Consider
FD = fibrous dysplasia; GH = growth hormone; IGF-1 = insulin-like growth factor 1; T
See
See
Growth acceleration can also be a sign of growth hormone excess.
See
Individuals with abnormalities on thyroid ultrasound examination but normal thyroid function tests are at risk for the development of frank hyperthyroidism.
See
Thyroid tissue can regrow after thyroidectomy.
See
Routine biochemical surveillance for hypercortisolism is not indicated.
To monitor for the development of FGF23-mediated hypophosphatemia and as part of routine bone health
Contact sports and other high-risk activities should be avoided in those with significant skeletal involvement.
Avoid prophylactic optic nerve decompression (see
Surgical removal of ovarian cysts should be performed with caution and only in limited circumstances.
Radiation therapy is not indicated for treatment of FD, and radiation exposure to FD lesions should be limited due to potential risk for malignant transformation [
Radioablation for hyperthyroidism is also typically avoided due to potential preferential uptake by tissues bearing a somatic activating
Because FD/MAS is not inherited, relatives are not at increased risk and do not require evaluation.
See
While the effects of pregnancy on bone and endocrine disease in women with FD/MAS are not well studied, in the authors' experience most affected women do not experience a worsening of disease during pregnancy.
There have been case reports of the use of denosumab in children that resulted in reduced expansion of rapidly growing FD lesions [
Search
• Total body bone scintigraphy to identify and determine the extent of fibrous dysplasia (FD). The majority of clinically significant skeletal lesions are apparent on bone scan by age five years.
• Imaging of identified areas of FD with radiographs (axial and appendicular FD) and/or CT (craniofacial FD) to more clearly evaluate the extent and anatomy of the lesions
• Baseline ophthalmologic, otolaryngologic, and audiologic evaluations in persons with craniofacial FD
• Skeletal evaluation (See
• Biochemical screening for hyperthyroidism, growth hormone excess (insulin-like growth factor 1 [IGF-1] level), and fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia (See
• In individuals with clinical signs or a previous history of precocious puberty: biochemical screening, pelvic ultrasound examination (in females), and bone age examination (See
• Ultrasound examination of the thyroid gland and testes (in all males) to evaluate for subclinical disease (See
• Testing for hypercortisolism in infants with clinical evidence of Cushing syndrome (hypertension, facial plethora, abdominal obesity, developmental delay, poor weight gain, decreased linear growth, small size for gestational age) (See
• Orthopedic surgery to repair fractures and to prevent and correct deformities. A surgeon experienced in FD should be consulted, as approaches previously considered standard (e.g., curettage, grafting, external fixation) are frequently ineffective [
• Diagnosis and treatment of scoliosis is of particular importance, as it may be rapidly progressive and in rare instances may lead to fatal respiratory compromise. For this reason, all individuals with spinal FD should be monitored closely by an orthopedic surgeon or physiatrist for possible progression. Surgical fusion has been shown to be effective at stabilizing the spine [
• Aneurysmal bone cysts, best detected by MRI, are rapidly expanding fluid-filled lesions that form within preexisting areas of FD. Affected individuals experience acute onset of severe pain, rapidly expanding localized deformity, and rarely – when cysts compress the optic nerve – rapid loss of vision. Aneurysmal bone cysts thus carry a high risk of morbidity and should be evaluated urgently by a surgeon [
• Optical coherence tomography (OCT) can be used to more accurately assess for developing optic neuropathy in individuals with FD, as retinal nerve fiber layer thickness has been shown to be a better indicator of optic neuropathy than conventional CT assessment of optic canal stenosis and optic nerve stretch [
• Prophylactic optic nerve decompression to reduce the risk of vision loss can in fact increase the risk of vision loss and is thus contraindicated [
• Physical therapy to optimize function and attenuate loss of mobility is appropriate. Affected individuals with lower-extremity FD in particular may benefit from therapies to address hip girdle weakness, range of motion, and leg length discrepancies [
• Intravenous bisphosphonates such as zoledronic acid and pamidronate are usually effective at relieving bone pain. Dosing should be based on symptoms, not on a fixed interval or bone turnover markers. The oral bisphosphonate alendronate has been shown to be ineffective for treatment of bone pain [
• Denosumab, a human monoclonal antibody to receptor activator of nuclear kappa-B ligand (RANKL), has been used in several individuals with FD, with an apparent significant reduction in bone turnover markers and lesion activity, and has demonstrated improvement in osteogenic cell maturation and bone formation [
• Burosumab, a human monoclonal antibody to FGF23, has been used in an individual with FD who demonstrated sustained normalization of serum phosphate and improvement in alkaline phosphatase levels along with clinical improvement in bone pain [
• Malignancy should remain a consideration for individuals with acute or rapidly expanding FD lesions, or with atypical radiographic features such as compromise of the bony cortex with an associated soft tissue mass.
• In growing children, the therapeutic goal is to maintain the insulin-like growth factor 1 (IGF-1) level in the middle of the normal range with an IGF-1 z score below zero.
• In skeletally mature individuals, the goal is to decrease the IGF-1 level to as low as possible.
• Definitive treatment includes surgical removal of the diseased adrenal glands.
• For medical treatment, metyrapone is frequently effective and is preferred over ketoconazole in children with liver abnormalities.
## Evaluations Following Initial Diagnosis
After the initial diagnosis, all individuals with fibrous dysplasia / McCune-Albright syndrome (FD/MAS) should be evaluated to determine the extent of disease. The presence of any features of FD/MAS should prompt more detailed clinical evaluation for additional manifestations. The authors recommend the following studies, if they have not already been completed.
Total body bone scintigraphy to identify and determine the extent of fibrous dysplasia (FD). The majority of clinically significant skeletal lesions are apparent on bone scan by age five years.
Imaging of identified areas of FD with radiographs (axial and appendicular FD) and/or CT (craniofacial FD) to more clearly evaluate the extent and anatomy of the lesions
Baseline ophthalmologic, otolaryngologic, and audiologic evaluations in persons with craniofacial FD
Skeletal evaluation (See
Biochemical screening for hyperthyroidism, growth hormone excess (insulin-like growth factor 1 [IGF-1] level), and fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia (See
In individuals with clinical signs or a previous history of precocious puberty: biochemical screening, pelvic ultrasound examination (in females), and bone age examination (See
Ultrasound examination of the thyroid gland and testes (in all males) to evaluate for subclinical disease (See
Testing for hypercortisolism in infants with clinical evidence of Cushing syndrome (hypertension, facial plethora, abdominal obesity, developmental delay, poor weight gain, decreased linear growth, small size for gestational age) (See
Recommended evaluations for growth hormone excess in individuals with fibrous dysplasia / McCune-Albright syndrome
GH = growth hormone; H&P = history and physical examination; IGF-1 = insulin-like growth factor 1; MAS = McCune-Albright syndrome; OGTT = oral glucose tolerance test; PP = precocious puberty; PRL = prolactin
1. To be performed at initial presentation in all individuals with MAS, regardless of clinical symptoms.
2. The majority of individuals with MAS-associated GH excess will have increased prolactin secretion [
3. Practitioners may consider pituitary MRI in individuals suspected of having MAS-associated GH excess; however, findings may be nonspecific and rarely change management [
4. There are a variety of techniques for frequent GH sampling. Collecting GH samples every 20 minutes for 12 hours from 8 PM to 8 AM, with a lack of nadir below 1.0 ng/mL, is considered consistent with GH excess.
5. In those with craniofacial FD it is prudent to have a low threshold for initiating treatment, as uncontrolled GH excess is associated with increased craniofacial morbidity [
6. MAS-associated GH excess may rarely present as late as young adulthood; therefore, ongoing monitoring with periodic IGF-1 levels is prudent in those with significant craniofacial FD.
Recommended evaluations for gonadal abnormalities in females with fibrous dysplasia / McCune-Albright syndrome
FSH = follicle-stimulating hormone; GH = growth hormone; H&P = history and physical examination; LH = luteinizing hormone; MAS = McCune-Albright syndrome; PP = precocious puberty; US = ultrasound
1. To be performed at initial presentation in all girls with MAS, regardless of clinical symptoms.
2. Gonadotropins should be suppressed in those with precocious puberty, unless autonomous estrogen production has induced central precocious puberty [
3. Estrogen production in MAS-associated precocious puberty is intermittent, and undetectable levels do not eliminate the possibility of disease.
4. Ovarian cysts are suggestive of MAS-associated precocious puberty; however, absence of cysts does not eliminate the possibility of disease [Authors, personal observation].
5. In isolated peripheral precocious puberty, the differential diagnosis includes estrogen-producing tumor. Evaluation for additional features of MAS may establish the diagnosis.
6. Unlike other features of MAS, autonomous ovarian activity may present at any time during infancy or childhood. Girls should continue to be monitored clinically for signs of peripheral precocious puberty; however, routine laboratory testing and imaging is not recommended.
7. Affected females may rarely present with intermittent ovarian activity with only subtle signs of estrogenization (mild intermittent breast development without vaginal bleeding).
8. Hyperthyroidism and GH excess may present with an advanced bone age compared to chronologic age.
Recommended evaluations for gonadal abnormalities in males with fibrous dysplasia / McCune-Albright syndrome
FSH = follicle-stimulating hormone; GH = growth hormone; H&P = history and physical examination; LH = luteinizing hormone; MAS = McCune-Albright syndrome; PP = precocious puberty; US = ultrasound
1. Performed at initial presentation in all boys with MAS, regardless of clinical symptoms.
2. Typical MAS-associated macro-orchidism presents with uniform, unilateral, or bilateral testicular enlargement without discrete palpable masses.
3. Precocious puberty is less likely to occur in males who do not have evidence of testicular involvement on ultrasound. The presence of macro-orchidism is typically associated with US abnormalities.
4. Hyperthyroidism and GH excess may present with an advanced bone age compared to chronologic age.
5. Autonomous testicular activity may present at any time during childhood. Boys should continue to be monitored clinically for signs of peripheral precocious puberty; however, routine laboratory testing and imaging is not recommended [
Recommended evaluations for thyroid abnormalities in individuals with fibrous dysplasia / McCune-Albright syndrome
H&P = history and physical examination; MAS = McCune-Albright syndrome; T3 = triiodothyronine; T4 = thyroxine; TFTs = thyroid function tests; TSH = thyroid-stimulating hormone; US = ultrasound
1. To be performed at initial presentation in all individuals with MAS, regardless of clinical symptoms.
2. An elevated T3:T4 ratio is suggestive of autonomous T3 production in individuals with MAS [
3. A small percentage of affected individuals with radiologic thyroid abnormalities and normal TFTs will develop hyperthyroidism at some point during childhood.
4. The absence of biochemical or radiologic thyroid abnormalities after age five years likely eliminates the possibility of MAS-associated thyroid disease, and no further routine monitoring is required.
5. MAS-associated thyroid disease is correlated with a slightly increased risk of thyroid cancer (see
Recommended evaluations for adrenal gland dysfunction in individuals with fibrous dysplasia / McCune-Albright syndrome
CT = computerized tomography; H&P = history and physical examination; SGA = small for gestational age; US = ultrasound
1. To be performed at initial presentation in all individuals with MAS, regardless of clinical symptoms.
2. Liver disease is highly correlated with MAS-associated hypercortisolism.
3. Prognosis of hypercortisolism is negatively correlated with the presence of comorbid heart disease [
4. Hypercortisolism in MAS results from autonomous activity of the adrenal fetal zone, which involutes rapidly after birth and is typically gone by age one year [
Recommended evaluations for gastrointestinal issues in individuals with fibrous dysplasia / McCune-Albright syndrome
GERD = gastroesophageal reflux disease; GI = gastrointestinal; H&P = history and physical examination; MAS = McCune-Albright syndrome; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging
1. To be performed at initial presentation in all individuals with MAS, regardless of clinical symptoms.
2. Age is not based upon clinical evidence, but on age at which affected individuals may undergo MRI/MRCP without requiring sedation, and should be individualized based on clinical judgment.
3. Age of onset of pancreatic cyst development is not established; therefore, clinical monitoring for gastrointestinal symptoms in these affected individuals is indicated.
4. Affected individuals should continue to be monitored clinically for new signs of gastrointestinal/pancreatic involvement, including pancreatitis and diabetes [
• Total body bone scintigraphy to identify and determine the extent of fibrous dysplasia (FD). The majority of clinically significant skeletal lesions are apparent on bone scan by age five years.
• Imaging of identified areas of FD with radiographs (axial and appendicular FD) and/or CT (craniofacial FD) to more clearly evaluate the extent and anatomy of the lesions
• Baseline ophthalmologic, otolaryngologic, and audiologic evaluations in persons with craniofacial FD
• Skeletal evaluation (See
• Biochemical screening for hyperthyroidism, growth hormone excess (insulin-like growth factor 1 [IGF-1] level), and fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia (See
• In individuals with clinical signs or a previous history of precocious puberty: biochemical screening, pelvic ultrasound examination (in females), and bone age examination (See
• Ultrasound examination of the thyroid gland and testes (in all males) to evaluate for subclinical disease (See
• Testing for hypercortisolism in infants with clinical evidence of Cushing syndrome (hypertension, facial plethora, abdominal obesity, developmental delay, poor weight gain, decreased linear growth, small size for gestational age) (See
## Treatment of Manifestations
Management is most effectively accomplished through the input of a multidisciplinary team of specialists, including an endocrinologist, orthopedic surgeon, physiatrist, ophthalmologist, audiologist, endocrine surgeon, craniofacial surgeon, and clinical geneticist. A consensus statement from the FD/MAS international consortium on best practice management guidelines was published in 2019 [
There are no established medical therapies capable of altering the disease course in FD. Current management is focused on optimizing function and minimizing morbidity related to fractures and deformity. The primary elements of management include the following (see also
Orthopedic surgery to repair fractures and to prevent and correct deformities. A surgeon experienced in FD should be consulted, as approaches previously considered standard (e.g., curettage, grafting, external fixation) are frequently ineffective [
Diagnosis and treatment of scoliosis is of particular importance, as it may be rapidly progressive and in rare instances may lead to fatal respiratory compromise. For this reason, all individuals with spinal FD should be monitored closely by an orthopedic surgeon or physiatrist for possible progression. Surgical fusion has been shown to be effective at stabilizing the spine [
Aneurysmal bone cysts, best detected by MRI, are rapidly expanding fluid-filled lesions that form within preexisting areas of FD. Affected individuals experience acute onset of severe pain, rapidly expanding localized deformity, and rarely – when cysts compress the optic nerve – rapid loss of vision. Aneurysmal bone cysts thus carry a high risk of morbidity and should be evaluated urgently by a surgeon [
Optical coherence tomography (OCT) can be used to more accurately assess for developing optic neuropathy in individuals with FD, as retinal nerve fiber layer thickness has been shown to be a better indicator of optic neuropathy than conventional CT assessment of optic canal stenosis and optic nerve stretch [
Prophylactic optic nerve decompression to reduce the risk of vision loss can in fact increase the risk of vision loss and is thus contraindicated [
Physical therapy to optimize function and attenuate loss of mobility is appropriate. Affected individuals with lower-extremity FD in particular may benefit from therapies to address hip girdle weakness, range of motion, and leg length discrepancies [
Intravenous bisphosphonates such as zoledronic acid and pamidronate are usually effective at relieving bone pain. Dosing should be based on symptoms, not on a fixed interval or bone turnover markers. The oral bisphosphonate alendronate has been shown to be ineffective for treatment of bone pain [
Denosumab, a human monoclonal antibody to receptor activator of nuclear kappa-B ligand (RANKL), has been used in several individuals with FD, with an apparent significant reduction in bone turnover markers and lesion activity, and has demonstrated improvement in osteogenic cell maturation and bone formation [
Burosumab, a human monoclonal antibody to FGF23, has been used in an individual with FD who demonstrated sustained normalization of serum phosphate and improvement in alkaline phosphatase levels along with clinical improvement in bone pain [
Malignancy should remain a consideration for individuals with acute or rapidly expanding FD lesions, or with atypical radiographic features such as compromise of the bony cortex with an associated soft tissue mass.
Recommended management for fibrous dysplasia in individuals with fibrous dysplasia / McCune-Albright syndrome
b.i.d. = twice daily; CT = computerized tomography; FD = fibrous dysplasia; GI = gastrointestinal; NSAIDs = nonsteroidal anti-inflammatory drugs
1. Affected individuals should be evaluated yearly by a neuro-ophthalmologist; less frequently once stability is demonstrated. Those with evidence of optic neuropathy should be referred to an experienced craniofacial surgical team.
2. Repeat head CT approximately every five years, potentially sooner in younger individuals, those with severe disease, or if vision or hearing deficits develop [
3. Optic nerve encasement is common and usually asymptomatic. Prophylactic optic nerve decompression in the absence of optic neuropathy is contraindicated [
4. Scoliosis may be progressive and potentially fatal in severe cases. All affected individuals with scoliosis should be followed regularly by an orthopedic surgeon [
5. Inadequately treated hypophosphatemia may significantly worsen bone pain and must be addressed before considering bisphosphonates [
6. Bisphosphonates have not been shown to affect disease progression and use should be limited to treatment of FD-related bone pain [
7. Doses should be repeated as needed when pain returns rather than on a set dosing schedule. In absence of significant decrease in bone pain, bisphosphonate treatment should be discontinued.
Children of both sexes frequently enter central precocious puberty due to premature sex steroid exposure (see
Recommended management for precocious puberty in girls with fibrous dysplasia / McCune-Albright syndrome
H&P = history and physical examination; PP = precocious puberty; US = ultrasound
1. The primary indication for treatment is to prevent impairment of adult height. Vaginal bleeding in the absence of bone age advancement does not typically warrant treatment. Exceptions may be made for very young children with frequent bleeding episodes deemed likely to lead to bone age advancement, or those who experience significant psychosocial distress related to pubertal episodes [
2. The primary end point for treatment efficacy is prevention of bone age advancement, which is assessed by growth velocity and bone age examination. Routine laboratory testing and US are unlikely to change management, and are not recommended.
Recommended management for gonadal involvement in boys with fibrous dysplasia / McCune-Albright syndrome
H&P = history and physical examination; b.i.d. = twice daily; PP = precocious puberty; US = ultrasound
1. The primary indication for treatment is to prevent impairment of adult height. Elevated testosterone levels in the absence of bone age advancement does not warrant treatment. Exceptions may be made for boys with testosterone-induced behavioral changes or progressive masculinization of the genitalia.
2. Routine laboratory testing is unlikely to change management and is not recommended.
3. Routine biopsy of affected testes is not recommended. Lesions should be followed with serial exam and US. Consider biopsy for lesions with atypical features such as a palpable mass, or for lesions that are large and/or progressive [
Radioablation is typically avoided due to potential preferential uptake by tissues bearing a somatic activating
Recommended management for hyperthyroidism in individuals with fibrous dysplasia / McCune-Albright syndrome
1. Total thyroidectomy is preferred over subtotal as any remaining abnormal tissue has the potential to regrow, with recurrence of hyperthyroidism. Accordingly, radioactive iodine uptake scan will not alter management and is not part of routine preoperative care.
2. After thyroidectomy affected individuals should continue to be monitored with yearly physical exam and thyroid ultrasound.
3. Preferential uptake of radioactive iodine by diseased tissue may lead to a theoretic risk of thyroid cancer in the remaining unaffected tissue.
4. Both thyroid and non-thyroidal tissues with an activating pathogenic
In growing children, the therapeutic goal is to maintain the insulin-like growth factor 1 (IGF-1) level in the middle of the normal range with an IGF-1 z score below zero.
In skeletally mature individuals, the goal is to decrease the IGF-1 level to as low as possible.
Medical therapy is typically continued indefinitely, as options for definitive treatment are associated with significant morbidity. Surgery may be technically difficult or precluded due to craniofacial FD. Additionally, given the diffuse pituitary infiltration of GH-producing cells, affected individuals treated surgically require total hypophysectomy with resulting total hypopituitarism [
The hyperprolactinemia that frequently accompanies GH excess is generally responsive to treatment with dopamine agonists, including cabergoline and bromocriptine. This class of drugs could also have an effect on GH excess treatment in those with modest elevations of GH and IGF-1 levels, with or without concomitant hyperprolactinemia [
Recommended management for growth hormone excess in individuals with fibrous dysplasia / McCune-Albright syndrome
FD = fibrous dysplasia; GH = growth hormone; IGF-1 = insulin-like growth factor 1; SD = standard deviation
1. Hyperprolactinemia accompanies GH excess in approximately 80% of individuals with MAS. It usually only requires treatment if levels are very high and/or it is interfering with pubertal progression, menses, or sexual function [
2. The authors' practice is to add pegvisomant after reaching a maximal dose of somatostatin analogs.
3. Effective for treatment of modest elevations of GH and IGF-1 levels, with or without concomitant hyperprolactinemia.
4. Due to characteristic diffuse somatolactotroph hyperplasia of the pituitary, total hypophysectomy is required for successful surgical treatment [
5. FD of the skull base is nearly universal in individuals with MAS-associated GH excess. There are reports of fatal skull base osteosarcomas arising after pituitary irradiation for treatment of MAS-associated GH excess [
Definitive treatment includes surgical removal of the diseased adrenal glands.
For medical treatment, metyrapone is frequently effective and is preferred over ketoconazole in children with liver abnormalities.
Spontaneous remission has been clearly documented in some affected individuals [
Recommended management for hypercortisolism in individuals with fibrous dysplasia / McCune-Albright syndrome
b.i.d. = twice daily; MAS = McCune-Albright syndrome; m
1. Affected individuals are often critically ill at presentation, which may impact treatment options.
2. Hepatotoxicity is an important consideration due to frequent comorbid liver disease [
3. Spontaneous resolution may occur due to involution of the adrenal fetal zone, which is the source of hypercortisolism in MAS [
4. Children with a current or remote history of MAS-associated hypercortisolism are at increased risk for neurodevelopmental delays, and should be considered for early interventional services [
Recommended management for pancreatic involvement in individuals with fibrous dysplasia / McCune-Albright syndrome
EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging
1. Based on the 2012 International Consensus Guidelines for the management of intraductal papillary mucinous neoplasm (IPMNs) [
2. The interval for repeat MRI/MRCP is not established [
• Orthopedic surgery to repair fractures and to prevent and correct deformities. A surgeon experienced in FD should be consulted, as approaches previously considered standard (e.g., curettage, grafting, external fixation) are frequently ineffective [
• Diagnosis and treatment of scoliosis is of particular importance, as it may be rapidly progressive and in rare instances may lead to fatal respiratory compromise. For this reason, all individuals with spinal FD should be monitored closely by an orthopedic surgeon or physiatrist for possible progression. Surgical fusion has been shown to be effective at stabilizing the spine [
• Aneurysmal bone cysts, best detected by MRI, are rapidly expanding fluid-filled lesions that form within preexisting areas of FD. Affected individuals experience acute onset of severe pain, rapidly expanding localized deformity, and rarely – when cysts compress the optic nerve – rapid loss of vision. Aneurysmal bone cysts thus carry a high risk of morbidity and should be evaluated urgently by a surgeon [
• Optical coherence tomography (OCT) can be used to more accurately assess for developing optic neuropathy in individuals with FD, as retinal nerve fiber layer thickness has been shown to be a better indicator of optic neuropathy than conventional CT assessment of optic canal stenosis and optic nerve stretch [
• Prophylactic optic nerve decompression to reduce the risk of vision loss can in fact increase the risk of vision loss and is thus contraindicated [
• Physical therapy to optimize function and attenuate loss of mobility is appropriate. Affected individuals with lower-extremity FD in particular may benefit from therapies to address hip girdle weakness, range of motion, and leg length discrepancies [
• Intravenous bisphosphonates such as zoledronic acid and pamidronate are usually effective at relieving bone pain. Dosing should be based on symptoms, not on a fixed interval or bone turnover markers. The oral bisphosphonate alendronate has been shown to be ineffective for treatment of bone pain [
• Denosumab, a human monoclonal antibody to receptor activator of nuclear kappa-B ligand (RANKL), has been used in several individuals with FD, with an apparent significant reduction in bone turnover markers and lesion activity, and has demonstrated improvement in osteogenic cell maturation and bone formation [
• Burosumab, a human monoclonal antibody to FGF23, has been used in an individual with FD who demonstrated sustained normalization of serum phosphate and improvement in alkaline phosphatase levels along with clinical improvement in bone pain [
• Malignancy should remain a consideration for individuals with acute or rapidly expanding FD lesions, or with atypical radiographic features such as compromise of the bony cortex with an associated soft tissue mass.
• In growing children, the therapeutic goal is to maintain the insulin-like growth factor 1 (IGF-1) level in the middle of the normal range with an IGF-1 z score below zero.
• In skeletally mature individuals, the goal is to decrease the IGF-1 level to as low as possible.
• Definitive treatment includes surgical removal of the diseased adrenal glands.
• For medical treatment, metyrapone is frequently effective and is preferred over ketoconazole in children with liver abnormalities.
## Fibrous Dysplasia
There are no established medical therapies capable of altering the disease course in FD. Current management is focused on optimizing function and minimizing morbidity related to fractures and deformity. The primary elements of management include the following (see also
Orthopedic surgery to repair fractures and to prevent and correct deformities. A surgeon experienced in FD should be consulted, as approaches previously considered standard (e.g., curettage, grafting, external fixation) are frequently ineffective [
Diagnosis and treatment of scoliosis is of particular importance, as it may be rapidly progressive and in rare instances may lead to fatal respiratory compromise. For this reason, all individuals with spinal FD should be monitored closely by an orthopedic surgeon or physiatrist for possible progression. Surgical fusion has been shown to be effective at stabilizing the spine [
Aneurysmal bone cysts, best detected by MRI, are rapidly expanding fluid-filled lesions that form within preexisting areas of FD. Affected individuals experience acute onset of severe pain, rapidly expanding localized deformity, and rarely – when cysts compress the optic nerve – rapid loss of vision. Aneurysmal bone cysts thus carry a high risk of morbidity and should be evaluated urgently by a surgeon [
Optical coherence tomography (OCT) can be used to more accurately assess for developing optic neuropathy in individuals with FD, as retinal nerve fiber layer thickness has been shown to be a better indicator of optic neuropathy than conventional CT assessment of optic canal stenosis and optic nerve stretch [
Prophylactic optic nerve decompression to reduce the risk of vision loss can in fact increase the risk of vision loss and is thus contraindicated [
Physical therapy to optimize function and attenuate loss of mobility is appropriate. Affected individuals with lower-extremity FD in particular may benefit from therapies to address hip girdle weakness, range of motion, and leg length discrepancies [
Intravenous bisphosphonates such as zoledronic acid and pamidronate are usually effective at relieving bone pain. Dosing should be based on symptoms, not on a fixed interval or bone turnover markers. The oral bisphosphonate alendronate has been shown to be ineffective for treatment of bone pain [
Denosumab, a human monoclonal antibody to receptor activator of nuclear kappa-B ligand (RANKL), has been used in several individuals with FD, with an apparent significant reduction in bone turnover markers and lesion activity, and has demonstrated improvement in osteogenic cell maturation and bone formation [
Burosumab, a human monoclonal antibody to FGF23, has been used in an individual with FD who demonstrated sustained normalization of serum phosphate and improvement in alkaline phosphatase levels along with clinical improvement in bone pain [
Malignancy should remain a consideration for individuals with acute or rapidly expanding FD lesions, or with atypical radiographic features such as compromise of the bony cortex with an associated soft tissue mass.
Recommended management for fibrous dysplasia in individuals with fibrous dysplasia / McCune-Albright syndrome
b.i.d. = twice daily; CT = computerized tomography; FD = fibrous dysplasia; GI = gastrointestinal; NSAIDs = nonsteroidal anti-inflammatory drugs
1. Affected individuals should be evaluated yearly by a neuro-ophthalmologist; less frequently once stability is demonstrated. Those with evidence of optic neuropathy should be referred to an experienced craniofacial surgical team.
2. Repeat head CT approximately every five years, potentially sooner in younger individuals, those with severe disease, or if vision or hearing deficits develop [
3. Optic nerve encasement is common and usually asymptomatic. Prophylactic optic nerve decompression in the absence of optic neuropathy is contraindicated [
4. Scoliosis may be progressive and potentially fatal in severe cases. All affected individuals with scoliosis should be followed regularly by an orthopedic surgeon [
5. Inadequately treated hypophosphatemia may significantly worsen bone pain and must be addressed before considering bisphosphonates [
6. Bisphosphonates have not been shown to affect disease progression and use should be limited to treatment of FD-related bone pain [
7. Doses should be repeated as needed when pain returns rather than on a set dosing schedule. In absence of significant decrease in bone pain, bisphosphonate treatment should be discontinued.
• Orthopedic surgery to repair fractures and to prevent and correct deformities. A surgeon experienced in FD should be consulted, as approaches previously considered standard (e.g., curettage, grafting, external fixation) are frequently ineffective [
• Diagnosis and treatment of scoliosis is of particular importance, as it may be rapidly progressive and in rare instances may lead to fatal respiratory compromise. For this reason, all individuals with spinal FD should be monitored closely by an orthopedic surgeon or physiatrist for possible progression. Surgical fusion has been shown to be effective at stabilizing the spine [
• Aneurysmal bone cysts, best detected by MRI, are rapidly expanding fluid-filled lesions that form within preexisting areas of FD. Affected individuals experience acute onset of severe pain, rapidly expanding localized deformity, and rarely – when cysts compress the optic nerve – rapid loss of vision. Aneurysmal bone cysts thus carry a high risk of morbidity and should be evaluated urgently by a surgeon [
• Optical coherence tomography (OCT) can be used to more accurately assess for developing optic neuropathy in individuals with FD, as retinal nerve fiber layer thickness has been shown to be a better indicator of optic neuropathy than conventional CT assessment of optic canal stenosis and optic nerve stretch [
• Prophylactic optic nerve decompression to reduce the risk of vision loss can in fact increase the risk of vision loss and is thus contraindicated [
• Physical therapy to optimize function and attenuate loss of mobility is appropriate. Affected individuals with lower-extremity FD in particular may benefit from therapies to address hip girdle weakness, range of motion, and leg length discrepancies [
• Intravenous bisphosphonates such as zoledronic acid and pamidronate are usually effective at relieving bone pain. Dosing should be based on symptoms, not on a fixed interval or bone turnover markers. The oral bisphosphonate alendronate has been shown to be ineffective for treatment of bone pain [
• Denosumab, a human monoclonal antibody to receptor activator of nuclear kappa-B ligand (RANKL), has been used in several individuals with FD, with an apparent significant reduction in bone turnover markers and lesion activity, and has demonstrated improvement in osteogenic cell maturation and bone formation [
• Burosumab, a human monoclonal antibody to FGF23, has been used in an individual with FD who demonstrated sustained normalization of serum phosphate and improvement in alkaline phosphatase levels along with clinical improvement in bone pain [
• Malignancy should remain a consideration for individuals with acute or rapidly expanding FD lesions, or with atypical radiographic features such as compromise of the bony cortex with an associated soft tissue mass.
## Endocrinopathies
Children of both sexes frequently enter central precocious puberty due to premature sex steroid exposure (see
Recommended management for precocious puberty in girls with fibrous dysplasia / McCune-Albright syndrome
H&P = history and physical examination; PP = precocious puberty; US = ultrasound
1. The primary indication for treatment is to prevent impairment of adult height. Vaginal bleeding in the absence of bone age advancement does not typically warrant treatment. Exceptions may be made for very young children with frequent bleeding episodes deemed likely to lead to bone age advancement, or those who experience significant psychosocial distress related to pubertal episodes [
2. The primary end point for treatment efficacy is prevention of bone age advancement, which is assessed by growth velocity and bone age examination. Routine laboratory testing and US are unlikely to change management, and are not recommended.
Recommended management for gonadal involvement in boys with fibrous dysplasia / McCune-Albright syndrome
H&P = history and physical examination; b.i.d. = twice daily; PP = precocious puberty; US = ultrasound
1. The primary indication for treatment is to prevent impairment of adult height. Elevated testosterone levels in the absence of bone age advancement does not warrant treatment. Exceptions may be made for boys with testosterone-induced behavioral changes or progressive masculinization of the genitalia.
2. Routine laboratory testing is unlikely to change management and is not recommended.
3. Routine biopsy of affected testes is not recommended. Lesions should be followed with serial exam and US. Consider biopsy for lesions with atypical features such as a palpable mass, or for lesions that are large and/or progressive [
Radioablation is typically avoided due to potential preferential uptake by tissues bearing a somatic activating
Recommended management for hyperthyroidism in individuals with fibrous dysplasia / McCune-Albright syndrome
1. Total thyroidectomy is preferred over subtotal as any remaining abnormal tissue has the potential to regrow, with recurrence of hyperthyroidism. Accordingly, radioactive iodine uptake scan will not alter management and is not part of routine preoperative care.
2. After thyroidectomy affected individuals should continue to be monitored with yearly physical exam and thyroid ultrasound.
3. Preferential uptake of radioactive iodine by diseased tissue may lead to a theoretic risk of thyroid cancer in the remaining unaffected tissue.
4. Both thyroid and non-thyroidal tissues with an activating pathogenic
In growing children, the therapeutic goal is to maintain the insulin-like growth factor 1 (IGF-1) level in the middle of the normal range with an IGF-1 z score below zero.
In skeletally mature individuals, the goal is to decrease the IGF-1 level to as low as possible.
Medical therapy is typically continued indefinitely, as options for definitive treatment are associated with significant morbidity. Surgery may be technically difficult or precluded due to craniofacial FD. Additionally, given the diffuse pituitary infiltration of GH-producing cells, affected individuals treated surgically require total hypophysectomy with resulting total hypopituitarism [
The hyperprolactinemia that frequently accompanies GH excess is generally responsive to treatment with dopamine agonists, including cabergoline and bromocriptine. This class of drugs could also have an effect on GH excess treatment in those with modest elevations of GH and IGF-1 levels, with or without concomitant hyperprolactinemia [
Recommended management for growth hormone excess in individuals with fibrous dysplasia / McCune-Albright syndrome
FD = fibrous dysplasia; GH = growth hormone; IGF-1 = insulin-like growth factor 1; SD = standard deviation
1. Hyperprolactinemia accompanies GH excess in approximately 80% of individuals with MAS. It usually only requires treatment if levels are very high and/or it is interfering with pubertal progression, menses, or sexual function [
2. The authors' practice is to add pegvisomant after reaching a maximal dose of somatostatin analogs.
3. Effective for treatment of modest elevations of GH and IGF-1 levels, with or without concomitant hyperprolactinemia.
4. Due to characteristic diffuse somatolactotroph hyperplasia of the pituitary, total hypophysectomy is required for successful surgical treatment [
5. FD of the skull base is nearly universal in individuals with MAS-associated GH excess. There are reports of fatal skull base osteosarcomas arising after pituitary irradiation for treatment of MAS-associated GH excess [
Definitive treatment includes surgical removal of the diseased adrenal glands.
For medical treatment, metyrapone is frequently effective and is preferred over ketoconazole in children with liver abnormalities.
Spontaneous remission has been clearly documented in some affected individuals [
Recommended management for hypercortisolism in individuals with fibrous dysplasia / McCune-Albright syndrome
b.i.d. = twice daily; MAS = McCune-Albright syndrome; m
1. Affected individuals are often critically ill at presentation, which may impact treatment options.
2. Hepatotoxicity is an important consideration due to frequent comorbid liver disease [
3. Spontaneous resolution may occur due to involution of the adrenal fetal zone, which is the source of hypercortisolism in MAS [
4. Children with a current or remote history of MAS-associated hypercortisolism are at increased risk for neurodevelopmental delays, and should be considered for early interventional services [
Recommended management for pancreatic involvement in individuals with fibrous dysplasia / McCune-Albright syndrome
EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging
1. Based on the 2012 International Consensus Guidelines for the management of intraductal papillary mucinous neoplasm (IPMNs) [
2. The interval for repeat MRI/MRCP is not established [
• In growing children, the therapeutic goal is to maintain the insulin-like growth factor 1 (IGF-1) level in the middle of the normal range with an IGF-1 z score below zero.
• In skeletally mature individuals, the goal is to decrease the IGF-1 level to as low as possible.
• Definitive treatment includes surgical removal of the diseased adrenal glands.
• For medical treatment, metyrapone is frequently effective and is preferred over ketoconazole in children with liver abnormalities.
## Surveillance
Due to the mosaic nature of FD/MAS, the clinical findings in affected individuals can vary significantly, with some individuals having involvement of only one organ system and others having more widespread involvement. Additionally, some features are age dependent and are either not likely to develop after a certain age or are more likely to affect older individuals. The following information on surveillance applies to individuals who have already been evaluated for signs and symptoms of the condition and in whom the extent of disease has been assessed; surveillance will need to be tailored to the individual's age and known affected organ systems (see
Fibrous Dysplasia / McCune Albright Syndrome: Surveillance to Consider
FD = fibrous dysplasia; GH = growth hormone; IGF-1 = insulin-like growth factor 1; T
See
See
Growth acceleration can also be a sign of growth hormone excess.
See
Individuals with abnormalities on thyroid ultrasound examination but normal thyroid function tests are at risk for the development of frank hyperthyroidism.
See
Thyroid tissue can regrow after thyroidectomy.
See
Routine biochemical surveillance for hypercortisolism is not indicated.
To monitor for the development of FGF23-mediated hypophosphatemia and as part of routine bone health
## Agents/Circumstances to Avoid
Contact sports and other high-risk activities should be avoided in those with significant skeletal involvement.
Avoid prophylactic optic nerve decompression (see
Surgical removal of ovarian cysts should be performed with caution and only in limited circumstances.
Radiation therapy is not indicated for treatment of FD, and radiation exposure to FD lesions should be limited due to potential risk for malignant transformation [
Radioablation for hyperthyroidism is also typically avoided due to potential preferential uptake by tissues bearing a somatic activating
## Evaluation of Relatives at Risk
Because FD/MAS is not inherited, relatives are not at increased risk and do not require evaluation.
See
## Pregnancy Management
While the effects of pregnancy on bone and endocrine disease in women with FD/MAS are not well studied, in the authors' experience most affected women do not experience a worsening of disease during pregnancy.
## Therapies Under Investigation
There have been case reports of the use of denosumab in children that resulted in reduced expansion of rapidly growing FD lesions [
Search
## Genetic Counseling
Fibrous dysplasia / McCune-Albright syndrome (FD/MAS) is not inherited.
Verified vertical transmission has never been observed.
Molecular data indicates that all affected individuals are mosaic for an activating
Counseling for recurrence risks in FD/MAS should emphasize that, while no pregnancy is at zero risk, evidence suggests that the risk of recurrence for this disorder is not increased over that of the general population.
As FD/MAS is the result of postzygotic somatic mutation of
• Verified vertical transmission has never been observed.
• Molecular data indicates that all affected individuals are mosaic for an activating
## Mode of Inheritance
Fibrous dysplasia / McCune-Albright syndrome (FD/MAS) is not inherited.
Verified vertical transmission has never been observed.
Molecular data indicates that all affected individuals are mosaic for an activating
• Verified vertical transmission has never been observed.
• Molecular data indicates that all affected individuals are mosaic for an activating
## Risk to Family Members
## Related Genetic Counseling Issues
Counseling for recurrence risks in FD/MAS should emphasize that, while no pregnancy is at zero risk, evidence suggests that the risk of recurrence for this disorder is not increased over that of the general population.
## Prenatal Testing
As FD/MAS is the result of postzygotic somatic mutation of
## Resources
Norway
United Kingdom
Australia
Netherlands
Spain
Portugal
•
•
•
•
•
• Norway
•
•
• United Kingdom
•
•
• Australia
•
•
•
•
•
•
• Netherlands
•
•
• Spain
•
•
• Portugal
•
## Molecular Genetics
Fibrous Dysplasia / McCune-Albright Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Fibrous Dysplasia / McCune-Albright Syndrome (
The phenotypic spectrum of FD/MAS is a reflection of the role of Gα
Techniques to Detect
PCR = polymerase chain reaction
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The phenotypic spectrum of FD/MAS is a reflection of the role of Gα
Techniques to Detect
PCR = polymerase chain reaction
Variants listed in the table have been provided by the authors.
## Chapter Notes
This research was supported by the Intramural Research Program of the NIH, NIDCR (AMB, MTC), and the Bone Health Program, Division of Orthopaedics and Sports Medicine, Children's National Health System (AMB). The authors are grateful to the patients and their families for participation in the research and the efforts of the trainees of the NIH Interinstitute Endocrine Training Program for the excellent care they provide to our research subjects at the NIH Mark O Hatfield Clinical Research Center.
8 February 2024 (sw) Comprehensive update posted live
16 August 2018 (ma) Comprehensive update posted live
26 February 2015 (me) Review posted live
17 October 2014 (amb) Original submission
• 8 February 2024 (sw) Comprehensive update posted live
• 16 August 2018 (ma) Comprehensive update posted live
• 26 February 2015 (me) Review posted live
• 17 October 2014 (amb) Original submission
## Author Notes
## Acknowledgments
This research was supported by the Intramural Research Program of the NIH, NIDCR (AMB, MTC), and the Bone Health Program, Division of Orthopaedics and Sports Medicine, Children's National Health System (AMB). The authors are grateful to the patients and their families for participation in the research and the efforts of the trainees of the NIH Interinstitute Endocrine Training Program for the excellent care they provide to our research subjects at the NIH Mark O Hatfield Clinical Research Center.
## Revision History
8 February 2024 (sw) Comprehensive update posted live
16 August 2018 (ma) Comprehensive update posted live
26 February 2015 (me) Review posted live
17 October 2014 (amb) Original submission
• 8 February 2024 (sw) Comprehensive update posted live
• 16 August 2018 (ma) Comprehensive update posted live
• 26 February 2015 (me) Review posted live
• 17 October 2014 (amb) Original submission
## References
## Literature Cited
Hyperpigmented macules
A. Skin lesions in a newborn demonstrating the characteristic association with the midline of the body, and distribution reflecting patterns of embryonic cell migration (developmental lines of Blaschko)
B. A typical lesion on the chest, face, and arm demonstrating the irregular "coast of Maine" borders, relationship with the midline of the body, and distribution following developmental lines of Blaschko
C. Typical lesions frequently found on the nape of the neck and crease of the buttocks
Fibrous dysplasia (FD)
A. FD of the proximal femur demonstrating the typical "ground-glass" appearance with a coxa vara ("shepherd's crook") deformity
B. 3D reconstructed CT of a man age 26 years with craniofacial FD and uncontrolled growth hormone excess, leading to macrocephaly and severe facial deformity
C. CT of a girl age ten years, demonstrating the typical "ground-glass" appearance of craniofacial FD in younger individuals. The optic canals are typically encased in FD (white arrows) without any visual disturbance.
D. CT of a woman age 40 years, demonstrating typical features of craniofacial FD in an older individual, including a more sclerotic appearance with mixed solid and cystic components. Optic nerves are encased in FD (white arrows) without visual disturbance.
E. Technetium-99 bone scintigraphy, posterior-anterior and anterior-posterior views (left and right panels, respectively), demonstrating patchy tracer uptake at affected skeletal sites, including the skull, ribs, femur, and tibia (arrows), consistent with a mosaic pattern of expression
Suggested evaluations to determine if fibrous dysplasia (FD) is present and the extent of disease if FD is present
1. Performed at initial presentation in all individuals suspected of having FD/MAS.
2. Areas of clinically significant FD will be apparent on bone scan by age five years. Prior to age five years, a normal
3. FGF23-mediated phosphate wasting is associated with a high FD burden. Phosphate wasting may worsen during rapid skeletal growth and improve or resolve in adulthood as FD becomes less active [
4. Consider performing
5. Significance of FD is determined by both the amount and location of affected bone [
6. A normal
Ultrasonography findings of ovarian, testicular, and thyroid disease
A. Pelvic ultrasound in a girl age seven years, showing a complex unilateral ovarian cyst (defined by crosshatches). The uterus is prepubertal in size (arrow).
B. Testicular ultrasound in an adult showing a heterogeneous lesion with mixed solid and cystic elements
C&D. Typical thyroid ultrasound findings, including heterogeneity and a cystic ("Swiss-cheese") appearance.
|
[] |
26/2/2015
|
8/2/2024
|
27/6/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mckd1
|
mckd1
|
[
"ADTKD-MUC1",
"Medullary Cystic Kidney Disease Type 1 (MCKD1)",
"MUC1 Kidney Disease (MKD)",
"ADTKD-MUC1",
"Medullary Cystic Kidney Disease Type 1 (MCKD1)",
"MUC1 Kidney Disease (MKD)",
"Mucin-1",
"MUC1",
"Autosomal Dominant Tubulointerstitial Kidney Disease – MUC1"
] |
Autosomal Dominant Tubulointerstitial Kidney Disease –
|
Anthony J Bleyer, Martina Živná, Kendrah Kidd, Stanislav Kmoch
|
Summary Autosomal dominant tubulointerstitial kidney disease – The diagnosis of ADTKD- Affected individuals are encouraged to prepare for kidney transplantation, the definitive treatment of ADTKD ADTKD-
|
## Diagnosis
Autosomal dominant tubulointerstitial kidney disease –
Consensus clinical diagnostic criteria for ADTKD-
ADTKD-
The majority of affected individuals are asymptomatic when abnormal laboratory findings initially appear, usually in the late teens or early twenties.
The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
Family history is consistent with
The diagnosis of ADTKD-
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Because of the complex molecular genetics of ADTKD-
Use of an inherited kidney disease multigene panel including
In 99% of individuals with ADTKD-
Clinically available multigene panels that include
If the multigene panel testing used in Step 1 does not identify a cause for the individual’s clinical findings, consider use of a laboratory specifically performing
If the specific
Molecular Genetic Testing Used in ADTKD-
See
See
Pathogenic variants are not identifiable by routine sequence analysis (Sanger sequencing or next generation sequencing) [
Evidence suggests that some families with ADTKD-
• The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
• In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
• The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
• In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
• The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
• In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
• In 99% of individuals with ADTKD-
• Clinically available multigene panels that include
## Suggestive Findings
ADTKD-
The majority of affected individuals are asymptomatic when abnormal laboratory findings initially appear, usually in the late teens or early twenties.
The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
Family history is consistent with
• The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
• In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
• The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
• In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
• The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
• In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
## Clinical Findings
## Laboratory Findings
The majority of affected individuals are asymptomatic when abnormal laboratory findings initially appear, usually in the late teens or early twenties.
The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
• The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
• In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
• The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
• In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
• The eGFR may decrease in childhood. The eGFR in ~50% of affected children is <90mL/min/1.73m
• In contrast, in some individuals, the eGFR may not begin to decrease until adulthood; 14% of individuals ages 20 to 29 years (from an ADTKD-
## Imaging
## Family History
Family history is consistent with
## Establishing the Diagnosis
The diagnosis of ADTKD-
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Because of the complex molecular genetics of ADTKD-
Use of an inherited kidney disease multigene panel including
In 99% of individuals with ADTKD-
Clinically available multigene panels that include
If the multigene panel testing used in Step 1 does not identify a cause for the individual’s clinical findings, consider use of a laboratory specifically performing
If the specific
Molecular Genetic Testing Used in ADTKD-
See
See
Pathogenic variants are not identifiable by routine sequence analysis (Sanger sequencing or next generation sequencing) [
Evidence suggests that some families with ADTKD-
• In 99% of individuals with ADTKD-
• Clinically available multigene panels that include
## Step 1
Use of an inherited kidney disease multigene panel including
In 99% of individuals with ADTKD-
Clinically available multigene panels that include
• In 99% of individuals with ADTKD-
• Clinically available multigene panels that include
## Step 2
If the multigene panel testing used in Step 1 does not identify a cause for the individual’s clinical findings, consider use of a laboratory specifically performing
## Step 3
If the specific
Molecular Genetic Testing Used in ADTKD-
See
See
Pathogenic variants are not identifiable by routine sequence analysis (Sanger sequencing or next generation sequencing) [
Evidence suggests that some families with ADTKD-
## Clinical Characteristics
Autosomal dominant tubulointerstitial kidney disease –
The rate of loss of kidney function for individuals is variable within and between families, with a median age of onset of ESRD of 46 years [
As kidney function worsens, manifestations of chronic kidney disease (CKD) develop, including high blood pressure, gout, and anemia.
Gout in ADTKD-
Kidney function progressively worsens until dialysis or kidney transplantation is required.
There are no known genotype-phenotype correlations.
Penetrance is complete.
ADTKD-
According to the 2015 nomenclature [
Autosomal dominant inheritance
Slowly progressive chronic tubulointerstitial kidney disease resulting in end-stage renal disease (ESRD) in the third through seventh decade of life
Urinalysis revealing a bland urinary sediment (i.e., little blood or protein)
Renal ultrasound examination that is normal early in the disease course
ADTKD
• Autosomal dominant inheritance
• Slowly progressive chronic tubulointerstitial kidney disease resulting in end-stage renal disease (ESRD) in the third through seventh decade of life
• Urinalysis revealing a bland urinary sediment (i.e., little blood or protein)
• Renal ultrasound examination that is normal early in the disease course
## Clinical Description
Autosomal dominant tubulointerstitial kidney disease –
The rate of loss of kidney function for individuals is variable within and between families, with a median age of onset of ESRD of 46 years [
As kidney function worsens, manifestations of chronic kidney disease (CKD) develop, including high blood pressure, gout, and anemia.
Gout in ADTKD-
Kidney function progressively worsens until dialysis or kidney transplantation is required.
## Genotype-Phenotype Correlations
There are no known genotype-phenotype correlations.
## Penetrance
Penetrance is complete.
## Nomenclature
ADTKD-
According to the 2015 nomenclature [
Autosomal dominant inheritance
Slowly progressive chronic tubulointerstitial kidney disease resulting in end-stage renal disease (ESRD) in the third through seventh decade of life
Urinalysis revealing a bland urinary sediment (i.e., little blood or protein)
Renal ultrasound examination that is normal early in the disease course
• Autosomal dominant inheritance
• Slowly progressive chronic tubulointerstitial kidney disease resulting in end-stage renal disease (ESRD) in the third through seventh decade of life
• Urinalysis revealing a bland urinary sediment (i.e., little blood or protein)
• Renal ultrasound examination that is normal early in the disease course
## Prevalence
ADTKD
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
See
If blood and protein are present, consider evaluation for inherited glomerulonephritis. If the urine sediment is bland (trace or no blood and protein <500 mg/24 h), obtain a family history to determine the likely inheritance pattern. If autosomal recessive (i.e., only sibs are affected), consider
Renal imaging should always be performed. Ultrasound examination is typically performed first. If numerous cortical and medullary cysts and enlarged kidneys are present, consider
If the number of cysts is fewer than required for a diagnosis of ADPKD, the family history suggests autosomal dominant inheritance, the urine is bland, the kidneys are normal or reduced in size with or without medullary cysts, and renal histology (if performed) has shown interstitial fibrosis, consider screening for pathogenic variants in
The most common condition in the differential will be
If family members have a history of anemia in childhood and mildly elevated serum potassium concentrations, consider
Monogenic Kidney Diseases in the Differential Diagnosis of ADTKD-
Absence of affected family members in multiple generations
ESRD usually occurs earlier (affected persons usually require dialysis in teens & early 20s).
Leukopenia (w/abscess formation), intrauterine & postnatal growth restriction
Renal disease often presents in childhood.
AD = autosomal dominant; AR = autosomal recessive; CAKUT = congenital anomalies of the kidneys and urinary tract; CKD = chronic kidney disease; ESRD = end-stage renal disease; Mat = maternal; MODY = maturity-onset diabetes of the young; MOI = mode of inheritance; mt(DNA) = mitochondrial; XL = X-linked
Listed genes represent the most common genetic causes of isolated nephronophthisis (NPH). Other genes known to be associated with nephronophthisis are
Bland refers to urinary sediment with little blood or protein.
Males with >1% α-Gal A activity have a cardiac or renal variant phenotype. Rarely, heterozygous (carrier) females may have symptoms as severe as those observed in males with the classic phenotype.
• Absence of affected family members in multiple generations
• ESRD usually occurs earlier (affected persons usually require dialysis in teens & early 20s).
• Leukopenia (w/abscess formation), intrauterine & postnatal growth restriction
• Renal disease often presents in childhood.
## Urinalysis
If blood and protein are present, consider evaluation for inherited glomerulonephritis. If the urine sediment is bland (trace or no blood and protein <500 mg/24 h), obtain a family history to determine the likely inheritance pattern. If autosomal recessive (i.e., only sibs are affected), consider
## Renal Imaging
Renal imaging should always be performed. Ultrasound examination is typically performed first. If numerous cortical and medullary cysts and enlarged kidneys are present, consider
If the number of cysts is fewer than required for a diagnosis of ADPKD, the family history suggests autosomal dominant inheritance, the urine is bland, the kidneys are normal or reduced in size with or without medullary cysts, and renal histology (if performed) has shown interstitial fibrosis, consider screening for pathogenic variants in
The most common condition in the differential will be
If family members have a history of anemia in childhood and mildly elevated serum potassium concentrations, consider
Monogenic Kidney Diseases in the Differential Diagnosis of ADTKD-
Absence of affected family members in multiple generations
ESRD usually occurs earlier (affected persons usually require dialysis in teens & early 20s).
Leukopenia (w/abscess formation), intrauterine & postnatal growth restriction
Renal disease often presents in childhood.
AD = autosomal dominant; AR = autosomal recessive; CAKUT = congenital anomalies of the kidneys and urinary tract; CKD = chronic kidney disease; ESRD = end-stage renal disease; Mat = maternal; MODY = maturity-onset diabetes of the young; MOI = mode of inheritance; mt(DNA) = mitochondrial; XL = X-linked
Listed genes represent the most common genetic causes of isolated nephronophthisis (NPH). Other genes known to be associated with nephronophthisis are
Bland refers to urinary sediment with little blood or protein.
Males with >1% α-Gal A activity have a cardiac or renal variant phenotype. Rarely, heterozygous (carrier) females may have symptoms as severe as those observed in males with the classic phenotype.
• Absence of affected family members in multiple generations
• ESRD usually occurs earlier (affected persons usually require dialysis in teens & early 20s).
• Leukopenia (w/abscess formation), intrauterine & postnatal growth restriction
• Renal disease often presents in childhood.
## Management
Consensus management guidelines for autosomal dominant tubulointerstitial kidney disease caused by pathogenic variants in
To establish the extent of disease and needs in an individual diagnosed with ADTKD-
Recommended Evaluations Following Initial Diagnosis in Individuals with ADTKD-
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Care by a nephrologist is recommended.
Treatment follows standard guidelines for chronic kidney disease – based on the level of the serum creatinine and estimated glomerular filtration rate (eGFR) – and its sequelae, which can include hypertension, anemia, and gout.
Affected individuals are encouraged to prepare for kidney transplantation, the definitive treatment of ADTKD
Affected individuals should be referred for evaluation for kidney transplantation when their eGFR declines to <19 mL/min/1.73m
Kidney transplantation is curative; the outcome is excellent [
Monitor the following annually, starting at the time of diagnosis and continuing until chronic kidney disease (CKD) Stage 3:
Hemoglobin concentration
Serum concentrations of uric acid and creatinine
Blood pressure
After CKD Stage 3, follow up is determined by the treating nephrologist.
Affected individuals should follow general recommendations for chronic kidney disease.
See
Pregnancies in women with ADTKD tend to have better outcomes for themselves and their children compared to women with other kidney diseases who have similar levels of kidney function: about 20% of women develop hypertension during pregnancy, about 10% deliver before 38 weeks' gestation, and the rate of cæsarean section is not increased. Fetal outcomes are in general excellent [Authors, unpublished data].
Women of childbearing age who are taking medications such as an angiotensin-converting enzyme (ACE) inhibitor or allopurinol should discuss their medication regimen with their physician. Ideally, women should avoid taking either an ACE inhibitor or allopurinol during pregnancy.
This finding is concerning because the mechanism of action of allopurinol (inhibiting purine degradation) is similar to the mechanism of action of mycophenolate mofetil (inhibition of
The acute treatment of gout may require the use of other medications, such as prednisone or colchicine.
See
Of note, basic science and animal studies have identified a potential therapy for the small molecule BRD4780, which was found to clear MUC1 frameshift protein deposits in cells in culture, organoids, and a mouse model of ADTKD-
Search
• Hemoglobin concentration
• Serum concentrations of uric acid and creatinine
• Blood pressure
• This finding is concerning because the mechanism of action of allopurinol (inhibiting purine degradation) is similar to the mechanism of action of mycophenolate mofetil (inhibition of
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with ADTKD-
Recommended Evaluations Following Initial Diagnosis in Individuals with ADTKD-
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
## Treatment of Manifestations
Care by a nephrologist is recommended.
Treatment follows standard guidelines for chronic kidney disease – based on the level of the serum creatinine and estimated glomerular filtration rate (eGFR) – and its sequelae, which can include hypertension, anemia, and gout.
Affected individuals are encouraged to prepare for kidney transplantation, the definitive treatment of ADTKD
Affected individuals should be referred for evaluation for kidney transplantation when their eGFR declines to <19 mL/min/1.73m
Kidney transplantation is curative; the outcome is excellent [
## Surveillance
Monitor the following annually, starting at the time of diagnosis and continuing until chronic kidney disease (CKD) Stage 3:
Hemoglobin concentration
Serum concentrations of uric acid and creatinine
Blood pressure
After CKD Stage 3, follow up is determined by the treating nephrologist.
• Hemoglobin concentration
• Serum concentrations of uric acid and creatinine
• Blood pressure
## Agents/Circumstances to Avoid
Affected individuals should follow general recommendations for chronic kidney disease.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Pregnancies in women with ADTKD tend to have better outcomes for themselves and their children compared to women with other kidney diseases who have similar levels of kidney function: about 20% of women develop hypertension during pregnancy, about 10% deliver before 38 weeks' gestation, and the rate of cæsarean section is not increased. Fetal outcomes are in general excellent [Authors, unpublished data].
Women of childbearing age who are taking medications such as an angiotensin-converting enzyme (ACE) inhibitor or allopurinol should discuss their medication regimen with their physician. Ideally, women should avoid taking either an ACE inhibitor or allopurinol during pregnancy.
This finding is concerning because the mechanism of action of allopurinol (inhibiting purine degradation) is similar to the mechanism of action of mycophenolate mofetil (inhibition of
The acute treatment of gout may require the use of other medications, such as prednisone or colchicine.
See
• This finding is concerning because the mechanism of action of allopurinol (inhibiting purine degradation) is similar to the mechanism of action of mycophenolate mofetil (inhibition of
## Therapies Under Investigation
Of note, basic science and animal studies have identified a potential therapy for the small molecule BRD4780, which was found to clear MUC1 frameshift protein deposits in cells in culture, organoids, and a mouse model of ADTKD-
Search
## Genetic Counseling
By definition, autosomal dominant tubulointerstitial kidney disease –
Most individuals diagnosed with ADTKD
A proband with ADTKD
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of an individual with ADTKD
If a parent of the proband has the
Although the penetrance of ADTKD-
If the proband has a known
If the parents have not been tested for the
See Management,
In general, predictive testing of minors for adult-onset disorders is considered inappropriate unless such testing has a compelling medical benefit. Concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For parents desiring closer surveillance of their children, blood pressure can be monitored and serum creatinine can be tested on an annual basis.
It is important for parents to realize that normal serum creatinine levels in childhood do not rule out ADTKD
For children in whom the serum creatinine is elevated, genetic testing can be considered to rule out other possible causes of kidney disease.
Genetic testing may be considered in children when affected family members have an earlier age of onset of kidney disease and end-stage renal disease.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of ADTKD
Women with ADTKD-
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Prenatal testing for the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors
• A proband with ADTKD
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of an individual with ADTKD
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband has the
• Although the penetrance of ADTKD-
• If the proband has a known
• If the parents have not been tested for the
• In general, predictive testing of minors for adult-onset disorders is considered inappropriate unless such testing has a compelling medical benefit. Concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For parents desiring closer surveillance of their children, blood pressure can be monitored and serum creatinine can be tested on an annual basis.
• It is important for parents to realize that normal serum creatinine levels in childhood do not rule out ADTKD
• For children in whom the serum creatinine is elevated, genetic testing can be considered to rule out other possible causes of kidney disease.
• It is important for parents to realize that normal serum creatinine levels in childhood do not rule out ADTKD
• For children in whom the serum creatinine is elevated, genetic testing can be considered to rule out other possible causes of kidney disease.
• Genetic testing may be considered in children when affected family members have an earlier age of onset of kidney disease and end-stage renal disease.
• For more information, see the National Society of Genetic Counselors
• It is important for parents to realize that normal serum creatinine levels in childhood do not rule out ADTKD
• For children in whom the serum creatinine is elevated, genetic testing can be considered to rule out other possible causes of kidney disease.
• Women with ADTKD-
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
By definition, autosomal dominant tubulointerstitial kidney disease –
## Risk to Family Members
Most individuals diagnosed with ADTKD
A proband with ADTKD
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of an individual with ADTKD
If a parent of the proband has the
Although the penetrance of ADTKD-
If the proband has a known
If the parents have not been tested for the
• A proband with ADTKD
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of an individual with ADTKD
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband has the
• Although the penetrance of ADTKD-
• If the proband has a known
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
In general, predictive testing of minors for adult-onset disorders is considered inappropriate unless such testing has a compelling medical benefit. Concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For parents desiring closer surveillance of their children, blood pressure can be monitored and serum creatinine can be tested on an annual basis.
It is important for parents to realize that normal serum creatinine levels in childhood do not rule out ADTKD
For children in whom the serum creatinine is elevated, genetic testing can be considered to rule out other possible causes of kidney disease.
Genetic testing may be considered in children when affected family members have an earlier age of onset of kidney disease and end-stage renal disease.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of ADTKD
Women with ADTKD-
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• In general, predictive testing of minors for adult-onset disorders is considered inappropriate unless such testing has a compelling medical benefit. Concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For parents desiring closer surveillance of their children, blood pressure can be monitored and serum creatinine can be tested on an annual basis.
• It is important for parents to realize that normal serum creatinine levels in childhood do not rule out ADTKD
• For children in whom the serum creatinine is elevated, genetic testing can be considered to rule out other possible causes of kidney disease.
• It is important for parents to realize that normal serum creatinine levels in childhood do not rule out ADTKD
• For children in whom the serum creatinine is elevated, genetic testing can be considered to rule out other possible causes of kidney disease.
• Genetic testing may be considered in children when affected family members have an earlier age of onset of kidney disease and end-stage renal disease.
• For more information, see the National Society of Genetic Counselors
• It is important for parents to realize that normal serum creatinine levels in childhood do not rule out ADTKD
• For children in whom the serum creatinine is elevated, genetic testing can be considered to rule out other possible causes of kidney disease.
• Women with ADTKD-
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Prenatal testing for the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors
## Resources
•
•
•
•
## Molecular Genetics
Autosomal Dominant Tubulointerstitial Kidney Disease -- MUC1: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Autosomal Dominant Tubulointerstitial Kidney Disease -- MUC1 (
Mucin-1, encoded by
Each VNTR is an oligonucleotide comprising 60 nucleotides (also referred to as a "60-mer"). Each 60-nucleotide repeat includes a sequence of seven cytosines (also called "a 7-cytosine tract").
The normal number of 60-mer VNTRs comprising a VNTR domain ranges from 20 to 125.
In most
The additional nucleotide can either be within the VNTR [
The CLIA-certified Broad Institute of Harvard and MIT laboratory performs targeted analysis for the common
Other published test methods for detecting variants not identified by standard genetic sequencing techniques include the following:
Long-read single-molecule real-time (SMRT) sequencing can identify the insertion of a cytosine within the seven-cytosine sequence as well as many (but not all) other disease-causing
Illumina-based sequencing of
Notable
Variants listed in the table have been provided by the authors.
VNTR = variable-number tandem repeat
Variant designation that does not conform to current naming conventions
• Each VNTR is an oligonucleotide comprising 60 nucleotides (also referred to as a "60-mer"). Each 60-nucleotide repeat includes a sequence of seven cytosines (also called "a 7-cytosine tract").
• The normal number of 60-mer VNTRs comprising a VNTR domain ranges from 20 to 125.
• Long-read single-molecule real-time (SMRT) sequencing can identify the insertion of a cytosine within the seven-cytosine sequence as well as many (but not all) other disease-causing
• Illumina-based sequencing of
## Molecular Pathogenesis
Mucin-1, encoded by
Each VNTR is an oligonucleotide comprising 60 nucleotides (also referred to as a "60-mer"). Each 60-nucleotide repeat includes a sequence of seven cytosines (also called "a 7-cytosine tract").
The normal number of 60-mer VNTRs comprising a VNTR domain ranges from 20 to 125.
In most
The additional nucleotide can either be within the VNTR [
The CLIA-certified Broad Institute of Harvard and MIT laboratory performs targeted analysis for the common
Other published test methods for detecting variants not identified by standard genetic sequencing techniques include the following:
Long-read single-molecule real-time (SMRT) sequencing can identify the insertion of a cytosine within the seven-cytosine sequence as well as many (but not all) other disease-causing
Illumina-based sequencing of
Notable
Variants listed in the table have been provided by the authors.
VNTR = variable-number tandem repeat
Variant designation that does not conform to current naming conventions
• Each VNTR is an oligonucleotide comprising 60 nucleotides (also referred to as a "60-mer"). Each 60-nucleotide repeat includes a sequence of seven cytosines (also called "a 7-cytosine tract").
• The normal number of 60-mer VNTRs comprising a VNTR domain ranges from 20 to 125.
• Long-read single-molecule real-time (SMRT) sequencing can identify the insertion of a cytosine within the seven-cytosine sequence as well as many (but not all) other disease-causing
• Illumina-based sequencing of
## Chapter Notes
Dr Stanislav Kmoch (
Dr Bleyer is also interested in hearing about families with ADTKD in whom no causative variant has been identified on molecular genetic testing of the genes known to cause ADTKD.
21 October 2021 (bp) Comprehensive update posted live
30 June 2016 (ha) Comprehensive update posted live
15 August 2013 (me) Review posted live
30 April 2013 (ab) Original submission
• 21 October 2021 (bp) Comprehensive update posted live
• 30 June 2016 (ha) Comprehensive update posted live
• 15 August 2013 (me) Review posted live
• 30 April 2013 (ab) Original submission
## Author Notes
Dr Stanislav Kmoch (
Dr Bleyer is also interested in hearing about families with ADTKD in whom no causative variant has been identified on molecular genetic testing of the genes known to cause ADTKD.
## Revision History
21 October 2021 (bp) Comprehensive update posted live
30 June 2016 (ha) Comprehensive update posted live
15 August 2013 (me) Review posted live
30 April 2013 (ab) Original submission
• 21 October 2021 (bp) Comprehensive update posted live
• 30 June 2016 (ha) Comprehensive update posted live
• 15 August 2013 (me) Review posted live
• 30 April 2013 (ab) Original submission
## References
## Literature Cited
Testing strategy for inherited kidney disease – 2021 update
Illustration of the mechanism by which the MUC1fs protein is encoded within a 60-mer block of repeated sequence that forms a
|
[
"AJ Bleyer, PS Hart, S Kmoch. Hereditary interstitial kidney disease.. Semin Nephrol. 2010;30:366-73",
"AJ Bleyer, K Kidd, E Johnson, V Robins, L Martin, A Taylor, AJ Pinder, I Bowline, V Frankova, M Živná, KB Taylor, N Kim, JJ Baek, H Hartmannová, K Hodaňová, P Vyleťal, M Votruba, S Kmoch. Quality of life in patients with autosomal dominant tubulointerstitial kidney disease.. Clin Nephrol. 2019;92:302-11",
"AJ Bleyer, MT Wolf, KO Kidd, M Zivna, S Kmoch. Autosomal dominant tubulointerstitial kidney disease: more than just HNF1β.. Pediatr Nephrol. 2022;37:933-46",
"TM Connor, S Hoer, A Mallett, DP Gale, A Gomez-Duran, V Posse, R Antrobus, P Moreno, M Sciacovelli, C Frezza, J Duff, NS Sheerin, JA Sayer, M Ashcroft, MS Wiesener, G Hudson, CM Gustafsson, PF Chinnery, PH Maxwell. Mutations in mitochondrial DNA causing tubulointerstitial kidney disease.. PloS Genet. 2017;13",
"S Cormican, C Kennedy, DM Connaughton, P O'Kelly, S Murray, M Živná, S Kmoch, NK Fennelly, KA Benson, ET Conlon, GL Cavalleri, C Foley, B Doyle, A Dorman, MA Little, P Lavin, K Kidd, AJ Bleyer, PJ Conlon. Renal transplant outcomes in patients with autosomal dominant tubulointerstitial kidney disease.. Clin Transplant. 2020;34",
"O Devuyst, E Olinger, S Weber, K-U Eckardt, S Kmoch, L Rampoldi, AJ Bleyer. Autosomal dominant tubulointerstitial kidney disease.. Nat Rev Dis Primers. 2019;5:60",
"M Dvela-Levitt, M Kost-Alimova, M Emani, E Kohnert, R Thompson, EH Sidhom, A Rivadeneira, N Sahakian, J Roignot, G Papagregoriou, MS Montesinos, AR Clark, D McKinney, J Gutierrez, M Roth, L Ronco, E Elonga, TA Carter, A Gnirke, M Melanson, K Hartland, N Wieder, JC Hsu, C Deltas, R Hughey, AJ Bleyer, S Kmoch, M Živná, V Barešova, S Kota, J Schlondorff, M Heiman, SL Alper, F Wagner, A Weins, TR Golub, ES Lander, A Greka. Small molecule targets TMED9 and promotes lysosomal degradation to reverse proteinopathy.. Cell. 2019;178:521-535.e23",
"KU Eckardt, SL Alper, C Antignac, AJ Bleyer, D Chauveau, K Dahan, C Deltas, A Hosking, S Kmoch, L Rampoldi, M Wiesener, MT Wolf, O Devuyst. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management--A KDIGO consensus report.. Kidney Int. 2015;88:676-83",
"M Hoeltzenbein, K Stieler, M Panse, E Wacker, C Schaefer. Allopurinol use during pregnancy - outcome of 31 prospectively ascertained cases and a phenotype possibly indicative for teratogenicity.. PLoS One. 2013;8",
"K Kidd, P Vylet'al, C Schaeffer, E Olinger, M Živná, K Hodaňová, V Robins, E Johnson, A Taylor, L Martin, C Izzi, SC Jorge, J Calado, RJ Torres, K Lhotta, D Steubl, DP Gale, C Gast, E Gombos, HC Ainsworth, YM Chen, JR Almeida, CF de Souza, C Silveira, R Raposeiro, N Weller, PJ Conlon, SL Murray, KA Benson, GL Cavalleri, M Votruba, A Vrbacká, A Amoroso, D Gianchino, G Caridi, GM Ghiggeri, J Divers, F Scolari, O Devuyst, L Rampoldi, S Kmoch, AJ Bleyer. Genetic and clinical predictors of age of ESKD in individuals with autosomal dominant tubulointerstitial kidney disease due to UMOD mutations.. Kidney Int Rep. 2020;5:1472-85",
"A Kirby, A Gnirke, DB Jaffe, V Barešová, N Pochet, B Blumenstiel, C Ye, D Aird, C Stevens, JT Robinson, MN Cabili, I Gat-Viks, E Kelliher, R Daza, M DeFelice, H Hůlková, J Sovová, P Vylet'al, C Antignac, M Guttman, RE Handsaker, D Perrin, S Steelman, S Sigurdsson, SJ Scheinman, C Sougnez, K Cibulskis, M Parkin, T Green, E Rossin, MC Zody, RJ Xavier, MR Pollak, SL Alper, K Lindblad-Toh, S Gabriel, PS Hart, A Regev, C Nusbaum, S Kmoch, AJ Bleyer, ES Lander, MJ Daly. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing.. Nat Genet. 2013;45:299-303",
"KX Knaup, T Hackenbeck, B Popp, J Stoeckert, A Wenzel, M Büttner-Herold, F Pfister, M Schueler, D Seven, AM May, J Halbritter, HJ Gröne, A Reis, BB Beck, K Amann, AB Ekici, MS Wiesener. Biallelic expression of mucin-1 in autosomal dominant tubulointerstitial kidney disease: Implications for nongenetic disease recognition.. J Am Soc Nephrol. 2018;29:2298-309",
"M Kozenko, D Grynspan, T Oluyomi-Obi, D Sitar, AM Elliott, BN Chodirker. Potential teratogenic effects of allopurinol: a case report.. Am J Med Genet A. 2011;155A:2247-52",
"E Olinger, P Hofmann, K Kidd, I Dufour, H Belge, C Schaeffer, A Kipp, O Bonny, C Deltas, N Demoulin, T Fehr, DG Fuster, DP Gale, E Goffin, K Hodaňová, U Huynh-Do, A Kistler, J Morelle, G Papagregoriou, Y Pirson, R Sandford, JA Sayer, R Torra, C Venzin, R Venzin, B Vogt, M Živná, A Greka, K Dahan, L Rampoldi, S Kmoch, AJ Bleyer, O Devuyst. Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1.. Kidney Int. 2020;98:717-31",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"S Staubach, A Wenzel, BB Beck, MM Rinschen, S Müller, FG Hanisch. Autosomal tubulointerstitial kidney disease-MUC1 type: differential proteomics suggests that mutated MUC1 (insC) affects vesicular transport in renal epithelial cells.. Proteomics. 2018;18",
"C Stavrou, M Koptides, C Tombazos, E Psara, C Patsias, I Zouvani, K Kyriacou, F Hildebrandt, T Christofides, A Pierides, CC Deltas. Autosomal-dominant medullary cystic kidney disease type 1: clinical and molecular findings in six large Cypriot families.. Kidney Int. 2002;62:1385-94",
"GQ Wang, HL Rui, HR Dong, LJ Sun, M Yang, YY Wang, N Ye, ZR Zhao, XJ Liu, XY Xu, YP Chen, H Cheng. SMRT sequencing revealed to be an effective method for ADTKD-MUC1 diagnosis through follow-up analysis of a Chinese family.. Sci Rep. 2020;10:8616",
"A Wenzel, J Altmueller, AB Ekici, B Popp, K Stueber, H Thiele, A Pannes, S Staubach, E Salido, P Nuernberg, R Reinhardt, A Reis, P Rump, FG Hanisch, MTF Wolf, M Wiesener, B Huettel, BB Beck. Single molecule real time sequencing in ADTKD-MUC1 allos complete assembly of the VNTR and exact positioning of causative mutations.. Sci Rep. 2018;8:4170",
"S Yamamoto, JY Kaimori, T Yoshimura, T Namba, A Imai, K Kobayashi, R Imamura, N Ichimaru, K Kato, A Nakaya, S Takahara, Y Isaka. Analysis of an ADTKD family with a novel frameshift mutation in MUC1 reveals characteristic features of mutant MUC1 protein.. Nephrol Dial Transplant. 2017;32:2010-7",
"M Živná, H Hůlková, M Matignon, K Hodanová, P Vylet'al, M Kalbácová, V Baresová, J Sikora, H Blazková, J Zivný, R Ivánek, V Stránecký, J Sovová, K Claes, E Lerut, JP Fryns, PS Hart, TC Hart, JN Adams, A Pawtowski, M Clemessy, JM Gasc, MC Gübler, C Antignac, M Elleder, K Kapp, P Grimbert, AJ Bleyer, S Kmoch. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure.. Am J Hum Genet. 2009;85:204-13",
"M Živná, K Kidd, A Přistoupilová, V Barešová, M DeFelice, B Blumenstiel, M Harden, P Conlon, P Lavin, DM Connaughton, H Hartmannová, K Hodaňová, V Stránecký, A Vrbacká, P Vyleťal, J Živný, M Votruba, J Sovová, H Hůlková, V Robins, R Perry, A Wenzel, BB Beck, T Seeman, O Viklický, S Rajnochová-Bloudíčková, G Papagregoriou, CC Deltas, SL Alper, A Greka, AJ Bleyer, S Kmoch. Noninvasive immunohistochemical diagnosis and novel MUC1 mutations causing autosomal dominant tubulointerstitial kidney disease.. J Am Soc Nephrol. 2018;29:2418-31"
] |
15/8/2013
|
21/10/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mckd2
|
mckd2
|
[
"ADTKD-UMOD",
"Uromodulin Kidney Disease",
"ADTKD-UMOD",
"Uromodulin Kidney Disease",
"Uromodulin",
"UMOD",
"Autosomal Dominant Tubulointerstitial Kidney Disease – UMOD"
] |
Autosomal Dominant Tubulointerstitial Kidney Disease –
|
Anthony J Bleyer, Kendrah Kidd, Martina Živná, Stanislav Kmoch
|
Summary Autosomal dominant tubulointerstitial kidney disease – The diagnosis of ADTKD- It is appropriate to clarify the genetic status of apparently asymptomatic at-risk adult relatives in order to identify those with the familial Any relative who is a potential kidney donor should be tested for the familial ADTKD-
|
## Diagnosis
Consensus clinical diagnostic criteria for autosomal dominant tubulointerstitial kidney disease –
ADTKD-
Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid >1 SD of the normal value for age and sex. It is important to use age-related norms for serum urate [
Serum Uric Acid Concentration in Individuals with Normal Renal Function
The diagnosis of ADTKD-
Note: Identification of a heterozygous
Molecular genetic testing approaches can include
Note: Single-gene testing of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in ADTKD-
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No exon or whole-gene deletions or duplications have been reported as a cause of ADTKD-
## Suggestive Findings
ADTKD-
Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid >1 SD of the normal value for age and sex. It is important to use age-related norms for serum urate [
Serum Uric Acid Concentration in Individuals with Normal Renal Function
## Establishing the Diagnosis
The diagnosis of ADTKD-
Note: Identification of a heterozygous
Molecular genetic testing approaches can include
Note: Single-gene testing of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in ADTKD-
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No exon or whole-gene deletions or duplications have been reported as a cause of ADTKD-
## Option 1
Note: Single-gene testing of
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in ADTKD-
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No exon or whole-gene deletions or duplications have been reported as a cause of ADTKD-
## Clinical Characteristics
Autosomal dominant tubulointerstitial kidney disease –
Most commonly, the presenting sign is elevated serum creatinine in an individual with a family history of kidney disease. A mild elevation in serum creatinine may occur in childhood and is usually incidentally noted on laboratory testing for other reasons or when screening children of an affected parent.
Kidney disease usually progresses to ESRD between the third and seventh decades of life [
Hyperuricemia occurs in the majority of individuals with this disorder, though there are exceptions [
Fifty-five percent of individuals with ADTKD-
Onset of gout is acute with severe tenderness and redness of the affected joint –characteristically the big toe, other areas of the feet, the ankles, and/or the knees. As kidney function worsens, gout worsens, and the frequency of attacks increases. Gout may occur in children and may be precipitated by a sporting event. As gout is uncommon in childhood, this condition may elude diagnosis. Without treatment, tophi (large subcutaneous depositions of uric acid) and crippling arthritis can develop.
Note: The following information is provided in the event that some affected individuals (or their relatives) may have undergone kidney biopsy prior to consideration of ADTKD-
Histologic examination reveals chronic interstitial fibrosis, with focal tubular atrophy and interstitial fibrosis, occasionally accompanied by lymphocytic infiltration. Accumulation of mutated uromodulin may be detected by PAS staining as polymorphic unstructured materials [
The pathogenic variant
Penetrance appears to be complete, but age related. Some individuals (especially females) may not develop ESRD until the sixth or seventh decade.
According to the 2015 nomenclature [
Autosomal dominant inheritance
Slowly progressive chronic tubulointerstitial kidney disease resulting in ESRD in the third through seventh decade of life
Urinalysis revealing a bland urinary sediment (i.e., little blood or protein)
Renal ultrasound examination that is normal early in the disease course [
Terms previously used to refer to ADTKD-
Familial juvenile hyperuricemic nephropathy 1
Medullary cystic kidney disease 2 (MCKD2)
ADTKD-
• Autosomal dominant inheritance
• Slowly progressive chronic tubulointerstitial kidney disease resulting in ESRD in the third through seventh decade of life
• Urinalysis revealing a bland urinary sediment (i.e., little blood or protein)
• Renal ultrasound examination that is normal early in the disease course [
• Familial juvenile hyperuricemic nephropathy 1
• Medullary cystic kidney disease 2 (MCKD2)
## Clinical Description
Autosomal dominant tubulointerstitial kidney disease –
Most commonly, the presenting sign is elevated serum creatinine in an individual with a family history of kidney disease. A mild elevation in serum creatinine may occur in childhood and is usually incidentally noted on laboratory testing for other reasons or when screening children of an affected parent.
Kidney disease usually progresses to ESRD between the third and seventh decades of life [
Hyperuricemia occurs in the majority of individuals with this disorder, though there are exceptions [
Fifty-five percent of individuals with ADTKD-
Onset of gout is acute with severe tenderness and redness of the affected joint –characteristically the big toe, other areas of the feet, the ankles, and/or the knees. As kidney function worsens, gout worsens, and the frequency of attacks increases. Gout may occur in children and may be precipitated by a sporting event. As gout is uncommon in childhood, this condition may elude diagnosis. Without treatment, tophi (large subcutaneous depositions of uric acid) and crippling arthritis can develop.
Note: The following information is provided in the event that some affected individuals (or their relatives) may have undergone kidney biopsy prior to consideration of ADTKD-
Histologic examination reveals chronic interstitial fibrosis, with focal tubular atrophy and interstitial fibrosis, occasionally accompanied by lymphocytic infiltration. Accumulation of mutated uromodulin may be detected by PAS staining as polymorphic unstructured materials [
## Slowly Progressive Chronic Tubulointerstitial Kidney Disease
Most commonly, the presenting sign is elevated serum creatinine in an individual with a family history of kidney disease. A mild elevation in serum creatinine may occur in childhood and is usually incidentally noted on laboratory testing for other reasons or when screening children of an affected parent.
Kidney disease usually progresses to ESRD between the third and seventh decades of life [
## Hyperuricemia and Gout
Hyperuricemia occurs in the majority of individuals with this disorder, though there are exceptions [
Fifty-five percent of individuals with ADTKD-
Onset of gout is acute with severe tenderness and redness of the affected joint –characteristically the big toe, other areas of the feet, the ankles, and/or the knees. As kidney function worsens, gout worsens, and the frequency of attacks increases. Gout may occur in children and may be precipitated by a sporting event. As gout is uncommon in childhood, this condition may elude diagnosis. Without treatment, tophi (large subcutaneous depositions of uric acid) and crippling arthritis can develop.
## Kidney Biopsy
Note: The following information is provided in the event that some affected individuals (or their relatives) may have undergone kidney biopsy prior to consideration of ADTKD-
Histologic examination reveals chronic interstitial fibrosis, with focal tubular atrophy and interstitial fibrosis, occasionally accompanied by lymphocytic infiltration. Accumulation of mutated uromodulin may be detected by PAS staining as polymorphic unstructured materials [
## Genotype-Phenotype Correlations
The pathogenic variant
## Penetrance
Penetrance appears to be complete, but age related. Some individuals (especially females) may not develop ESRD until the sixth or seventh decade.
## Nomenclature
According to the 2015 nomenclature [
Autosomal dominant inheritance
Slowly progressive chronic tubulointerstitial kidney disease resulting in ESRD in the third through seventh decade of life
Urinalysis revealing a bland urinary sediment (i.e., little blood or protein)
Renal ultrasound examination that is normal early in the disease course [
Terms previously used to refer to ADTKD-
Familial juvenile hyperuricemic nephropathy 1
Medullary cystic kidney disease 2 (MCKD2)
• Autosomal dominant inheritance
• Slowly progressive chronic tubulointerstitial kidney disease resulting in ESRD in the third through seventh decade of life
• Urinalysis revealing a bland urinary sediment (i.e., little blood or protein)
• Renal ultrasound examination that is normal early in the disease course [
• Familial juvenile hyperuricemic nephropathy 1
• Medullary cystic kidney disease 2 (MCKD2)
## Prevalence
ADTKD-
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Monogenic Kidney Diseases in the Differential Diagnosis of ADTKD-
α-Gal = α-galactosidase; AD = autosomal dominant; AR = autosomal recessive; CAKUT = congenital anomalies of the kidneys and urinary tract; CKD = chronic kidney disease; ESRD = end-stage renal disease; IUGR = intrauterine growth restriction; Mat = maternal; MODY = maturity-onset diabetes of the young; MOI = mode of inheritance; TKD = tubulointerstitial kidney disease; XL = X-linked
Listed genes represent the most common genetic causes of isolated nephronophthisis. Other genes known to be associated with nephronophthisis are
Bland refers to urinary sediment with little blood or protein.
Males with >1% α-Gal A activity have a cardiac or renal variant phenotype. Rarely, heterozygous carrier females may have symptoms as severe as those observed in males with the classic phenotype.
## Management
Consensus management guidelines for autosomal dominant tubulointerstitial kidney disease,
To establish the extent of disease and needs in an individual diagnosed with ADTKD-
Recommended Evaluations Following Initial Diagnosis in Individuals with ADTKD-
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Care by a nephrologist is recommended.
Prevention of gout attacks with allopurinol should be considered in individuals with gout. With allopurinol treatment, serum uric acid concentration returns to normal and gout attacks can be entirely prevented. Lifelong therapy with allopurinol is required for future gout prevention.
In individuals with allergies or intolerance to allopurinol, febuxostat may be considered; however, no data on the use of this medication in ADTKD-
Acute gout typically responds well to prednisone, short-term nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine. One should avoid NSAIDs in the setting of CKD Stage 3 or greater.
Referral to a nephrologist is indicated to monitor kidney function, evaluate for manifestations of CKD, and prepare for renal replacement therapy when end-stage renal disease (ESRD) occurs.
Renal replacement therapies such as hemodialysis and peritoneal dialysis replace kidney function but are associated with potential complications.
Individuals with ADTKD-
There is insufficient evidence that allopurinol slows the progression of kidney disease. Some authors have suggested that it may slow progression, but these studies were small, not randomized, and with short-term follow-up. In addition, genetic diagnoses were not available at the time of these studies [
Appropriate surveillance includes the following:
Measurement of serum creatinine concentration at least annually in affected individuals, and more frequently in those with severe disease
Measurement of serum uric acid concentration at least annually
Avoid use of the following:
Nonsteroidal anti-inflammatory drugs. NSAIDs are generally discouraged except for short-term treatment of gout or similar painful conditions in early CKD (prior to Stage 3 CKD). Chronic daily use should be avoided.
Drugs known to be nephrotoxic
The low sodium diet, which is typically prescribed in the treatment of CKD
Volume depletion, dehydration, and physical exertion under extreme conditions (e.g., in hot weather), as these may worsen hyperuricemia, leading to more frequent attacks of gout
If performed, testing should only be done after a full discussion with the child and after obtaining the child's assent and the parents'/guardians' consent.
* Chronic kidney disease, one of the primary manifestations of this disorder, is often asymptomatic.
See
Pregnancy in women with ADTKD-
Women of childbearing age who are taking medications such as an angiotensin-converting enzyme (ACE) inhibitor or allopurinol should discuss their medication regimen with their physician prior to conception.
This finding is concerning because the mechanism of action of allopurinol (inhibiting purine degradation) is similar to the mechanism of action of mycophenolate mofetil (inhibition of
See
Search
• Measurement of serum creatinine concentration at least annually in affected individuals, and more frequently in those with severe disease
• Measurement of serum uric acid concentration at least annually
• Nonsteroidal anti-inflammatory drugs. NSAIDs are generally discouraged except for short-term treatment of gout or similar painful conditions in early CKD (prior to Stage 3 CKD). Chronic daily use should be avoided.
• Drugs known to be nephrotoxic
• The low sodium diet, which is typically prescribed in the treatment of CKD
• Volume depletion, dehydration, and physical exertion under extreme conditions (e.g., in hot weather), as these may worsen hyperuricemia, leading to more frequent attacks of gout
• If performed, testing should only be done after a full discussion with the child and after obtaining the child's assent and the parents'/guardians' consent.
• * Chronic kidney disease, one of the primary manifestations of this disorder, is often asymptomatic.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with ADTKD-
Recommended Evaluations Following Initial Diagnosis in Individuals with ADTKD-
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
## Treatment of Manifestations
Care by a nephrologist is recommended.
Prevention of gout attacks with allopurinol should be considered in individuals with gout. With allopurinol treatment, serum uric acid concentration returns to normal and gout attacks can be entirely prevented. Lifelong therapy with allopurinol is required for future gout prevention.
In individuals with allergies or intolerance to allopurinol, febuxostat may be considered; however, no data on the use of this medication in ADTKD-
Acute gout typically responds well to prednisone, short-term nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine. One should avoid NSAIDs in the setting of CKD Stage 3 or greater.
Referral to a nephrologist is indicated to monitor kidney function, evaluate for manifestations of CKD, and prepare for renal replacement therapy when end-stage renal disease (ESRD) occurs.
Renal replacement therapies such as hemodialysis and peritoneal dialysis replace kidney function but are associated with potential complications.
Individuals with ADTKD-
There is insufficient evidence that allopurinol slows the progression of kidney disease. Some authors have suggested that it may slow progression, but these studies were small, not randomized, and with short-term follow-up. In addition, genetic diagnoses were not available at the time of these studies [
## Hyperuricemia/Gout
Prevention of gout attacks with allopurinol should be considered in individuals with gout. With allopurinol treatment, serum uric acid concentration returns to normal and gout attacks can be entirely prevented. Lifelong therapy with allopurinol is required for future gout prevention.
In individuals with allergies or intolerance to allopurinol, febuxostat may be considered; however, no data on the use of this medication in ADTKD-
Acute gout typically responds well to prednisone, short-term nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine. One should avoid NSAIDs in the setting of CKD Stage 3 or greater.
## Kidney Disease
Referral to a nephrologist is indicated to monitor kidney function, evaluate for manifestations of CKD, and prepare for renal replacement therapy when end-stage renal disease (ESRD) occurs.
Renal replacement therapies such as hemodialysis and peritoneal dialysis replace kidney function but are associated with potential complications.
Individuals with ADTKD-
There is insufficient evidence that allopurinol slows the progression of kidney disease. Some authors have suggested that it may slow progression, but these studies were small, not randomized, and with short-term follow-up. In addition, genetic diagnoses were not available at the time of these studies [
## Surveillance
Appropriate surveillance includes the following:
Measurement of serum creatinine concentration at least annually in affected individuals, and more frequently in those with severe disease
Measurement of serum uric acid concentration at least annually
• Measurement of serum creatinine concentration at least annually in affected individuals, and more frequently in those with severe disease
• Measurement of serum uric acid concentration at least annually
## Agents/Circumstances to Avoid
Avoid use of the following:
Nonsteroidal anti-inflammatory drugs. NSAIDs are generally discouraged except for short-term treatment of gout or similar painful conditions in early CKD (prior to Stage 3 CKD). Chronic daily use should be avoided.
Drugs known to be nephrotoxic
The low sodium diet, which is typically prescribed in the treatment of CKD
Volume depletion, dehydration, and physical exertion under extreme conditions (e.g., in hot weather), as these may worsen hyperuricemia, leading to more frequent attacks of gout
• Nonsteroidal anti-inflammatory drugs. NSAIDs are generally discouraged except for short-term treatment of gout or similar painful conditions in early CKD (prior to Stage 3 CKD). Chronic daily use should be avoided.
• Drugs known to be nephrotoxic
• The low sodium diet, which is typically prescribed in the treatment of CKD
• Volume depletion, dehydration, and physical exertion under extreme conditions (e.g., in hot weather), as these may worsen hyperuricemia, leading to more frequent attacks of gout
## Evaluation of Relatives at Risk
If performed, testing should only be done after a full discussion with the child and after obtaining the child's assent and the parents'/guardians' consent.
* Chronic kidney disease, one of the primary manifestations of this disorder, is often asymptomatic.
See
• If performed, testing should only be done after a full discussion with the child and after obtaining the child's assent and the parents'/guardians' consent.
• * Chronic kidney disease, one of the primary manifestations of this disorder, is often asymptomatic.
## Pregnancy Management
Pregnancy in women with ADTKD-
Women of childbearing age who are taking medications such as an angiotensin-converting enzyme (ACE) inhibitor or allopurinol should discuss their medication regimen with their physician prior to conception.
This finding is concerning because the mechanism of action of allopurinol (inhibiting purine degradation) is similar to the mechanism of action of mycophenolate mofetil (inhibition of
See
## Therapies Under Investigation
Search
## Genetic Counseling
By definition, autosomal dominant tubulointerstitial kidney disease –
Most individuals diagnosed with ADTKD-
A proband with ADTKD-
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
If a parent of the proband has the
The rate of chronic kidney disease progression and age of onset of end-stage renal disease (ESRD) can vary significantly between heterozygous sibs and does not correlate well with the age of ESRD in the affected parent.
If the proband has a known
If the parents have not been tested for the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with ADTKD-
• A proband with ADTKD-
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband has the
• The rate of chronic kidney disease progression and age of onset of end-stage renal disease (ESRD) can vary significantly between heterozygous sibs and does not correlate well with the age of ESRD in the affected parent.
• If the proband has a known
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
By definition, autosomal dominant tubulointerstitial kidney disease –
## Risk to Family Members
Most individuals diagnosed with ADTKD-
A proband with ADTKD-
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
If a parent of the proband has the
The rate of chronic kidney disease progression and age of onset of end-stage renal disease (ESRD) can vary significantly between heterozygous sibs and does not correlate well with the age of ESRD in the affected parent.
If the proband has a known
If the parents have not been tested for the
• Most individuals diagnosed with ADTKD-
• A proband with ADTKD-
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband has the
• The rate of chronic kidney disease progression and age of onset of end-stage renal disease (ESRD) can vary significantly between heterozygous sibs and does not correlate well with the age of ESRD in the affected parent.
• If the proband has a known
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
## Molecular Genetics
Autosomal Dominant Tubulointerstitial Kidney Disease -- UMOD: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Autosomal Dominant Tubulointerstitial Kidney Disease -- UMOD (
Autosomal dominant tubulointerstitial kidney disease –
Pathogenic variants in
For interpretation of variants of uncertain significance:
An updated list of more than 200 clinically significant
Variants that affect cysteine residues are highly likely to be pathogenic.
Other testing can include in vitro testing [
Notable
ESRD = end-stage renal disease
Variants listed in the table have been provided by the authors.
Comments shown in ( )s are possible associations that require further evidence.
• An updated list of more than 200 clinically significant
• Variants that affect cysteine residues are highly likely to be pathogenic.
• Other testing can include in vitro testing [
## Molecular Pathogenesis
Autosomal dominant tubulointerstitial kidney disease –
Pathogenic variants in
For interpretation of variants of uncertain significance:
An updated list of more than 200 clinically significant
Variants that affect cysteine residues are highly likely to be pathogenic.
Other testing can include in vitro testing [
Notable
ESRD = end-stage renal disease
Variants listed in the table have been provided by the authors.
Comments shown in ( )s are possible associations that require further evidence.
• An updated list of more than 200 clinically significant
• Variants that affect cysteine residues are highly likely to be pathogenic.
• Other testing can include in vitro testing [
## Chapter Notes
Dr Bleyer pursues clinical and genetic research of autosomal dominant tubulointerstitial kidney disease (ADTKD).
Regarding ADTKD-
He and his colleagues (who have diagnosed more than 200 families with ADTKD-
He is developing a registry of individuals with benign and pathogenic
In addition:
He is most interested in hearing about families with ADTKD in whom no causative variant has been identified on molecular genetic testing of the genes known to cause ADTKD.
Single-gene testing for
Please contact Dr Bleyer ([email protected]) with any questions about ADTKD.
Related website:
Anthony J Bleyer, MD, MS (2007-present)Karn Gupta, MD; Wake Forest University School of Medicine (2007-2011)P Suzanne Hart, PhD; National Human Genome Research Institute (2011-2021)Kendrah Kidd, MS (2021-present)Stanislav Kmoch, PhD (2016-present)Martina Živná, PhD (2021-present)
23 December 2021 (sw) Revision: nomenclature corrections (
8 April 2021 (bp) Comprehensive update posted live
30 June 2016 (ha) Comprehensive update posted live
12 September 2013 (me) Comprehensive update posted live
15 March 2011 (me) Comprehensive update posted live
26 September 2007 (cd) Revision: prenatal diagnosis available
12 January 2007 (me) Review posted live
3 August 2006 (ajb) Original submission
• He and his colleagues (who have diagnosed more than 200 families with ADTKD-
• He is developing a registry of individuals with benign and pathogenic
• He is most interested in hearing about families with ADTKD in whom no causative variant has been identified on molecular genetic testing of the genes known to cause ADTKD.
• Single-gene testing for
• 23 December 2021 (sw) Revision: nomenclature corrections (
• 8 April 2021 (bp) Comprehensive update posted live
• 30 June 2016 (ha) Comprehensive update posted live
• 12 September 2013 (me) Comprehensive update posted live
• 15 March 2011 (me) Comprehensive update posted live
• 26 September 2007 (cd) Revision: prenatal diagnosis available
• 12 January 2007 (me) Review posted live
• 3 August 2006 (ajb) Original submission
## Author Notes
Dr Bleyer pursues clinical and genetic research of autosomal dominant tubulointerstitial kidney disease (ADTKD).
Regarding ADTKD-
He and his colleagues (who have diagnosed more than 200 families with ADTKD-
He is developing a registry of individuals with benign and pathogenic
In addition:
He is most interested in hearing about families with ADTKD in whom no causative variant has been identified on molecular genetic testing of the genes known to cause ADTKD.
Single-gene testing for
Please contact Dr Bleyer ([email protected]) with any questions about ADTKD.
Related website:
• He and his colleagues (who have diagnosed more than 200 families with ADTKD-
• He is developing a registry of individuals with benign and pathogenic
• He is most interested in hearing about families with ADTKD in whom no causative variant has been identified on molecular genetic testing of the genes known to cause ADTKD.
• Single-gene testing for
## Author History
Anthony J Bleyer, MD, MS (2007-present)Karn Gupta, MD; Wake Forest University School of Medicine (2007-2011)P Suzanne Hart, PhD; National Human Genome Research Institute (2011-2021)Kendrah Kidd, MS (2021-present)Stanislav Kmoch, PhD (2016-present)Martina Živná, PhD (2021-present)
## Revision History
23 December 2021 (sw) Revision: nomenclature corrections (
8 April 2021 (bp) Comprehensive update posted live
30 June 2016 (ha) Comprehensive update posted live
12 September 2013 (me) Comprehensive update posted live
15 March 2011 (me) Comprehensive update posted live
26 September 2007 (cd) Revision: prenatal diagnosis available
12 January 2007 (me) Review posted live
3 August 2006 (ajb) Original submission
• 23 December 2021 (sw) Revision: nomenclature corrections (
• 8 April 2021 (bp) Comprehensive update posted live
• 30 June 2016 (ha) Comprehensive update posted live
• 12 September 2013 (me) Comprehensive update posted live
• 15 March 2011 (me) Comprehensive update posted live
• 26 September 2007 (cd) Revision: prenatal diagnosis available
• 12 January 2007 (me) Review posted live
• 3 August 2006 (ajb) Original submission
## References
## Published Guidelines / Consensus Statements
## Literature Cited
Testing strategy for inherited kidney disease – 2015 update
|
[] |
12/1/2007
|
8/4/2021
|
23/12/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mcleod
|
mcleod
|
[
"Endoplasmic reticulum membrane adapter protein XK",
"XK",
"McLeod Neuroacanthocytosis Syndrome"
] |
McLeod Neuroacanthocytosis Syndrome
|
Hans H Jung, Adrian Danek, Ruth H Walker, Beat M Frey, Kevin Peikert
|
Summary McLeod neuroacanthocytosis syndrome (designated as MLS throughout this review) is a multisystem disorder with central nervous system (CNS), neuromuscular, cardiovascular, and hematologic manifestations in males: CNS manifestations are a neurodegenerative basal ganglia disease including movement disorders, cognitive alterations, and psychiatric symptoms. Neuromuscular manifestations include a (mostly subclinical) sensorimotor axonopathy and muscle weakness or atrophy of different degrees. Cardiac manifestations include dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia. Hematologically, MLS is defined as a specific blood group phenotype (named after the first proband, Hugh McLeod) that results from absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens. The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis. Alloantibodies in the Kell and Kx blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in affected male newborns of Kell-negative mothers. Females heterozygous for The diagnosis of MLS is established in a male proband with: suggestive clinical, laboratory, and neuroimaging studies; a family history consistent with X-linked inheritance; and either a hemizygous MLS is inherited in an X-linked manner. If the mother of an affected male is heterozygous, the chance of transmitting the
|
## Diagnosis
The diagnosis of McLeod neuroacanthocytosis syndrome (MLS)
Progressive chorea syndrome, which also can be part of a clinical triad of movement disorders, cognitive alterations, and psychiatric symptoms ("Huntington-like syndrome")
Seizures, mostly generalized
Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
Brain MRI in two males demonstrated extended T
Sensorimotor axonopathy
Neurogenic muscle atrophy, including unexplained elevation of creatine phosphokinase
Myopathy
Muscle enzymes. All affected males examined to date have had elevated serum creatine phosphokinase (CK) concentration values up to 4,000 U/L [
Electromyography may demonstrate neurogenic and myopathic changes [
Nerve conduction studies may demonstrate axonal damage of variable degree [
Muscle CT and MRI may reveal a selective pattern of fatty degeneration of lower-leg muscles preferentially affecting the vastus lateralis, biceps femoris, and adductor magnus muscles, and sparing the gracilis, semitendinosus, and lateral head of the gastrocnemius muscle [
Echocardiography and cardiac MRI may demonstrate congestive cardiomyopathy or dilated cardiomyopathy with reduced left ventricular ejection fraction [
Electrocardiography may demonstrate atrial fibrillation or critical ventricular tachycardia [
Cardiac MRI may demonstrate focal late gadolinium enhancement [
Myocardial biopsy and cardiac MRI T
McLeod blood group phenotype is established by showing negativity for Kx erythrocyte antigen and weakened or absent expression of Kell antigens, thus differentiating the phenotype from individuals with
Accurate determination of RBC acanthocytosis is challenging. The recommendation to "send at least three blood smears" preferably of wet preparations of peripheral blood to an experienced laboratory [
The best procedure requires diluting whole blood samples 1:1 with heparinized saline followed by incubation for 60 minutes at room temperature; wet cell monolayers are then prepared for phase-contrast microscopy. When all RBCs with spicules (corresponding to type AI/AII acanthocytes and echinocytes) are counted, normal controls show fewer than 6.3% acanthocytes/echinocytes [
Confirmation of erythrocyte morphology by scanning electron microscopy or confocal microscopy with 3D-rendering [
Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
Family history is consistent with
A hemizygous pathogenic variant involving
A hemizygous deletion of Xp21.1 involving
Note: Deletions involving
Note: Based on published cases, heterozygous females do not have RBC acanthocytosis or elevated CK serum levels.
Molecular genetic testing approaches can include a combination of
There are three options for establishing the diagnosis of McLeod neuroacanthocytosis syndrome:
Option 1 is the determination of the McLeod blood group phenotype followed by CMA for individuals with findings suggestive of a contiguous-gene deletion.
Note: Alternatively,
Option 2 is the determination of the McLeod blood group phenotype followed by single-gene testing for those in whom McLeod blood group phenotyping supports the diagnosis.
Note: Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected in an affected female using these methods and may require CMA (see
Option 3 is for symptomatic individuals in whom the diagnosis of McLeod neuroacanthocytosis syndrome has not been considered.
When the diagnosis of McLeod neuroacanthocytosis syndrome has not been considered in a symptomatic individual, the options are a multigene panel or comprehensive genomic testing:
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in McLeod Neuroacanthocytosis Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
A current list of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (see
Note that most reported deletions and duplications are large enough to likely be detected by CMA; however, gene-targeted deletion/duplication analysis does have a higher resolution.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Progressive chorea syndrome, which also can be part of a clinical triad of movement disorders, cognitive alterations, and psychiatric symptoms ("Huntington-like syndrome")
• Seizures, mostly generalized
•
• Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
• Brain MRI in two males demonstrated extended T
• Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
• Brain MRI in two males demonstrated extended T
• Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
• Brain MRI in two males demonstrated extended T
• Sensorimotor axonopathy
• Neurogenic muscle atrophy, including unexplained elevation of creatine phosphokinase
• Myopathy
• Muscle enzymes. All affected males examined to date have had elevated serum creatine phosphokinase (CK) concentration values up to 4,000 U/L [
• Electromyography may demonstrate neurogenic and myopathic changes [
• Nerve conduction studies may demonstrate axonal damage of variable degree [
• Muscle CT and MRI may reveal a selective pattern of fatty degeneration of lower-leg muscles preferentially affecting the vastus lateralis, biceps femoris, and adductor magnus muscles, and sparing the gracilis, semitendinosus, and lateral head of the gastrocnemius muscle [
• Echocardiography and cardiac MRI may demonstrate congestive cardiomyopathy or dilated cardiomyopathy with reduced left ventricular ejection fraction [
• Electrocardiography may demonstrate atrial fibrillation or critical ventricular tachycardia [
• Cardiac MRI may demonstrate focal late gadolinium enhancement [
• Myocardial biopsy and cardiac MRI T
• McLeod blood group phenotype is established by showing negativity for Kx erythrocyte antigen and weakened or absent expression of Kell antigens, thus differentiating the phenotype from individuals with
• Accurate determination of RBC acanthocytosis is challenging. The recommendation to "send at least three blood smears" preferably of wet preparations of peripheral blood to an experienced laboratory [
• The best procedure requires diluting whole blood samples 1:1 with heparinized saline followed by incubation for 60 minutes at room temperature; wet cell monolayers are then prepared for phase-contrast microscopy. When all RBCs with spicules (corresponding to type AI/AII acanthocytes and echinocytes) are counted, normal controls show fewer than 6.3% acanthocytes/echinocytes [
• Confirmation of erythrocyte morphology by scanning electron microscopy or confocal microscopy with 3D-rendering [
• Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
• Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
• Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
• Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
• Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
• Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
• Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
• Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
• Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
• A hemizygous pathogenic variant involving
• A hemizygous deletion of Xp21.1 involving
• Note: Deletions involving
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
The diagnosis of McLeod neuroacanthocytosis syndrome (MLS)
Progressive chorea syndrome, which also can be part of a clinical triad of movement disorders, cognitive alterations, and psychiatric symptoms ("Huntington-like syndrome")
Seizures, mostly generalized
Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
Brain MRI in two males demonstrated extended T
Sensorimotor axonopathy
Neurogenic muscle atrophy, including unexplained elevation of creatine phosphokinase
Myopathy
Muscle enzymes. All affected males examined to date have had elevated serum creatine phosphokinase (CK) concentration values up to 4,000 U/L [
Electromyography may demonstrate neurogenic and myopathic changes [
Nerve conduction studies may demonstrate axonal damage of variable degree [
Muscle CT and MRI may reveal a selective pattern of fatty degeneration of lower-leg muscles preferentially affecting the vastus lateralis, biceps femoris, and adductor magnus muscles, and sparing the gracilis, semitendinosus, and lateral head of the gastrocnemius muscle [
Echocardiography and cardiac MRI may demonstrate congestive cardiomyopathy or dilated cardiomyopathy with reduced left ventricular ejection fraction [
Electrocardiography may demonstrate atrial fibrillation or critical ventricular tachycardia [
Cardiac MRI may demonstrate focal late gadolinium enhancement [
Myocardial biopsy and cardiac MRI T
McLeod blood group phenotype is established by showing negativity for Kx erythrocyte antigen and weakened or absent expression of Kell antigens, thus differentiating the phenotype from individuals with
Accurate determination of RBC acanthocytosis is challenging. The recommendation to "send at least three blood smears" preferably of wet preparations of peripheral blood to an experienced laboratory [
The best procedure requires diluting whole blood samples 1:1 with heparinized saline followed by incubation for 60 minutes at room temperature; wet cell monolayers are then prepared for phase-contrast microscopy. When all RBCs with spicules (corresponding to type AI/AII acanthocytes and echinocytes) are counted, normal controls show fewer than 6.3% acanthocytes/echinocytes [
Confirmation of erythrocyte morphology by scanning electron microscopy or confocal microscopy with 3D-rendering [
Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
Family history is consistent with
• Progressive chorea syndrome, which also can be part of a clinical triad of movement disorders, cognitive alterations, and psychiatric symptoms ("Huntington-like syndrome")
• Seizures, mostly generalized
•
• Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
• Brain MRI in two males demonstrated extended T
• Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
• Brain MRI in two males demonstrated extended T
• Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
• Brain MRI in two males demonstrated extended T
• Sensorimotor axonopathy
• Neurogenic muscle atrophy, including unexplained elevation of creatine phosphokinase
• Myopathy
• Muscle enzymes. All affected males examined to date have had elevated serum creatine phosphokinase (CK) concentration values up to 4,000 U/L [
• Electromyography may demonstrate neurogenic and myopathic changes [
• Nerve conduction studies may demonstrate axonal damage of variable degree [
• Muscle CT and MRI may reveal a selective pattern of fatty degeneration of lower-leg muscles preferentially affecting the vastus lateralis, biceps femoris, and adductor magnus muscles, and sparing the gracilis, semitendinosus, and lateral head of the gastrocnemius muscle [
• Echocardiography and cardiac MRI may demonstrate congestive cardiomyopathy or dilated cardiomyopathy with reduced left ventricular ejection fraction [
• Electrocardiography may demonstrate atrial fibrillation or critical ventricular tachycardia [
• Cardiac MRI may demonstrate focal late gadolinium enhancement [
• Myocardial biopsy and cardiac MRI T
• McLeod blood group phenotype is established by showing negativity for Kx erythrocyte antigen and weakened or absent expression of Kell antigens, thus differentiating the phenotype from individuals with
• Accurate determination of RBC acanthocytosis is challenging. The recommendation to "send at least three blood smears" preferably of wet preparations of peripheral blood to an experienced laboratory [
• The best procedure requires diluting whole blood samples 1:1 with heparinized saline followed by incubation for 60 minutes at room temperature; wet cell monolayers are then prepared for phase-contrast microscopy. When all RBCs with spicules (corresponding to type AI/AII acanthocytes and echinocytes) are counted, normal controls show fewer than 6.3% acanthocytes/echinocytes [
• Confirmation of erythrocyte morphology by scanning electron microscopy or confocal microscopy with 3D-rendering [
• Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
• Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
• Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
• Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
• Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
• Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
• Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
• Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
• Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
## CNS Manifestations
Progressive chorea syndrome, which also can be part of a clinical triad of movement disorders, cognitive alterations, and psychiatric symptoms ("Huntington-like syndrome")
Seizures, mostly generalized
Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
Brain MRI in two males demonstrated extended T
• Progressive chorea syndrome, which also can be part of a clinical triad of movement disorders, cognitive alterations, and psychiatric symptoms ("Huntington-like syndrome")
• Seizures, mostly generalized
•
• Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
• Brain MRI in two males demonstrated extended T
• Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
• Brain MRI in two males demonstrated extended T
• Brain CT and MRI may demonstrate variable atrophy of the caudate nucleus and putamen [
• Brain MRI in two males demonstrated extended T
## Neuromuscular Manifestations
Sensorimotor axonopathy
Neurogenic muscle atrophy, including unexplained elevation of creatine phosphokinase
Myopathy
Muscle enzymes. All affected males examined to date have had elevated serum creatine phosphokinase (CK) concentration values up to 4,000 U/L [
Electromyography may demonstrate neurogenic and myopathic changes [
Nerve conduction studies may demonstrate axonal damage of variable degree [
Muscle CT and MRI may reveal a selective pattern of fatty degeneration of lower-leg muscles preferentially affecting the vastus lateralis, biceps femoris, and adductor magnus muscles, and sparing the gracilis, semitendinosus, and lateral head of the gastrocnemius muscle [
• Sensorimotor axonopathy
• Neurogenic muscle atrophy, including unexplained elevation of creatine phosphokinase
• Myopathy
• Muscle enzymes. All affected males examined to date have had elevated serum creatine phosphokinase (CK) concentration values up to 4,000 U/L [
• Electromyography may demonstrate neurogenic and myopathic changes [
• Nerve conduction studies may demonstrate axonal damage of variable degree [
• Muscle CT and MRI may reveal a selective pattern of fatty degeneration of lower-leg muscles preferentially affecting the vastus lateralis, biceps femoris, and adductor magnus muscles, and sparing the gracilis, semitendinosus, and lateral head of the gastrocnemius muscle [
## Cardiac Manifestations
Echocardiography and cardiac MRI may demonstrate congestive cardiomyopathy or dilated cardiomyopathy with reduced left ventricular ejection fraction [
Electrocardiography may demonstrate atrial fibrillation or critical ventricular tachycardia [
Cardiac MRI may demonstrate focal late gadolinium enhancement [
Myocardial biopsy and cardiac MRI T
• Echocardiography and cardiac MRI may demonstrate congestive cardiomyopathy or dilated cardiomyopathy with reduced left ventricular ejection fraction [
• Electrocardiography may demonstrate atrial fibrillation or critical ventricular tachycardia [
• Cardiac MRI may demonstrate focal late gadolinium enhancement [
• Myocardial biopsy and cardiac MRI T
## Red Blood Cell Manifestations
McLeod blood group phenotype is established by showing negativity for Kx erythrocyte antigen and weakened or absent expression of Kell antigens, thus differentiating the phenotype from individuals with
Accurate determination of RBC acanthocytosis is challenging. The recommendation to "send at least three blood smears" preferably of wet preparations of peripheral blood to an experienced laboratory [
The best procedure requires diluting whole blood samples 1:1 with heparinized saline followed by incubation for 60 minutes at room temperature; wet cell monolayers are then prepared for phase-contrast microscopy. When all RBCs with spicules (corresponding to type AI/AII acanthocytes and echinocytes) are counted, normal controls show fewer than 6.3% acanthocytes/echinocytes [
Confirmation of erythrocyte morphology by scanning electron microscopy or confocal microscopy with 3D-rendering [
Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
• McLeod blood group phenotype is established by showing negativity for Kx erythrocyte antigen and weakened or absent expression of Kell antigens, thus differentiating the phenotype from individuals with
• Accurate determination of RBC acanthocytosis is challenging. The recommendation to "send at least three blood smears" preferably of wet preparations of peripheral blood to an experienced laboratory [
• The best procedure requires diluting whole blood samples 1:1 with heparinized saline followed by incubation for 60 minutes at room temperature; wet cell monolayers are then prepared for phase-contrast microscopy. When all RBCs with spicules (corresponding to type AI/AII acanthocytes and echinocytes) are counted, normal controls show fewer than 6.3% acanthocytes/echinocytes [
• Confirmation of erythrocyte morphology by scanning electron microscopy or confocal microscopy with 3D-rendering [
• Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
• Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
• Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
• Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
• Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
• Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
• Assessment for alloantibodies against high-frequency antigens (anti-public antibodies) such as anti-Kx, anti-K20, and anti-Km antibodies. While these anti-public antibodies do not contribute to the autohemolysis in MLS, they need to be considered in homologous transfusion.
• Exclusion of autoimmune hemolytic anemia by negative direct antiglobulin test
• Investigation for biochemical markers of hemolysis (LDH, haptoglobin, bilirubin, reticulocytes)
## Family History
Family history is consistent with
## Establishing the Diagnosis
A hemizygous pathogenic variant involving
A hemizygous deletion of Xp21.1 involving
Note: Deletions involving
Note: Based on published cases, heterozygous females do not have RBC acanthocytosis or elevated CK serum levels.
Molecular genetic testing approaches can include a combination of
There are three options for establishing the diagnosis of McLeod neuroacanthocytosis syndrome:
Option 1 is the determination of the McLeod blood group phenotype followed by CMA for individuals with findings suggestive of a contiguous-gene deletion.
Note: Alternatively,
Option 2 is the determination of the McLeod blood group phenotype followed by single-gene testing for those in whom McLeod blood group phenotyping supports the diagnosis.
Note: Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected in an affected female using these methods and may require CMA (see
Option 3 is for symptomatic individuals in whom the diagnosis of McLeod neuroacanthocytosis syndrome has not been considered.
When the diagnosis of McLeod neuroacanthocytosis syndrome has not been considered in a symptomatic individual, the options are a multigene panel or comprehensive genomic testing:
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in McLeod Neuroacanthocytosis Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
A current list of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (see
Note that most reported deletions and duplications are large enough to likely be detected by CMA; however, gene-targeted deletion/duplication analysis does have a higher resolution.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• A hemizygous pathogenic variant involving
• A hemizygous deletion of Xp21.1 involving
• Note: Deletions involving
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Option 1
Option 1 is the determination of the McLeod blood group phenotype followed by CMA for individuals with findings suggestive of a contiguous-gene deletion.
Note: Alternatively,
## Option 2
Option 2 is the determination of the McLeod blood group phenotype followed by single-gene testing for those in whom McLeod blood group phenotyping supports the diagnosis.
Note: Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected in an affected female using these methods and may require CMA (see
## Option 3
Option 3 is for symptomatic individuals in whom the diagnosis of McLeod neuroacanthocytosis syndrome has not been considered.
When the diagnosis of McLeod neuroacanthocytosis syndrome has not been considered in a symptomatic individual, the options are a multigene panel or comprehensive genomic testing:
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in McLeod Neuroacanthocytosis Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
A current list of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (see
Note that most reported deletions and duplications are large enough to likely be detected by CMA; however, gene-targeted deletion/duplication analysis does have a higher resolution.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
McLeod neuroacanthocytosis syndrome (MLS) is a multisystem disorder with central nervous system (CNS), neuromuscular, cardiovascular, and hematologic manifestations in males. Heterozygous females have mosaicism for the Kell and Kx blood group antigens but usually lack CNS and neuromuscular manifestations; however, some heterozygous females may develop clinical manifestations including chorea or late-onset cognitive decline.
Choreiform movements are the presenting manifestation in about 30% of individuals with MLS, and develop in up to 95% of individuals over time [
Cognitive alterations are not a major presenting feature of MLS; however, frontal-type cognitive deficits are eventually found in at least 50% of individuals during the course of the disease [
About 20% of individuals initially manifest psychiatric abnormalities including personality disorder, anxiety, depression, obsessive-compulsive disorder, bipolar disorder, or schizo-affective disorder. Psychopathology develops in about 80% of individuals over time [
Seizures are the presenting manifestation in about 20% of individuals. Up to 40% of individuals with MLS eventually have seizures, usually described as generalized.
Obstructive sleep apnea, mentioned in a number of individuals with MLS, must be better characterized to qualify as a disease feature [
In a cardiac MRI study confirming the potentially malignant nature of cardiac involvement in MLS, four of five individuals with MLS had a dilated left ventricle, two of four a dilated right ventricle, and three of five a reduced left ventricular ejection fraction. Two of four individuals with MLS experienced ventricular tachycardia; Troponin T and CK values were elevated in all individuals for whom data were available [
In seven males with MLS, one presented with a cardiomyopathy and died from sudden cardiac death in the absence of any cardiovascular risk factors. Autopsy demonstrated eccentric hypertrophy and mild left ventricular dilatation. Histopathology was not specific and revealed focal myocyte hypertrophy, slight variation of myofiber size, and patchy interstitial fibrosis [
The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis. Alloantibodies in the Kell and Kx blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in newborns of Kell-negative mothers.
The interval between reported disease onset and death ranges from seven to 51 years; the mean age of death is 53 years (range: age 31-69 years) [
Females heterozygous for an
The most probable reason for the following clinical manifestations observed in female heterozygotes is skewed X-chromosome inactivation, in which the X chromosome with the normal
One heterozygous female developed the typical MLS phenotype [
A heterozygous female had acanthocytosis, a bimodal pattern of Kell blood group antigens on flow cytometry, elevated serum creatine kinase concentrations, and a tic-like movement disorder [
In one family, heterozygous females had slight cognitive deficits and reduced striatal glucose uptake in the absence of an obvious movement disorder [
The mother of a male with a contiguous-gene deletion of
Two deceased women from a larger pedigree (the mother of a male with proven MLS and her cousin – the mother of a proven heterozygous female) had shown involuntary movements according to family members [
[
Several studies demonstrated fiber type grouping, type 1 fiber predominance, type 2 fiber atrophy, increased variability in fiber size, and increased central nucleation [
In a series of ten individuals with MLS, including the original index patient, all had abnormal muscle histology: four had clear but nonspecific myopathic changes; however, all had neurogenic changes of variable degree consistent with predominant neurogenic muscle atrophy [
One individual with an
In muscle of healthy individuals, Kell antigen was located in the sarcoplasmic membranes and Kx immunohistochemistry revealed type 2 fiber-specific intracellular staining most probably confined to the sarcoplasmic reticulum, supporting the finding that XK forms a complex with VPS13A (see
Nerve biopsy may demonstrate a chronic axonal neuropathy with prominent regenerative activity and selective loss of large myelinated fibers [
Postmortem motor and sensory nerve examinations demonstrated axonal motor neuropathy [
In the manifesting female heterozygote, marked striatal atrophy was noted, corresponding to nonspecific loss of nerve cells and reactive astrocytic gliosis with predominant alterations in the head of the caudate nucleus [
In two males similar alterations were found with severe atrophy of the striatum and (less pronounced) of the globus pallidus [
In contrast to
Data presently available are insufficient to draw conclusions about genotype-phenotype correlations in McLeod neuroacanthocytosis syndrome [
Only three pathogenic
The
An individual with the
A single-base substitution in an intron near a splice junction (
In males, the penetrance of neurologic and neuromuscular manifestations of MLS is high – perhaps even complete – after age 50 years. Available data indicate that most males with the McLeod blood group phenotype will develop clinical manifestations of McLeod neuroacanthocytosis syndrome [
In a few individuals, however, neurologic and neuromuscular manifestations may be absent or only minor even after long-term follow up [
In the past, many reports (including that of the index case) described only hematologic findings, and no neurologic or neuroimaging workup was performed in these individuals [
The term "neuroacanthocytosis" refers to several genetically and phenotypically distinct disorders [
The term "McLeod blood group phenotype" (named after the first proband, Hugh McLeod) describes the immunohematologic abnormalities consisting of absent expression of Kx RBC antigen and reduced expression of Kell RBC antigens in the index case originally described by
The terms "Kell blood group precursor" and "Kell blood group precursor substance" for the XK protein or the Kx RBC antigen, respectively, are incorrect and no longer in use.
The prevalence of MLS cannot be determined based on the data available from the approximately 250 cases known worldwide. The prevalence is estimated at 1:10,000,000 [
• One heterozygous female developed the typical MLS phenotype [
• A heterozygous female had acanthocytosis, a bimodal pattern of Kell blood group antigens on flow cytometry, elevated serum creatine kinase concentrations, and a tic-like movement disorder [
• In one family, heterozygous females had slight cognitive deficits and reduced striatal glucose uptake in the absence of an obvious movement disorder [
• The mother of a male with a contiguous-gene deletion of
• Two deceased women from a larger pedigree (the mother of a male with proven MLS and her cousin – the mother of a proven heterozygous female) had shown involuntary movements according to family members [
• Several studies demonstrated fiber type grouping, type 1 fiber predominance, type 2 fiber atrophy, increased variability in fiber size, and increased central nucleation [
• In a series of ten individuals with MLS, including the original index patient, all had abnormal muscle histology: four had clear but nonspecific myopathic changes; however, all had neurogenic changes of variable degree consistent with predominant neurogenic muscle atrophy [
• One individual with an
• In muscle of healthy individuals, Kell antigen was located in the sarcoplasmic membranes and Kx immunohistochemistry revealed type 2 fiber-specific intracellular staining most probably confined to the sarcoplasmic reticulum, supporting the finding that XK forms a complex with VPS13A (see
• Nerve biopsy may demonstrate a chronic axonal neuropathy with prominent regenerative activity and selective loss of large myelinated fibers [
• Postmortem motor and sensory nerve examinations demonstrated axonal motor neuropathy [
• In the manifesting female heterozygote, marked striatal atrophy was noted, corresponding to nonspecific loss of nerve cells and reactive astrocytic gliosis with predominant alterations in the head of the caudate nucleus [
• In two males similar alterations were found with severe atrophy of the striatum and (less pronounced) of the globus pallidus [
• In contrast to
• The
• An individual with the
• A single-base substitution in an intron near a splice junction (
## Clinical Description
McLeod neuroacanthocytosis syndrome (MLS) is a multisystem disorder with central nervous system (CNS), neuromuscular, cardiovascular, and hematologic manifestations in males. Heterozygous females have mosaicism for the Kell and Kx blood group antigens but usually lack CNS and neuromuscular manifestations; however, some heterozygous females may develop clinical manifestations including chorea or late-onset cognitive decline.
Choreiform movements are the presenting manifestation in about 30% of individuals with MLS, and develop in up to 95% of individuals over time [
Cognitive alterations are not a major presenting feature of MLS; however, frontal-type cognitive deficits are eventually found in at least 50% of individuals during the course of the disease [
About 20% of individuals initially manifest psychiatric abnormalities including personality disorder, anxiety, depression, obsessive-compulsive disorder, bipolar disorder, or schizo-affective disorder. Psychopathology develops in about 80% of individuals over time [
Seizures are the presenting manifestation in about 20% of individuals. Up to 40% of individuals with MLS eventually have seizures, usually described as generalized.
Obstructive sleep apnea, mentioned in a number of individuals with MLS, must be better characterized to qualify as a disease feature [
In a cardiac MRI study confirming the potentially malignant nature of cardiac involvement in MLS, four of five individuals with MLS had a dilated left ventricle, two of four a dilated right ventricle, and three of five a reduced left ventricular ejection fraction. Two of four individuals with MLS experienced ventricular tachycardia; Troponin T and CK values were elevated in all individuals for whom data were available [
In seven males with MLS, one presented with a cardiomyopathy and died from sudden cardiac death in the absence of any cardiovascular risk factors. Autopsy demonstrated eccentric hypertrophy and mild left ventricular dilatation. Histopathology was not specific and revealed focal myocyte hypertrophy, slight variation of myofiber size, and patchy interstitial fibrosis [
The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis. Alloantibodies in the Kell and Kx blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in newborns of Kell-negative mothers.
The interval between reported disease onset and death ranges from seven to 51 years; the mean age of death is 53 years (range: age 31-69 years) [
Females heterozygous for an
The most probable reason for the following clinical manifestations observed in female heterozygotes is skewed X-chromosome inactivation, in which the X chromosome with the normal
One heterozygous female developed the typical MLS phenotype [
A heterozygous female had acanthocytosis, a bimodal pattern of Kell blood group antigens on flow cytometry, elevated serum creatine kinase concentrations, and a tic-like movement disorder [
In one family, heterozygous females had slight cognitive deficits and reduced striatal glucose uptake in the absence of an obvious movement disorder [
The mother of a male with a contiguous-gene deletion of
Two deceased women from a larger pedigree (the mother of a male with proven MLS and her cousin – the mother of a proven heterozygous female) had shown involuntary movements according to family members [
[
Several studies demonstrated fiber type grouping, type 1 fiber predominance, type 2 fiber atrophy, increased variability in fiber size, and increased central nucleation [
In a series of ten individuals with MLS, including the original index patient, all had abnormal muscle histology: four had clear but nonspecific myopathic changes; however, all had neurogenic changes of variable degree consistent with predominant neurogenic muscle atrophy [
One individual with an
In muscle of healthy individuals, Kell antigen was located in the sarcoplasmic membranes and Kx immunohistochemistry revealed type 2 fiber-specific intracellular staining most probably confined to the sarcoplasmic reticulum, supporting the finding that XK forms a complex with VPS13A (see
Nerve biopsy may demonstrate a chronic axonal neuropathy with prominent regenerative activity and selective loss of large myelinated fibers [
Postmortem motor and sensory nerve examinations demonstrated axonal motor neuropathy [
In the manifesting female heterozygote, marked striatal atrophy was noted, corresponding to nonspecific loss of nerve cells and reactive astrocytic gliosis with predominant alterations in the head of the caudate nucleus [
In two males similar alterations were found with severe atrophy of the striatum and (less pronounced) of the globus pallidus [
In contrast to
• One heterozygous female developed the typical MLS phenotype [
• A heterozygous female had acanthocytosis, a bimodal pattern of Kell blood group antigens on flow cytometry, elevated serum creatine kinase concentrations, and a tic-like movement disorder [
• In one family, heterozygous females had slight cognitive deficits and reduced striatal glucose uptake in the absence of an obvious movement disorder [
• The mother of a male with a contiguous-gene deletion of
• Two deceased women from a larger pedigree (the mother of a male with proven MLS and her cousin – the mother of a proven heterozygous female) had shown involuntary movements according to family members [
• Several studies demonstrated fiber type grouping, type 1 fiber predominance, type 2 fiber atrophy, increased variability in fiber size, and increased central nucleation [
• In a series of ten individuals with MLS, including the original index patient, all had abnormal muscle histology: four had clear but nonspecific myopathic changes; however, all had neurogenic changes of variable degree consistent with predominant neurogenic muscle atrophy [
• One individual with an
• In muscle of healthy individuals, Kell antigen was located in the sarcoplasmic membranes and Kx immunohistochemistry revealed type 2 fiber-specific intracellular staining most probably confined to the sarcoplasmic reticulum, supporting the finding that XK forms a complex with VPS13A (see
• Nerve biopsy may demonstrate a chronic axonal neuropathy with prominent regenerative activity and selective loss of large myelinated fibers [
• Postmortem motor and sensory nerve examinations demonstrated axonal motor neuropathy [
• In the manifesting female heterozygote, marked striatal atrophy was noted, corresponding to nonspecific loss of nerve cells and reactive astrocytic gliosis with predominant alterations in the head of the caudate nucleus [
• In two males similar alterations were found with severe atrophy of the striatum and (less pronounced) of the globus pallidus [
• In contrast to
## Affected Males
Choreiform movements are the presenting manifestation in about 30% of individuals with MLS, and develop in up to 95% of individuals over time [
Cognitive alterations are not a major presenting feature of MLS; however, frontal-type cognitive deficits are eventually found in at least 50% of individuals during the course of the disease [
About 20% of individuals initially manifest psychiatric abnormalities including personality disorder, anxiety, depression, obsessive-compulsive disorder, bipolar disorder, or schizo-affective disorder. Psychopathology develops in about 80% of individuals over time [
Seizures are the presenting manifestation in about 20% of individuals. Up to 40% of individuals with MLS eventually have seizures, usually described as generalized.
Obstructive sleep apnea, mentioned in a number of individuals with MLS, must be better characterized to qualify as a disease feature [
In a cardiac MRI study confirming the potentially malignant nature of cardiac involvement in MLS, four of five individuals with MLS had a dilated left ventricle, two of four a dilated right ventricle, and three of five a reduced left ventricular ejection fraction. Two of four individuals with MLS experienced ventricular tachycardia; Troponin T and CK values were elevated in all individuals for whom data were available [
In seven males with MLS, one presented with a cardiomyopathy and died from sudden cardiac death in the absence of any cardiovascular risk factors. Autopsy demonstrated eccentric hypertrophy and mild left ventricular dilatation. Histopathology was not specific and revealed focal myocyte hypertrophy, slight variation of myofiber size, and patchy interstitial fibrosis [
The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis. Alloantibodies in the Kell and Kx blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in newborns of Kell-negative mothers.
The interval between reported disease onset and death ranges from seven to 51 years; the mean age of death is 53 years (range: age 31-69 years) [
## Heterozygous Females
Females heterozygous for an
The most probable reason for the following clinical manifestations observed in female heterozygotes is skewed X-chromosome inactivation, in which the X chromosome with the normal
One heterozygous female developed the typical MLS phenotype [
A heterozygous female had acanthocytosis, a bimodal pattern of Kell blood group antigens on flow cytometry, elevated serum creatine kinase concentrations, and a tic-like movement disorder [
In one family, heterozygous females had slight cognitive deficits and reduced striatal glucose uptake in the absence of an obvious movement disorder [
The mother of a male with a contiguous-gene deletion of
Two deceased women from a larger pedigree (the mother of a male with proven MLS and her cousin – the mother of a proven heterozygous female) had shown involuntary movements according to family members [
• One heterozygous female developed the typical MLS phenotype [
• A heterozygous female had acanthocytosis, a bimodal pattern of Kell blood group antigens on flow cytometry, elevated serum creatine kinase concentrations, and a tic-like movement disorder [
• In one family, heterozygous females had slight cognitive deficits and reduced striatal glucose uptake in the absence of an obvious movement disorder [
• The mother of a male with a contiguous-gene deletion of
• Two deceased women from a larger pedigree (the mother of a male with proven MLS and her cousin – the mother of a proven heterozygous female) had shown involuntary movements according to family members [
## Other Studies
[
Several studies demonstrated fiber type grouping, type 1 fiber predominance, type 2 fiber atrophy, increased variability in fiber size, and increased central nucleation [
In a series of ten individuals with MLS, including the original index patient, all had abnormal muscle histology: four had clear but nonspecific myopathic changes; however, all had neurogenic changes of variable degree consistent with predominant neurogenic muscle atrophy [
One individual with an
In muscle of healthy individuals, Kell antigen was located in the sarcoplasmic membranes and Kx immunohistochemistry revealed type 2 fiber-specific intracellular staining most probably confined to the sarcoplasmic reticulum, supporting the finding that XK forms a complex with VPS13A (see
Nerve biopsy may demonstrate a chronic axonal neuropathy with prominent regenerative activity and selective loss of large myelinated fibers [
Postmortem motor and sensory nerve examinations demonstrated axonal motor neuropathy [
In the manifesting female heterozygote, marked striatal atrophy was noted, corresponding to nonspecific loss of nerve cells and reactive astrocytic gliosis with predominant alterations in the head of the caudate nucleus [
In two males similar alterations were found with severe atrophy of the striatum and (less pronounced) of the globus pallidus [
In contrast to
• Several studies demonstrated fiber type grouping, type 1 fiber predominance, type 2 fiber atrophy, increased variability in fiber size, and increased central nucleation [
• In a series of ten individuals with MLS, including the original index patient, all had abnormal muscle histology: four had clear but nonspecific myopathic changes; however, all had neurogenic changes of variable degree consistent with predominant neurogenic muscle atrophy [
• One individual with an
• In muscle of healthy individuals, Kell antigen was located in the sarcoplasmic membranes and Kx immunohistochemistry revealed type 2 fiber-specific intracellular staining most probably confined to the sarcoplasmic reticulum, supporting the finding that XK forms a complex with VPS13A (see
• Nerve biopsy may demonstrate a chronic axonal neuropathy with prominent regenerative activity and selective loss of large myelinated fibers [
• Postmortem motor and sensory nerve examinations demonstrated axonal motor neuropathy [
• In the manifesting female heterozygote, marked striatal atrophy was noted, corresponding to nonspecific loss of nerve cells and reactive astrocytic gliosis with predominant alterations in the head of the caudate nucleus [
• In two males similar alterations were found with severe atrophy of the striatum and (less pronounced) of the globus pallidus [
• In contrast to
## Genotype-Phenotype Correlations
Data presently available are insufficient to draw conclusions about genotype-phenotype correlations in McLeod neuroacanthocytosis syndrome [
Only three pathogenic
The
An individual with the
A single-base substitution in an intron near a splice junction (
• The
• An individual with the
• A single-base substitution in an intron near a splice junction (
## Penetrance
In males, the penetrance of neurologic and neuromuscular manifestations of MLS is high – perhaps even complete – after age 50 years. Available data indicate that most males with the McLeod blood group phenotype will develop clinical manifestations of McLeod neuroacanthocytosis syndrome [
In a few individuals, however, neurologic and neuromuscular manifestations may be absent or only minor even after long-term follow up [
In the past, many reports (including that of the index case) described only hematologic findings, and no neurologic or neuroimaging workup was performed in these individuals [
## Nomenclature
The term "neuroacanthocytosis" refers to several genetically and phenotypically distinct disorders [
The term "McLeod blood group phenotype" (named after the first proband, Hugh McLeod) describes the immunohematologic abnormalities consisting of absent expression of Kx RBC antigen and reduced expression of Kell RBC antigens in the index case originally described by
The terms "Kell blood group precursor" and "Kell blood group precursor substance" for the XK protein or the Kx RBC antigen, respectively, are incorrect and no longer in use.
## Prevalence
The prevalence of MLS cannot be determined based on the data available from the approximately 250 cases known worldwide. The prevalence is estimated at 1:10,000,000 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
5' of
3' of
Note: Concurrent deletion of
• 5' of
• 3' of
## Differential Diagnosis
The two disorders of primary interest in the differential diagnosis of McLeod neuroacanthocytosis syndrome (MLS) are chorea-acanthocytosis and Huntington disease. These disorders – which may appear clinically indistinguishable from MLS – and other disorders in the differential diagnosis of MLS are summarized in
Genes of Interest in the Differential Diagnosis of McLeod Neuroacanthocytosis Syndrome (MLS)
May appear indistinguishable from MLS
Progressive choreatic mvmt disorder
Cognitive & psychiatric disturbances
Anticipation
Absence of acanthocytes, seizures, myopathy, & cardiomyopathy
Normal CK
Progressive mvmt disorder (primarily chorea)
Subclinical myopathy → progressive distal muscle wasting & weakness
Mental changes
Seizures
Progressive cognitive & behavioral changes that resemble a frontal lobe syndrome
Dystonia affecting trunk & esp oral region & tongue → dysarthria & serious dysphagia → weight loss
May present w/a parkinsonian syndrome
Habitual tongue & lip biting characteristic
Cardiac disease less severe, if present
May appear indistinguishable from MLS
Progressive choreatic movement disorder
Cognitive & psychiatric disturbances
Progressive dystonia
Dysarthria
Rigidity
In ~25% of persons: "atypical" presentation w/onset age >10 yrs, prominent speech defects, psychiatric disturbance, & more gradual disease progression
In ≥8%: acanthocytosis
Chorea not observed
Usually childhood or adolescent onset
Basal ganglia iron deposition
"Eye of the tiger" sign on MRI characteristic
Pigmentary retinopathy
Rapidly progressive course
No hematologic, neuromuscular, or cardiac manifestations
Acanthocytosis
Dysarthria
Neuropathy
Areflexia
Pigmentary retinopathy
No basal ganglia involvement
AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DRPLA = dentatorubral-pallidoluysian atrophy; MOI = mode of inheritance; PKAN = pantothenate kinase-associated neurodegeneration; PNS = peripheral nervous system; SCA = spinocerebellar ataxia; XL = X-linked
See also
HARP (
Neurologic disorders associated with RBC acanthocytosis have been summarized as neuroacanthocytosis syndromes [
Neurologic findings include [
• May appear indistinguishable from MLS
• Progressive choreatic mvmt disorder
• Cognitive & psychiatric disturbances
• Anticipation
• Absence of acanthocytes, seizures, myopathy, & cardiomyopathy
• Normal CK
• Progressive mvmt disorder (primarily chorea)
• Subclinical myopathy → progressive distal muscle wasting & weakness
• Mental changes
• Seizures
• Progressive cognitive & behavioral changes that resemble a frontal lobe syndrome
• Dystonia affecting trunk & esp oral region & tongue → dysarthria & serious dysphagia → weight loss
• May present w/a parkinsonian syndrome
• Habitual tongue & lip biting characteristic
• Cardiac disease less severe, if present
• May appear indistinguishable from MLS
• Progressive choreatic movement disorder
• Cognitive & psychiatric disturbances
• Progressive dystonia
• Dysarthria
• Rigidity
• In ~25% of persons: "atypical" presentation w/onset age >10 yrs, prominent speech defects, psychiatric disturbance, & more gradual disease progression
• In ≥8%: acanthocytosis
• Chorea not observed
• Usually childhood or adolescent onset
• Basal ganglia iron deposition
• "Eye of the tiger" sign on MRI characteristic
• Pigmentary retinopathy
• Rapidly progressive course
• No hematologic, neuromuscular, or cardiac manifestations
• Acanthocytosis
• Dysarthria
• Neuropathy
• Areflexia
• Pigmentary retinopathy
• No basal ganglia involvement
## Management
To establish the extent of disease in an individual diagnosed with McLeod neuroacanthocytosis syndrome (MLS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with McLeod Neuroacanthocytosis Syndrome
Choreiform mvmts; head drop
Apply UHDRS & perform brain MRI.
Usually generalized seizures
Perform EEG.
Absent DTRs, muscle weakness, or atrophy
Determine serum CK, ALT, AST, & LDH levels.
EMG & NCV studies
Executive deficits
Perform formal neuropsychological eval &/or Montreal cognitive assessment.
Perform standardized psychiatric assessment; eval of symptom-oriented psychotherapeutic & psychopharmacologic interventions.
Contact w/patient advocacy org may provide addl benefit.
Feeding dystonia
Consider clinical &/or fiberoptic feeding eval
Usually develop over time
Perform echocardiography, Holter EKG, & cardiac biomarker analysis (e.g., Troponin T/I, pro-BNP).
If available, perform cardiac MRI & electrophysiologic investigations.
Erythrocyte phenotyping for Kell & Kx antigens
Expression of Kell protein by flow cytometry
Search for anti-public alloantibodies
Direct antiglobulin test
↑ risk of transfusion reactions w/repetitive blood transfusions
Consider autologous blood banking when planned surgery may require blood transfusions.
Consider homologous blood banking for emergencies.
Community or
Social work involvement for caregiver support;
Home nursing referral.
DTRs = deep tendon reflexes; EEG = electroencephalogram; EKG = electrocardiogram; OCD = obsessive-compulsive disorder; UHDRS = Unified Huntington Disease Rating Scale
Early recognition and treatment of cardiac manifestations and seizures are important, as these potential complications may be severe and could cause premature death [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with McLeod Neuroacanthocytosis Syndrome
Dopamine antagonists incl tiapride, clozapine, or quetiapine
Dopamine depletor: tetrabenazine
PT
Sufficient supplementation of calories & protein
Supplementation of vitamins D & B
Endurance exercise as tolerated may be helpful.
Avoid strength exercises, esp of the eccentric type.
Avoid repetitive blood transfusions.
Consider cryopreservation of autologous or homologous blood for future use.
EKG = electrocardiogram; PT = physical therapy
When epilepsy is suspected, EEG should be performed and anti-seizure medication treatment considered (based on standard guidelines including the monitoring of medication-specific laboratory parameters and serum concentrations). Because of the increased risk of rhabdomyolysis, treatment with neuroleptics – in particular clozapine – should be carefully monitored, both clinically and with serum CK measurements.
Recommended Surveillance for Individuals with McLeod Neuroacanthocytosis Syndrome
Every 2 yrs
When findings are abnormal, more frequently depending on cardiologist's eval
EEG = electroencephalogram; EKG = electrocardiogram
Blood transfusions with Kx antigens should be avoided in males with the McLeod blood group phenotype. Kx-negative blood or, if possible, banked autologous or homologous blood should be used for transfusions. Note that because heterozygous females have both Kx+ and Kx- red blood cells, they can be transfused with Kx+ homologous blood products.
It is appropriate to clarify the genetic status of apparently asymptomatic at-risk male relatives of any age in order to identify as early as possible those who would benefit from:
Detailed blood compatibility information to prevent transfusion of Kx+ homologous blood products;
Possible prophylactic cryopreservation of autologous or homologous blood for use in future transfusions; and
Prevention of sudden cardiac events.
See
In female heterozygotes, the probability of manifestations of the McLeod neuroacanthocytosis syndrome in the reproductive period is presumably very low; thus, no particular recommendations can be made.
Search
• Choreiform mvmts; head drop
• Apply UHDRS & perform brain MRI.
• Usually generalized seizures
• Perform EEG.
• Absent DTRs, muscle weakness, or atrophy
• Determine serum CK, ALT, AST, & LDH levels.
• EMG & NCV studies
• Executive deficits
• Perform formal neuropsychological eval &/or Montreal cognitive assessment.
• Perform standardized psychiatric assessment; eval of symptom-oriented psychotherapeutic & psychopharmacologic interventions.
• Contact w/patient advocacy org may provide addl benefit.
• Feeding dystonia
• Consider clinical &/or fiberoptic feeding eval
• Usually develop over time
• Perform echocardiography, Holter EKG, & cardiac biomarker analysis (e.g., Troponin T/I, pro-BNP).
• If available, perform cardiac MRI & electrophysiologic investigations.
• Erythrocyte phenotyping for Kell & Kx antigens
• Expression of Kell protein by flow cytometry
• Search for anti-public alloantibodies
• Direct antiglobulin test
• ↑ risk of transfusion reactions w/repetitive blood transfusions
• Consider autologous blood banking when planned surgery may require blood transfusions.
• Consider homologous blood banking for emergencies.
• Community or
• Social work involvement for caregiver support;
• Home nursing referral.
• Dopamine antagonists incl tiapride, clozapine, or quetiapine
• Dopamine depletor: tetrabenazine
• PT
• Sufficient supplementation of calories & protein
• Supplementation of vitamins D & B
• Endurance exercise as tolerated may be helpful.
• Avoid strength exercises, esp of the eccentric type.
• Avoid repetitive blood transfusions.
• Consider cryopreservation of autologous or homologous blood for future use.
• Every 2 yrs
• When findings are abnormal, more frequently depending on cardiologist's eval
• Detailed blood compatibility information to prevent transfusion of Kx+ homologous blood products;
• Possible prophylactic cryopreservation of autologous or homologous blood for use in future transfusions; and
• Prevention of sudden cardiac events.
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with McLeod neuroacanthocytosis syndrome (MLS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with McLeod Neuroacanthocytosis Syndrome
Choreiform mvmts; head drop
Apply UHDRS & perform brain MRI.
Usually generalized seizures
Perform EEG.
Absent DTRs, muscle weakness, or atrophy
Determine serum CK, ALT, AST, & LDH levels.
EMG & NCV studies
Executive deficits
Perform formal neuropsychological eval &/or Montreal cognitive assessment.
Perform standardized psychiatric assessment; eval of symptom-oriented psychotherapeutic & psychopharmacologic interventions.
Contact w/patient advocacy org may provide addl benefit.
Feeding dystonia
Consider clinical &/or fiberoptic feeding eval
Usually develop over time
Perform echocardiography, Holter EKG, & cardiac biomarker analysis (e.g., Troponin T/I, pro-BNP).
If available, perform cardiac MRI & electrophysiologic investigations.
Erythrocyte phenotyping for Kell & Kx antigens
Expression of Kell protein by flow cytometry
Search for anti-public alloantibodies
Direct antiglobulin test
↑ risk of transfusion reactions w/repetitive blood transfusions
Consider autologous blood banking when planned surgery may require blood transfusions.
Consider homologous blood banking for emergencies.
Community or
Social work involvement for caregiver support;
Home nursing referral.
DTRs = deep tendon reflexes; EEG = electroencephalogram; EKG = electrocardiogram; OCD = obsessive-compulsive disorder; UHDRS = Unified Huntington Disease Rating Scale
Early recognition and treatment of cardiac manifestations and seizures are important, as these potential complications may be severe and could cause premature death [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Choreiform mvmts; head drop
• Apply UHDRS & perform brain MRI.
• Usually generalized seizures
• Perform EEG.
• Absent DTRs, muscle weakness, or atrophy
• Determine serum CK, ALT, AST, & LDH levels.
• EMG & NCV studies
• Executive deficits
• Perform formal neuropsychological eval &/or Montreal cognitive assessment.
• Perform standardized psychiatric assessment; eval of symptom-oriented psychotherapeutic & psychopharmacologic interventions.
• Contact w/patient advocacy org may provide addl benefit.
• Feeding dystonia
• Consider clinical &/or fiberoptic feeding eval
• Usually develop over time
• Perform echocardiography, Holter EKG, & cardiac biomarker analysis (e.g., Troponin T/I, pro-BNP).
• If available, perform cardiac MRI & electrophysiologic investigations.
• Erythrocyte phenotyping for Kell & Kx antigens
• Expression of Kell protein by flow cytometry
• Search for anti-public alloantibodies
• Direct antiglobulin test
• ↑ risk of transfusion reactions w/repetitive blood transfusions
• Consider autologous blood banking when planned surgery may require blood transfusions.
• Consider homologous blood banking for emergencies.
• Community or
• Social work involvement for caregiver support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with McLeod Neuroacanthocytosis Syndrome
Dopamine antagonists incl tiapride, clozapine, or quetiapine
Dopamine depletor: tetrabenazine
PT
Sufficient supplementation of calories & protein
Supplementation of vitamins D & B
Endurance exercise as tolerated may be helpful.
Avoid strength exercises, esp of the eccentric type.
Avoid repetitive blood transfusions.
Consider cryopreservation of autologous or homologous blood for future use.
EKG = electrocardiogram; PT = physical therapy
When epilepsy is suspected, EEG should be performed and anti-seizure medication treatment considered (based on standard guidelines including the monitoring of medication-specific laboratory parameters and serum concentrations). Because of the increased risk of rhabdomyolysis, treatment with neuroleptics – in particular clozapine – should be carefully monitored, both clinically and with serum CK measurements.
• Dopamine antagonists incl tiapride, clozapine, or quetiapine
• Dopamine depletor: tetrabenazine
• PT
• Sufficient supplementation of calories & protein
• Supplementation of vitamins D & B
• Endurance exercise as tolerated may be helpful.
• Avoid strength exercises, esp of the eccentric type.
• Avoid repetitive blood transfusions.
• Consider cryopreservation of autologous or homologous blood for future use.
## Surveillance
Recommended Surveillance for Individuals with McLeod Neuroacanthocytosis Syndrome
Every 2 yrs
When findings are abnormal, more frequently depending on cardiologist's eval
EEG = electroencephalogram; EKG = electrocardiogram
• Every 2 yrs
• When findings are abnormal, more frequently depending on cardiologist's eval
## Agents/Circumstances to Avoid
Blood transfusions with Kx antigens should be avoided in males with the McLeod blood group phenotype. Kx-negative blood or, if possible, banked autologous or homologous blood should be used for transfusions. Note that because heterozygous females have both Kx+ and Kx- red blood cells, they can be transfused with Kx+ homologous blood products.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic at-risk male relatives of any age in order to identify as early as possible those who would benefit from:
Detailed blood compatibility information to prevent transfusion of Kx+ homologous blood products;
Possible prophylactic cryopreservation of autologous or homologous blood for use in future transfusions; and
Prevention of sudden cardiac events.
See
• Detailed blood compatibility information to prevent transfusion of Kx+ homologous blood products;
• Possible prophylactic cryopreservation of autologous or homologous blood for use in future transfusions; and
• Prevention of sudden cardiac events.
## Pregnancy Management
In female heterozygotes, the probability of manifestations of the McLeod neuroacanthocytosis syndrome in the reproductive period is presumably very low; thus, no particular recommendations can be made.
## Therapies Under Investigation
Search
## Genetic Counseling
McLeod neuroacanthocytosis syndrome (MLS) is inherited in an X-linked manner.
The father of an affected male will not have the disease nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected son and the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
One
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
Males who inherit the variant will be affected. Significant interfamilial phenotypic variability has been observed in MLS (see
Females who inherit the pathogenic variant will be heterozygotes. Females who are heterozygous for an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the theoretic possibility of maternal germline mosaicism.
All of their daughters, who will be heterozygotes and will usually not be affected. Some heterozygous females may develop clinical manifestations such as chorea or late-onset cognitive decline (see Clinical Description,
None of their sons.
Identification of female heterozygotes requires either (a) prior identification of the
Note: Some heterozygous females may develop clinical manifestations such as chorea or late-onset cognitive decline (see Clinical Description,
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disease nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected son and the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• One
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
• Males who inherit the variant will be affected. Significant interfamilial phenotypic variability has been observed in MLS (see
• Females who inherit the pathogenic variant will be heterozygotes. Females who are heterozygous for an
• Males who inherit the variant will be affected. Significant interfamilial phenotypic variability has been observed in MLS (see
• Females who inherit the pathogenic variant will be heterozygotes. Females who are heterozygous for an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the theoretic possibility of maternal germline mosaicism.
• Males who inherit the variant will be affected. Significant interfamilial phenotypic variability has been observed in MLS (see
• Females who inherit the pathogenic variant will be heterozygotes. Females who are heterozygous for an
• All of their daughters, who will be heterozygotes and will usually not be affected. Some heterozygous females may develop clinical manifestations such as chorea or late-onset cognitive decline (see Clinical Description,
• None of their sons.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes.
## Mode of Inheritance
McLeod neuroacanthocytosis syndrome (MLS) is inherited in an X-linked manner.
## Risk to Family Members
The father of an affected male will not have the disease nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected son and the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
One
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
Males who inherit the variant will be affected. Significant interfamilial phenotypic variability has been observed in MLS (see
Females who inherit the pathogenic variant will be heterozygotes. Females who are heterozygous for an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the theoretic possibility of maternal germline mosaicism.
All of their daughters, who will be heterozygotes and will usually not be affected. Some heterozygous females may develop clinical manifestations such as chorea or late-onset cognitive decline (see Clinical Description,
None of their sons.
• The father of an affected male will not have the disease nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected son and the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• One
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
• Males who inherit the variant will be affected. Significant interfamilial phenotypic variability has been observed in MLS (see
• Females who inherit the pathogenic variant will be heterozygotes. Females who are heterozygous for an
• Males who inherit the variant will be affected. Significant interfamilial phenotypic variability has been observed in MLS (see
• Females who inherit the pathogenic variant will be heterozygotes. Females who are heterozygous for an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the theoretic possibility of maternal germline mosaicism.
• Males who inherit the variant will be affected. Significant interfamilial phenotypic variability has been observed in MLS (see
• Females who inherit the pathogenic variant will be heterozygotes. Females who are heterozygous for an
• All of their daughters, who will be heterozygotes and will usually not be affected. Some heterozygous females may develop clinical manifestations such as chorea or late-onset cognitive decline (see Clinical Description,
• None of their sons.
## Heterozygote Detection
Identification of female heterozygotes requires either (a) prior identification of the
Note: Some heterozygous females may develop clinical manifestations such as chorea or late-onset cognitive decline (see Clinical Description,
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
2285 Harlock Road
Melbourne FL 32934
United Kingdom
Germany
•
• United Kingdom
•
•
• 2285 Harlock Road
• Melbourne FL 32934
•
•
• United Kingdom
•
•
• Germany
•
•
•
## Molecular Genetics
McLeod Neuroacanthocytosis Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for McLeod Neuroacanthocytosis Syndrome (
XK forms a complex with VPS13A, a protein that acts as lipid transporter protein at different membrane contact sites, for example, between the mitochondria and the endoplasmic reticulum [
XK and Kell are predominantly coexpressed in erythroid tissues, but their expression in non-erythroid tissues differs. XK is ubiquitously expressed in many other tissues, especially in high amounts in skeletal muscle and brain [
Note: Stepwise partitioning of Xp21 has been used as an alternative method to define the exact breakpoints of contiguous-gene deletions [
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
XK forms a complex with VPS13A, a protein that acts as lipid transporter protein at different membrane contact sites, for example, between the mitochondria and the endoplasmic reticulum [
XK and Kell are predominantly coexpressed in erythroid tissues, but their expression in non-erythroid tissues differs. XK is ubiquitously expressed in many other tissues, especially in high amounts in skeletal muscle and brain [
Note: Stepwise partitioning of Xp21 has been used as an alternative method to define the exact breakpoints of contiguous-gene deletions [
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Chapter Notes
Hans H Jung is a leading senior consultant at the Department of Neurology, University Hospital Zurich, Switzerland where he is head of the Center for Neurogenetic and Neuromuscular Disorders. His research focuses on the clinical, pathologic, and molecular basis of chorea syndromes, in particular the McLeod neuroacanthocytosis syndrome.
Adrian Danek, a professor of cognitive neurology at the University of Munich, has contributed to neuroacanthocytosis research since 1990. His interests also include functional brain anatomy, problem solving (Towers of Hanoi/London), the frontotemporal lobe degeneration syndromes (see
Ruth H Walker is a movement disorders-trained neurologist whose research focuses on the functional neuroanatomy of the basal ganglia and clinicopathologic correlations of neurogenetic disorders. Her particular clinical interests are the hyperkinetic disorders, especially the rarer inherited causes of chorea.
Beat M Frey is a board certified hematologist/oncologist/transfusion specialist running the Swiss Transfusion Service SRC in Schlieren/Zürich, Switzerland. His research interests focus on functional and genetic aspects of blood group antigens and their implication for clinical practice.
Kevin Peikert is supported by the Rostock Academy for Clinician Scientists (RACS) and the FORUN program (both University of Rostock, Germany).
The authors thank the Advocacy for Neuroacanthocytosis Patients, in particular the late Glenn Irvine and his wife Ginger, for their continuous and ongoing support.
Adrian Danek, MD (2004-present)Carol Dobson-Stone, DPhil; University of New South Wales (2004-2012)Beat M Frey, MD (2012-present)Christoph Gassner, PhD; Swiss Red Cross (2012-2021)Hans H Jung, MD (2004-present)Sohee Lee, PhD; New York Blood Center (2007-2012)Kevin Peikert, MD (2021-present)Colvin M Redman, PhD; New York Blood Center (2004-2007)Ruth H Walker, MD, MBBS, PhD (2012-present)
16 September 2021 (bp) Comprehensive update posted live
23 May 2019 (bp) Comprehensive update posted live
17 May 2012 (me) Comprehensive update posted live
26 March 2007 (me) Comprehensive update posted live
3 December 2004 (ca) Review posted live
8 April 2004 (hj, ad) Original submission
• 16 September 2021 (bp) Comprehensive update posted live
• 23 May 2019 (bp) Comprehensive update posted live
• 17 May 2012 (me) Comprehensive update posted live
• 26 March 2007 (me) Comprehensive update posted live
• 3 December 2004 (ca) Review posted live
• 8 April 2004 (hj, ad) Original submission
## Author Notes
Hans H Jung is a leading senior consultant at the Department of Neurology, University Hospital Zurich, Switzerland where he is head of the Center for Neurogenetic and Neuromuscular Disorders. His research focuses on the clinical, pathologic, and molecular basis of chorea syndromes, in particular the McLeod neuroacanthocytosis syndrome.
Adrian Danek, a professor of cognitive neurology at the University of Munich, has contributed to neuroacanthocytosis research since 1990. His interests also include functional brain anatomy, problem solving (Towers of Hanoi/London), the frontotemporal lobe degeneration syndromes (see
Ruth H Walker is a movement disorders-trained neurologist whose research focuses on the functional neuroanatomy of the basal ganglia and clinicopathologic correlations of neurogenetic disorders. Her particular clinical interests are the hyperkinetic disorders, especially the rarer inherited causes of chorea.
Beat M Frey is a board certified hematologist/oncologist/transfusion specialist running the Swiss Transfusion Service SRC in Schlieren/Zürich, Switzerland. His research interests focus on functional and genetic aspects of blood group antigens and their implication for clinical practice.
Kevin Peikert is supported by the Rostock Academy for Clinician Scientists (RACS) and the FORUN program (both University of Rostock, Germany).
## Acknowledgments
The authors thank the Advocacy for Neuroacanthocytosis Patients, in particular the late Glenn Irvine and his wife Ginger, for their continuous and ongoing support.
## Author History
Adrian Danek, MD (2004-present)Carol Dobson-Stone, DPhil; University of New South Wales (2004-2012)Beat M Frey, MD (2012-present)Christoph Gassner, PhD; Swiss Red Cross (2012-2021)Hans H Jung, MD (2004-present)Sohee Lee, PhD; New York Blood Center (2007-2012)Kevin Peikert, MD (2021-present)Colvin M Redman, PhD; New York Blood Center (2004-2007)Ruth H Walker, MD, MBBS, PhD (2012-present)
## Revision History
16 September 2021 (bp) Comprehensive update posted live
23 May 2019 (bp) Comprehensive update posted live
17 May 2012 (me) Comprehensive update posted live
26 March 2007 (me) Comprehensive update posted live
3 December 2004 (ca) Review posted live
8 April 2004 (hj, ad) Original submission
• 16 September 2021 (bp) Comprehensive update posted live
• 23 May 2019 (bp) Comprehensive update posted live
• 17 May 2012 (me) Comprehensive update posted live
• 26 March 2007 (me) Comprehensive update posted live
• 3 December 2004 (ca) Review posted live
• 8 April 2004 (hj, ad) Original submission
## References
## Literature Cited
|
[
"FH Allen, SM Krabbe, PA Corcoran. A new phenotype (McLeod) in the Kell blood-group system.. Vox Sang 1961;6:555-60",
"DG Anderson, S Carmona, K Naidoo, TL Coetzer, J Carr, DD Rudnicki, RH Walker, RL Margolis, A Krause. Absence of acanthocytosis in Huntington's disease-like 2: a prospective comparison with Huntington's disease.. Tremor Other Hyperkinet Mov (N Y) 2017;7:512",
"B Balint, AE Lang. Expert comment to: novel Xp21.1 deletion associated with unusual features in large McLeod syndrome kindred.. Parkinsonism Relat Disord. 2020;79:133-4",
"CJ Bertelson, AO Pogo, A Chaudhuri, WL Marsh, CM Redman, D Banerjee, WA Symmans, T Simon, D Frey, LM Kunkel. Localization of the McLeod locus (XK) within Xp21 by deletion analysis.. Am J Hum Genet 1988;42:703-11",
"V Camara-Clayette, C Rahuel, C Lopez, C Hattab, V Verkarre, O Bertrand, JP Cartron. Transcriptional regulation of the KEL gene and Kell protein expression in erythroid and non-erythroid cells.. Biochem J 2001;356:171-80",
"M Chauveau, N Damon-Perriere, H Jung, C Latxague, U Spampinato, P Burbaud, F Tison. Head drops are also observed in the McLeod syndrome.. Mov Disord 2011;26:1562-3",
"KH Ching, SK Westaway, J Gitschier, JJ Higgins, SJ Hayflick. HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration.. Neurology 2002;58:1673-4",
"A Danek, HH Jung, MA Melone, L Rampoldi, V Broccoli, RH Walker. Neuroacanthocytosis: new developments in a neglected group of dementing disorders.. J Neurol Sci 2005;229-230:171-86",
"A Danek, JP Rubio, L Rampoldi, M Ho, C Dobson-Stone, F Tison, WA Symmans, M Oechsner, W Kalckreuth, JM Watt, AJ Corbett, HH Hamdalla, AG Marshall, I Sutton, MT Dotti, A Malandrini, RH Walker, G Daniels, AP Monaco. McLeod neuroacanthocytosis: genotype and phenotype.. Ann Neurol 2001a;50:755-64",
"A Danek, F Tison, J Rubio, M Oechsner, W Kalckreuth, AP Monaco. The chorea of McLeod syndrome.. Mov Disord 2001b;16:882-9",
"A Danek, I Uttner, T Vogl, K Tatsch, TN Witt. Cerebral involvement in McLeod syndrome.. Neurology 1994;44:117-20",
"A Darras, K Peikert, A Rabe, F Yaya, G Simionato, T John, AK Dasanna, S Buvalyy, J Geisel, A Hermann, DA Fedosov, A Danek, C Wagner, L Kaestner. Acanthocyte sedimentation rate as a diagnostic biomarker for neuroacanthocytosis syndromes: experimental evidence and physical justification.. Cells. 2021;10:788",
"L De Franceschi, A Rivera, M Fleming, M Honczarenko, L Peters, P Gascard, N Mohandas, C Brugnara. Evidence for a protective role of the Gardos channel against hemolysis in murine spherocytosis.. Blood. 2005;106:1454-9",
"MT Dotti, C Battisti, A Malandrini, A Federico, JP Rubio, G Circiarello, AP Monaco. McLeod syndrome and neuroacanthocytosis with a novel mutation in the XK gene.. Mov Disord 2000;15:1282-4",
"U Dydak, S Mueller, PS Sandor, D Meier, P Boesiger, HH Jung. Cerebral metabolic alterations in McLeod syndrome.. Eur Neurol 2006;56:17-23",
"W El Nemer, Y Colin, E Collec, P Gane, JP Cartron, CL Kim. Analysis of deletions in three McLeod patients: exclusion of the XS locus from the Xp21.1-Xp21.2 region.. Eur J Immunogenet. 2000;27:29-33",
"BM Frey, C Gassner, HH Jung. Neurodegeneration in the elderly - When the blood type matters: An overview of the McLeod syndrome with focus on hematological features.. Transfus Apher Sci. 2015;52:277-84",
"AR Gantenbein, N Damon-Perrière, JE Bohlender, M Chauveau, C Latxague, M Miranda, HH. Jung, F Tison. Feeding dystonia in McLeod syndrome.. Mov Disord 2011;26:2123-6",
"C Gassner, C Brönnimann, Y Merki, MP Mattle-Greminger, S Sigurdardottir, E Meyer, C Engström, JD O'Sullivan, HH Jung, BM Frey. Stepwise partitioning of Xp21: a profiling method for XK deletions causative of the McLeod syndrome.. Transfusion. 2017;57:2125-35",
"RJ Hardie, HW Pullon, AE Harding, JS Owen, M Pires, GL Daniels, Y Imai, VP Misra, RH King, JM Jacobs. Neuroacanthocytosis. A clinical, haematological and pathological study of 19 cases.. Brain 1991;114:13-49",
"E Hewer, A Danek, BG Schoser, M Miranda, R Reichard, C Castiglioni, M Oechsner, HH Goebel, FL Heppner, HH Jung. McLeod myopathy revisited – more neurogenic and less benign.. Brain 2007;130:3285-96",
"M Ho, J Chelly, N Carter, A Danek, P Crocker, AP Monaco. Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein.. Cell 1994;77:869-80",
"MF Ho, RM Chalmers, MB Davis, AE Harding, AP Monaco. A novel point mutation in the McLeod syndrome gene in neuroacanthocytosis.. Ann Neurol 1996;39:672-5",
"H Houlden, S Lincoln, M Farrer, PG Cleland, J Hardy, RW Orrell. Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz syndromes are allelic.. Neurology 2003;61:1423-6",
"S Ishikawa, N Tachibana, KI Tabata, N Fujimori, RI Hayashi, J Takahashi, SI Ikeda, N Hanyu. Muscle CT scan findings in McLeod syndrome and chorea-acanthocytosis.. Muscle Nerve 2000;23:1113-6",
"HH Jung, A Danek, BM Frey. McLeod Syndrome – a neurohaematological disorder.. Vox Sang 2007;93:112-21",
"HH Jung, A Danek, RH Walker. Neuroacanthocytosis syndromes.. Orphanet J Rare Dis. 2011;6:68",
"HH Jung, H Haker. Schizophrenia as a manifestation of X-linked Mcleod-Neuroacanthocytosis syndrome.. J Clin Psychiatry 2004;65:722-3",
"HH Jung, M Hergersberg, S Kneifel, H Alkadhi, R Schiess, M Weigell-Weber, G Daniels, S Kollias, K Hess. McLeod syndrome: a novel mutation, predominant psychiatric manifestations, and distinct striatal imaging findings.. Ann Neurol 2001a;49:384-92",
"HH Jung, M Hergersberg, M Vogt, J Pahnke, V Treyer, B Rothlisberger, SS Kollias, D Russo, BM Frey. McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement.. Transfusion 2003;43:928-38",
"HH Jung, D Russo, C Redman, S Brandner. Kell and XK immunohistochemistry in McLeod myopathy.. Muscle Nerve 2001b;24:1346-51",
"R Kassubek, I Uttner, C Schönfeldt-Lecuona, J Kassubek, BJ Connemann. Extending the aceruloplasminemia phenotype: NBIA on imaging and acanthocytosis, yet only minor neurological findings.. J Neurol Sci. 2017;376:151-2",
"T Kawakami, Y Takiyama, K Sakoe, T Ogawa, T Yoshioka, M Nishizawa, ME Reid, O Kobayashi, I Nonaka, I Nakano. A case of McLeod syndrome with unusually severe myopathy.. J Neurol Sci 1999;166:36-9",
"N Kumar, M Leonzino, W Hancock-Cerutti, FA Horenkamp, P Li, JA Lees, H Wheeler, KM Reinisch, P De Camilli. VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites.. J Cell Biol. 2018;217:3625-39",
"C Laurencin, L Sebbag, G Jousserand, M Demontes, L Campean, F Thivolet-Bejui, AS Lebre, S Thobois. Novel XK mutation in a McLeod patient diagnosed after heart transplant.. Clin Neurol Neurosurg. 2018;168:64-66",
"S Lee, D Russo, C Redman. Functional and structural aspects of the Kell blood group system.. Transfus Med Rev 2000;14:93-103",
"S Lee, Q Sha, X Wu, G Calenda, J Peng. Expression profiles of mouse Kell, XK, and XPLAC mRNA.. J Histochem Cytochem. 2007;55:365-74",
"SE Lux. Anatomy of the red cell membrane skeleton: unanswered questions.. Blood 2016;127:187-99",
"DJ Nicholl, I Sutton, MT Dotti, SG Supple, A Danek, M Lawden. White matter abnormalities on MRI in neuroacanthocytosis.. J Neurol Neurosurg Psychiatry 2004;75:1200-1",
"E Oechslin, D Kaup, R Jenni, HH Jung. Cardiac abnormalities in McLeod syndrome.. Int J Cardiol. 2009;132:130-2",
"M Oechsner, R Buchert, W Beyer, A Danek. Reduction of striatal glucose metabolism in McLeod choreoacanthocytosis.. J Neurol Neurosurg Psychiatry 2001;70:517-20",
"R Øyen, ME Reid, P Rubinstein, H Ralph. A method to detect McLeod phenotype red blood cells.. Immunohematology. 1996;12:160-3",
"JS Park, AM Neiman. XK is a partner for VPS13A: a molecular link between chorea-acanthocytosis and McLeod syndrome.. Mol Biol Cell. 2020;31:2425-36",
"J Peng, CM Redman, X Wu, X Song, RH Walker, CM Westhoff, S Lee. Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases.. Gene. 2007;392:142-50",
"S Quick, FM Heidrich, MV Winkler, AH Winkler, K Ibrahim, A Linke, U Speiser, U Grabmaier, C Buhmann, F Marxreiter, C Saft, A Danek, A Hermann, K Peikert. Cardiac manifestation is evident in chorea-acanthocytosis but different from McLeod syndrome.. Parkinsonism Relat Disord. 2021;88:90-5",
"A Rivera, S Kam, M Ho, J Romero, S. Lee. Ablation of the Kell/Xk complex alters erythrocyte divalent cation homeostasis.. Blood Cells Mol Dis. 2013;50:80-5",
"E Roulis, C Hyland, R Flower, C Gassner, HH Jung, BM Frey. JAMA Neurol. 2018;75:1554-62",
"D Russo, C Redman, S Lee. Association of XK and Kell blood group proteins.. J Biol Chem 1998;273:13950-6",
"D Russo, X Wu, CM Redman, S Lee. Expression of Kell blood group protein in nonerythroid tissues.. Blood 2000;96:340-6",
"BK Singleton, CA Green, S Renaud, P Fuhr, J Poole, GL Daniels. McLeod syndrome resulting from a novel XK mutation.. Br J Haematol 2003;122:682-5",
"A Storch, M Kornhass, J Schwarz. Testing for acanthocytosis A prospective reader-blinded study in movement disorder patients.. J Neurol 2005;252:84-90",
"SG Supple, HJ Iland, MH Barnett, JD Pollard. A spontaneous novel XK gene mutation in a patient with McLeod syndrome.. Br J Haematol 2001;115:369-72",
"O Sveinsson, B Udd, P Svenningsson, C Gassner, C Engström, J Laffita-Mesa, G Solders, S Hertegård, I Savitcheva, HH Jung, M Tolnay, BM Frey, M Paucar. Involuntary movements, vocalizations and cognitive decline.. Parkinsonism Relat Disord. 2020;79:135-7",
"M Swash, MS Schwartz, ND Carter, R Heath, M Leak, KL Rogers. Benign X-linked myopathy with acanthocytes (McLeod syndrome). Its relationship to X-linked muscular dystrophy.. Brain 1983;106:717-33",
"WA Symmans, CS Shepherd, WL Marsh, R Øyen, SB Shohet, BJ Linehan. Hereditary acanthocytosis associated with the McLeod phenotype of the Kell blood group system.. Br J Haematol 1979;42:575-83",
"P Tarugi, M Averna. Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum.. Adv Clin Chem 2011;54:81-107",
"Y Urata, M Nakamura, N Sasaki, N Shiokawa, Y Nishida, K Arai, H Hiwatashi, I Yokoyama, S Narumi, Y Terayama, T Murakami, Y Ugawa, H Sakamoto, S Kaneko, Y Nakazawa, R Yamasaki, S Sadashima, T Sakai, H Arai, A. Sano. Novel pathogenic XK mutations in McLeod syndrome and interaction between XK protein and chorein.. Neurol Genet. 2019;5",
"PO Valko, J Hänggi, M Meyer, HH Jung. Evolution of striatal degeneration in McLeod syndrome.. Eur J Neurol. 2010;17:612-8",
"RH Walker, A Danek. \"Neuroacanthocytosis\" - overdue for a taxonomic update.. Tremor Other Hyperkinet Mov (N Y) 2021;11:1",
"RH Walker, A Danek, I Uttner, R Offner, M Reid, S Lee. McLeod phenotype without the McLeod syndrome.. Transfusion. 2007a;47:299-305",
"RH Walker, RA Hegele, A Danek. Comment on \"A New Allelic Variant in the PANK2 gene in a patient with incomplete HARP syndrome.\". J Mov Disord. 2021;14:254-5",
"RH Walker, HH Jung, F Tison, S Lee, A Danek. Phenotypic variation among brothers with the McLeod neuroacanthocytosis syndrome.. Mov Disord 2007b;22:244-8",
"RH Walker, M Miranda, HH Jung, A Danek. Life expectancy and mortality in chorea-acanthocytosis and McLeod syndrome.. Parkinsonism Relat Disord. 2019;60:158-61",
"M Walterfang, A Evans, JC Looi, HH Jung, A Danek, RH Walker, D Velakoulis. The neuropsychiatry of neuroacanthocytosis syndromes.. Neurosci Biobehav Rev. 2011;35:1275-83",
"J Weaver, H Sarva, D Barone, S Bobker, K Bushara, A Hiller, M Ishii, J Jankovic, S Lakhani, K Niotis, DW Scharre, P Tuite, A Stutz, CM Westhoff, RH Walker. McLeod syndrome: five new pedigrees with novel mutations.. Parkinsonism Relat Disord. 2019;64:293-9",
"S Wendel, R Fontão-Wendel, JE Levi, MG Aravechia, RF Bordokan, D Russo, MS. A Haddad. McLeod phenotype detected by random screening for K:-4 [Kp(b-)] blood donors in Brazil.. Transfusion. 2004;44:1579-87",
"TN Witt, A Danek, M Reiter, MU Heim, J Dirschinger, EG Olsen. McLeod syndrome: a distinct form of neuroacanthocytosis. Report of two cases and literature review with emphasis on neuromuscular manifestations.. J Neurol 1992;239:302-6",
"WM Yeshaw, M van der Zwaag, F Pinto, LL Lahaye, AI Faber, R Gómez-Sánchez, AM Dolga, C Poland, AP Monaco, SC van IJzendoorn, NA Grzeschik, A Velayos-Baeza, OC Sibon. Human VPS13A is associated with multiple organelles and influences mitochondrial morphology and lipid droplet motility.. Elife. 2019;8"
] |
3/12/2004
|
16/9/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mdef-cmd
|
mdef-cmd
|
[
"Laminin α2 Chain-Deficiency",
"Laminin a2 Chain-Deficiency",
"Congenital Muscular Dystrophy Type 1A (MDC1A)",
"Late-Onset LAMA2 Muscular Dystrophy",
"Laminin subunit alpha-2",
"LAMA2",
"LAMA2 Muscular Dystrophy"
] |
Jorge Oliveira, João Parente Freixo, Manuela Santos, Teresa Coelho
|
Summary The clinical manifestations of In late-onset The diagnosis of
|
Congenital muscular dystrophy type 1A (MDC1A)
Late-onset
For synonyms and outdated names see
• Congenital muscular dystrophy type 1A (MDC1A)
• Late-onset
## Diagnosis
The phenotypic spectrum of
No consensus clinical diagnostic criteria for
Onset at birth or within the first six months of life: profound hypotonia with muscle weakness
Poor spontaneous movements with contractures of the large joints
Feeding difficulties with failure to thrive, aspiration, and recurrent chest infections
Delayed motor development milestones: the majority of affected individuals are able to sit but rarely achieve independent ambulation.
Axial weakness, difficulties in head control (mainly due to flexor muscles of the neck); progressive scoliosis starting in childhood
Absence of findings that could suggest lower motor neuron disease (i.e., tongue fasciculation and areflexia)
Usually normal intellect
Less common findings:
Weak cry often associated with respiratory failure
Epilepsy, including of a refractory nature
Cardiac involvement
Demyelinating progressive sensorimotor neuropathy
Onset during childhood or even adulthood
Proximal muscle weakness with or without muscle hypertrophy, as seen in limb-girdle muscular dystrophies
Delayed motor milestones in childhood, but independent ambulation usually achieved
Less common findings:
Rigid spine syndrome with joint contractures usually most prominent in the elbows
Childhood-onset seizures
Progressive respiratory insufficiency and scoliosis
Cardiomyopathy with or without conduction defect
Polymicrogyria-like patterns (bilaterally in the temporal and occipital lobes) were reported in the majority of 25 individuals. When extensive, the polymicrogyria correlated with epilepsy [
Complete or partial laminin α2 deficiency (muscle and skin)
Increased expression of laminin α4 and α5
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
When the diagnosis of
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Onset at birth or within the first six months of life: profound hypotonia with muscle weakness
• Poor spontaneous movements with contractures of the large joints
• Feeding difficulties with failure to thrive, aspiration, and recurrent chest infections
• Delayed motor development milestones: the majority of affected individuals are able to sit but rarely achieve independent ambulation.
• Axial weakness, difficulties in head control (mainly due to flexor muscles of the neck); progressive scoliosis starting in childhood
• Absence of findings that could suggest lower motor neuron disease (i.e., tongue fasciculation and areflexia)
• Usually normal intellect
• Less common findings:
• Weak cry often associated with respiratory failure
• Epilepsy, including of a refractory nature
• Cardiac involvement
• Demyelinating progressive sensorimotor neuropathy
• Weak cry often associated with respiratory failure
• Epilepsy, including of a refractory nature
• Cardiac involvement
• Demyelinating progressive sensorimotor neuropathy
• Weak cry often associated with respiratory failure
• Epilepsy, including of a refractory nature
• Cardiac involvement
• Demyelinating progressive sensorimotor neuropathy
• Onset during childhood or even adulthood
• Proximal muscle weakness with or without muscle hypertrophy, as seen in limb-girdle muscular dystrophies
• Delayed motor milestones in childhood, but independent ambulation usually achieved
• Less common findings:
• Rigid spine syndrome with joint contractures usually most prominent in the elbows
• Childhood-onset seizures
• Progressive respiratory insufficiency and scoliosis
• Cardiomyopathy with or without conduction defect
• Rigid spine syndrome with joint contractures usually most prominent in the elbows
• Childhood-onset seizures
• Progressive respiratory insufficiency and scoliosis
• Cardiomyopathy with or without conduction defect
• Rigid spine syndrome with joint contractures usually most prominent in the elbows
• Childhood-onset seizures
• Progressive respiratory insufficiency and scoliosis
• Cardiomyopathy with or without conduction defect
• Polymicrogyria-like patterns (bilaterally in the temporal and occipital lobes) were reported in the majority of 25 individuals. When extensive, the polymicrogyria correlated with epilepsy [
• Complete or partial laminin α2 deficiency (muscle and skin)
• Increased expression of laminin α4 and α5
## Suggestive Findings
Onset at birth or within the first six months of life: profound hypotonia with muscle weakness
Poor spontaneous movements with contractures of the large joints
Feeding difficulties with failure to thrive, aspiration, and recurrent chest infections
Delayed motor development milestones: the majority of affected individuals are able to sit but rarely achieve independent ambulation.
Axial weakness, difficulties in head control (mainly due to flexor muscles of the neck); progressive scoliosis starting in childhood
Absence of findings that could suggest lower motor neuron disease (i.e., tongue fasciculation and areflexia)
Usually normal intellect
Less common findings:
Weak cry often associated with respiratory failure
Epilepsy, including of a refractory nature
Cardiac involvement
Demyelinating progressive sensorimotor neuropathy
Onset during childhood or even adulthood
Proximal muscle weakness with or without muscle hypertrophy, as seen in limb-girdle muscular dystrophies
Delayed motor milestones in childhood, but independent ambulation usually achieved
Less common findings:
Rigid spine syndrome with joint contractures usually most prominent in the elbows
Childhood-onset seizures
Progressive respiratory insufficiency and scoliosis
Cardiomyopathy with or without conduction defect
Polymicrogyria-like patterns (bilaterally in the temporal and occipital lobes) were reported in the majority of 25 individuals. When extensive, the polymicrogyria correlated with epilepsy [
Complete or partial laminin α2 deficiency (muscle and skin)
Increased expression of laminin α4 and α5
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
• Onset at birth or within the first six months of life: profound hypotonia with muscle weakness
• Poor spontaneous movements with contractures of the large joints
• Feeding difficulties with failure to thrive, aspiration, and recurrent chest infections
• Delayed motor development milestones: the majority of affected individuals are able to sit but rarely achieve independent ambulation.
• Axial weakness, difficulties in head control (mainly due to flexor muscles of the neck); progressive scoliosis starting in childhood
• Absence of findings that could suggest lower motor neuron disease (i.e., tongue fasciculation and areflexia)
• Usually normal intellect
• Less common findings:
• Weak cry often associated with respiratory failure
• Epilepsy, including of a refractory nature
• Cardiac involvement
• Demyelinating progressive sensorimotor neuropathy
• Weak cry often associated with respiratory failure
• Epilepsy, including of a refractory nature
• Cardiac involvement
• Demyelinating progressive sensorimotor neuropathy
• Weak cry often associated with respiratory failure
• Epilepsy, including of a refractory nature
• Cardiac involvement
• Demyelinating progressive sensorimotor neuropathy
• Onset during childhood or even adulthood
• Proximal muscle weakness with or without muscle hypertrophy, as seen in limb-girdle muscular dystrophies
• Delayed motor milestones in childhood, but independent ambulation usually achieved
• Less common findings:
• Rigid spine syndrome with joint contractures usually most prominent in the elbows
• Childhood-onset seizures
• Progressive respiratory insufficiency and scoliosis
• Cardiomyopathy with or without conduction defect
• Rigid spine syndrome with joint contractures usually most prominent in the elbows
• Childhood-onset seizures
• Progressive respiratory insufficiency and scoliosis
• Cardiomyopathy with or without conduction defect
• Rigid spine syndrome with joint contractures usually most prominent in the elbows
• Childhood-onset seizures
• Progressive respiratory insufficiency and scoliosis
• Cardiomyopathy with or without conduction defect
• Polymicrogyria-like patterns (bilaterally in the temporal and occipital lobes) were reported in the majority of 25 individuals. When extensive, the polymicrogyria correlated with epilepsy [
• Complete or partial laminin α2 deficiency (muscle and skin)
• Increased expression of laminin α4 and α5
## Clinical Findings by Age of Onset
Onset at birth or within the first six months of life: profound hypotonia with muscle weakness
Poor spontaneous movements with contractures of the large joints
Feeding difficulties with failure to thrive, aspiration, and recurrent chest infections
Delayed motor development milestones: the majority of affected individuals are able to sit but rarely achieve independent ambulation.
Axial weakness, difficulties in head control (mainly due to flexor muscles of the neck); progressive scoliosis starting in childhood
Absence of findings that could suggest lower motor neuron disease (i.e., tongue fasciculation and areflexia)
Usually normal intellect
Less common findings:
Weak cry often associated with respiratory failure
Epilepsy, including of a refractory nature
Cardiac involvement
Demyelinating progressive sensorimotor neuropathy
Onset during childhood or even adulthood
Proximal muscle weakness with or without muscle hypertrophy, as seen in limb-girdle muscular dystrophies
Delayed motor milestones in childhood, but independent ambulation usually achieved
Less common findings:
Rigid spine syndrome with joint contractures usually most prominent in the elbows
Childhood-onset seizures
Progressive respiratory insufficiency and scoliosis
Cardiomyopathy with or without conduction defect
• Onset at birth or within the first six months of life: profound hypotonia with muscle weakness
• Poor spontaneous movements with contractures of the large joints
• Feeding difficulties with failure to thrive, aspiration, and recurrent chest infections
• Delayed motor development milestones: the majority of affected individuals are able to sit but rarely achieve independent ambulation.
• Axial weakness, difficulties in head control (mainly due to flexor muscles of the neck); progressive scoliosis starting in childhood
• Absence of findings that could suggest lower motor neuron disease (i.e., tongue fasciculation and areflexia)
• Usually normal intellect
• Less common findings:
• Weak cry often associated with respiratory failure
• Epilepsy, including of a refractory nature
• Cardiac involvement
• Demyelinating progressive sensorimotor neuropathy
• Weak cry often associated with respiratory failure
• Epilepsy, including of a refractory nature
• Cardiac involvement
• Demyelinating progressive sensorimotor neuropathy
• Weak cry often associated with respiratory failure
• Epilepsy, including of a refractory nature
• Cardiac involvement
• Demyelinating progressive sensorimotor neuropathy
• Onset during childhood or even adulthood
• Proximal muscle weakness with or without muscle hypertrophy, as seen in limb-girdle muscular dystrophies
• Delayed motor milestones in childhood, but independent ambulation usually achieved
• Less common findings:
• Rigid spine syndrome with joint contractures usually most prominent in the elbows
• Childhood-onset seizures
• Progressive respiratory insufficiency and scoliosis
• Cardiomyopathy with or without conduction defect
• Rigid spine syndrome with joint contractures usually most prominent in the elbows
• Childhood-onset seizures
• Progressive respiratory insufficiency and scoliosis
• Cardiomyopathy with or without conduction defect
• Rigid spine syndrome with joint contractures usually most prominent in the elbows
• Childhood-onset seizures
• Progressive respiratory insufficiency and scoliosis
• Cardiomyopathy with or without conduction defect
## Laboratory and Neuroimaging Findings
Polymicrogyria-like patterns (bilaterally in the temporal and occipital lobes) were reported in the majority of 25 individuals. When extensive, the polymicrogyria correlated with epilepsy [
Complete or partial laminin α2 deficiency (muscle and skin)
Increased expression of laminin α4 and α5
• Polymicrogyria-like patterns (bilaterally in the temporal and occipital lobes) were reported in the majority of 25 individuals. When extensive, the polymicrogyria correlated with epilepsy [
• Complete or partial laminin α2 deficiency (muscle and skin)
• Increased expression of laminin α4 and α5
## Family History
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
When the diagnosis of
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of
## Option 2
For an introduction to multigene panels click
## Option 3
When the diagnosis of
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
The clinical manifestations of
Those with congenital muscular dystrophy type 1A (MDC1A) typically have neonatal profound hypotonia, poor spontaneous movements, and respiratory failure [
Late-onset
The need for ventilatory support is most likely to occur during two time periods [
Between birth and age five years in the most severely affected children mainly due to respiratory muscle weakness, hypotonia, and fatigue. Depending on age, total hours of ventilatory support required, frequency of hospitalizations, and institutional practice patterns, ventilatory support may be noninvasive or mechanical with tracheostomy. Respiratory issues in these infants and young children often stabilize in the first years, likely as a result of improved muscle tone.
Between ages ten and 15 years due to progressive restrictive lung disease leading to respiratory insufficiency [
Hyperlaxity of the distal phalanges of the fingers is observed in a number of affected children.
Cognitive impairment, reported in fewer than 7% of individuals [
Secondary pulmonary hypertension may be observed as a complication of respiratory insufficiency [
The onset of this milder phenotype ranges from early childhood to adulthood. Although children may have delayed motor milestones, they acquire independent ambulation. Proximal muscle weakness is slowly progressive in a pattern similar to that of other limb-girdle muscular dystrophies. Long-term consequences include wheelchair dependence, scoliosis, and respiratory problems [
Weakness is also associated with marked contractures (mainly in the elbows and Achilles tendon) [
Some individuals have rigid spine syndrome and/or muscle pseudohypertrophy [
Peripheral nerve demyelination may be detected with nerve conduction studies; however, most commonly there are no significant clinical consequences [
Severe epilepsy and intellectual disability are described in some individuals.
Prognostication of clinical severity depends on several variables including age at onset of first manifestations,
Individuals with early-onset
The abbreviation
Based on a nomenclature system that describes which chains are present in each laminin isoform, merosin was given the name
Late-onset
Exact prevalence of congenital muscular dystrophy type 1A (MDC1A) is still unknown. The prevalence of congenital muscular dystrophies (CMD) has been estimated between 0.563:100,000 (in Italy [
Geographic prevalence of MDC1A is also quite variable:
In Europe it accounts for about 30% of CMD, whereas in Japan it accounts for only 6% [
In the United Kingdom it accounts for 37.4% of CMD, making it the most common cause [
In Italy it accounts for 24.1% of CMD, making it the second most common cause [
In Australia it accounts for 16% of CMD, making it the third most common cause [
• Between birth and age five years in the most severely affected children mainly due to respiratory muscle weakness, hypotonia, and fatigue. Depending on age, total hours of ventilatory support required, frequency of hospitalizations, and institutional practice patterns, ventilatory support may be noninvasive or mechanical with tracheostomy. Respiratory issues in these infants and young children often stabilize in the first years, likely as a result of improved muscle tone.
• Between ages ten and 15 years due to progressive restrictive lung disease leading to respiratory insufficiency [
• In Europe it accounts for about 30% of CMD, whereas in Japan it accounts for only 6% [
• In the United Kingdom it accounts for 37.4% of CMD, making it the most common cause [
• In Italy it accounts for 24.1% of CMD, making it the second most common cause [
• In Australia it accounts for 16% of CMD, making it the third most common cause [
## Clinical Description
The clinical manifestations of
Those with congenital muscular dystrophy type 1A (MDC1A) typically have neonatal profound hypotonia, poor spontaneous movements, and respiratory failure [
Late-onset
The need for ventilatory support is most likely to occur during two time periods [
Between birth and age five years in the most severely affected children mainly due to respiratory muscle weakness, hypotonia, and fatigue. Depending on age, total hours of ventilatory support required, frequency of hospitalizations, and institutional practice patterns, ventilatory support may be noninvasive or mechanical with tracheostomy. Respiratory issues in these infants and young children often stabilize in the first years, likely as a result of improved muscle tone.
Between ages ten and 15 years due to progressive restrictive lung disease leading to respiratory insufficiency [
Hyperlaxity of the distal phalanges of the fingers is observed in a number of affected children.
Cognitive impairment, reported in fewer than 7% of individuals [
Secondary pulmonary hypertension may be observed as a complication of respiratory insufficiency [
The onset of this milder phenotype ranges from early childhood to adulthood. Although children may have delayed motor milestones, they acquire independent ambulation. Proximal muscle weakness is slowly progressive in a pattern similar to that of other limb-girdle muscular dystrophies. Long-term consequences include wheelchair dependence, scoliosis, and respiratory problems [
Weakness is also associated with marked contractures (mainly in the elbows and Achilles tendon) [
Some individuals have rigid spine syndrome and/or muscle pseudohypertrophy [
Peripheral nerve demyelination may be detected with nerve conduction studies; however, most commonly there are no significant clinical consequences [
Severe epilepsy and intellectual disability are described in some individuals.
• Between birth and age five years in the most severely affected children mainly due to respiratory muscle weakness, hypotonia, and fatigue. Depending on age, total hours of ventilatory support required, frequency of hospitalizations, and institutional practice patterns, ventilatory support may be noninvasive or mechanical with tracheostomy. Respiratory issues in these infants and young children often stabilize in the first years, likely as a result of improved muscle tone.
• Between ages ten and 15 years due to progressive restrictive lung disease leading to respiratory insufficiency [
## Congenital Muscular Dystrophy Type 1A (MDC1A)
The need for ventilatory support is most likely to occur during two time periods [
Between birth and age five years in the most severely affected children mainly due to respiratory muscle weakness, hypotonia, and fatigue. Depending on age, total hours of ventilatory support required, frequency of hospitalizations, and institutional practice patterns, ventilatory support may be noninvasive or mechanical with tracheostomy. Respiratory issues in these infants and young children often stabilize in the first years, likely as a result of improved muscle tone.
Between ages ten and 15 years due to progressive restrictive lung disease leading to respiratory insufficiency [
Hyperlaxity of the distal phalanges of the fingers is observed in a number of affected children.
Cognitive impairment, reported in fewer than 7% of individuals [
Secondary pulmonary hypertension may be observed as a complication of respiratory insufficiency [
• Between birth and age five years in the most severely affected children mainly due to respiratory muscle weakness, hypotonia, and fatigue. Depending on age, total hours of ventilatory support required, frequency of hospitalizations, and institutional practice patterns, ventilatory support may be noninvasive or mechanical with tracheostomy. Respiratory issues in these infants and young children often stabilize in the first years, likely as a result of improved muscle tone.
• Between ages ten and 15 years due to progressive restrictive lung disease leading to respiratory insufficiency [
## Late-Onset
The onset of this milder phenotype ranges from early childhood to adulthood. Although children may have delayed motor milestones, they acquire independent ambulation. Proximal muscle weakness is slowly progressive in a pattern similar to that of other limb-girdle muscular dystrophies. Long-term consequences include wheelchair dependence, scoliosis, and respiratory problems [
Weakness is also associated with marked contractures (mainly in the elbows and Achilles tendon) [
Some individuals have rigid spine syndrome and/or muscle pseudohypertrophy [
Peripheral nerve demyelination may be detected with nerve conduction studies; however, most commonly there are no significant clinical consequences [
Severe epilepsy and intellectual disability are described in some individuals.
## Genotype-Phenotype Correlations
Prognostication of clinical severity depends on several variables including age at onset of first manifestations,
## Nomenclature
Individuals with early-onset
The abbreviation
Based on a nomenclature system that describes which chains are present in each laminin isoform, merosin was given the name
Late-onset
## Prevalence
Exact prevalence of congenital muscular dystrophy type 1A (MDC1A) is still unknown. The prevalence of congenital muscular dystrophies (CMD) has been estimated between 0.563:100,000 (in Italy [
Geographic prevalence of MDC1A is also quite variable:
In Europe it accounts for about 30% of CMD, whereas in Japan it accounts for only 6% [
In the United Kingdom it accounts for 37.4% of CMD, making it the most common cause [
In Italy it accounts for 24.1% of CMD, making it the second most common cause [
In Australia it accounts for 16% of CMD, making it the third most common cause [
• In Europe it accounts for about 30% of CMD, whereas in Japan it accounts for only 6% [
• In the United Kingdom it accounts for 37.4% of CMD, making it the most common cause [
• In Italy it accounts for 24.1% of CMD, making it the second most common cause [
• In Australia it accounts for 16% of CMD, making it the third most common cause [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Progressive improvement of tone and strength (in some affected individuals), CK levels near normal range values, diagnostic structural abnormalities on muscle biopsy (by light and electron microscopy), and an absence of joint contractures (even when the disease is severe) in the congenital myopathies;
Multisystemic presentation (e.g., liver and cardiac involvement besides muscle weakness) in congenital metabolic myopathies.
Selected Genes of Interest in the Differential Diagnosis of MDC1A
AD = autosomal dominant; AR = autosomal recessive; CMD = congenital muscular dystrophy; MOI = mode of inheritance; XL = X-linked
In addition to absence of brain white matter changes
Immunohistochemical analysis of muscle or skin biopsies can be diagnostically useful, showing variable reduction of antibody labeling against collagen VI or glycosylated α-dystroglycan.
The Ullrich congenital muscular dystrophy phenotype is usually inherited in an autosomal recessive manner; however, exceptions occur.
Selected examples of congenital myopathies are included in
Minicore disease is most often inherited in an autosomal recessive manner. The report of minicore disease in two generations in a few families also suggested autosomal dominant inheritance.
Most commonly associated of ~30 known genes; pathogenic variants in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of congenital myasthenic syndromes.
The detection of the genetic defect causing spinal muscular atrophy (deletion involving
Genes of Interest in the Differential Diagnosis of Late-Onset
Cardiac disease (in all affected persons) w/conduction defects & arrhythmias
Absence of the characteristic brain MRI findings assoc w/
Contractures, present early in disease, can be more disabling than muscle weakness & usually → persistent severe flexion contractures.
If no typical skin changes (e.g., keloids), differential diagnosis is difficult.
Suggestive findings on muscle MRI
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Immunofluorescence and/or western blot in fresh muscle biopsies (or from other affected tissues) can be used to detect changes in emerin or FHL1 proteins.
Immunohistochemical (IHC) analysis of muscle or skin biopsies can be diagnostically useful, showing variable reduction of antibody labeling against collagen VI.
• Progressive improvement of tone and strength (in some affected individuals), CK levels near normal range values, diagnostic structural abnormalities on muscle biopsy (by light and electron microscopy), and an absence of joint contractures (even when the disease is severe) in the congenital myopathies;
• Multisystemic presentation (e.g., liver and cardiac involvement besides muscle weakness) in congenital metabolic myopathies.
• Cardiac disease (in all affected persons) w/conduction defects & arrhythmias
• Absence of the characteristic brain MRI findings assoc w/
• Contractures, present early in disease, can be more disabling than muscle weakness & usually → persistent severe flexion contractures.
• If no typical skin changes (e.g., keloids), differential diagnosis is difficult.
• Suggestive findings on muscle MRI
## Management
Published consensus clinical practice guidelines for congenital muscular dystrophies list recommendations for the following six clinical care areas: neurology, pulmonary, gastrointestinal/nutritional/oral care, orthopedics and rehabilitation, cardiology, and palliative care [
To establish the extent of disease and needs of a child diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Need for adaptive devices
Need for PT (for improving gross motor skills) &/or OT (for improving fine motor skills)
Nutritional status
For GERD
Constipation
Secretion management, aspiration risk
Optimal position for feeding
Bone health (serum concentrations of vitamin D & calcium)
Assess pulmonary function.
Evaluate for evidence of nocturnal hypoventilation esp in children w/recurrent respiratory infections, FTT, poor cry, or feeding fatigue.
To incl motor, speech/language eval, & general cognitive skills
Eval for early intervention/special education in least restrictive educational environment
Social work involvement to connect families w/local resources, respite, & support;
Use of
Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies;
Need for palliative care.
FTT = failure to thrive; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Management ideally involves multidisciplinary care by specialists in relevant fields (see
Treatment of Manifestations in Individuals with Congenital Muscular Dystrophy Type 1A
Low threshold for radiographic swallowing study if evidence of dysphagia
Gastrostomy tube placement may be required for persistent feeding issues.
Maintenance of function & mobility
Prevention or treatment of joint & neck contractures & spine deformities
Activities to improve respiratory function
Adequate seating & wheelchair support
Appropriate conservation vs surgical management of spine, hips, & ankles
Goals are clearance of secretions & assisted ventilation as needed to maintain oxygenation & avoid hypercapnia.
Aggressive treatment of respiratory infections
Consider positive-pressure ventilation & tracheostomy in individuals w/severe bulbar involvement & chronic aspiration & pneumonia.
ASM = anti-seizure medication; DD = developmental delay; FTT = failure to thrive; ID = intellectual disability; OT = occupational therapist; PT = physical therapist
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary significantly from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Consider evaluation for alternative means of communication (e.g.,
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications such as medication used to treat attention-deficit/hyperactivity disorder when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
The care measures are similar to those described for children but adapted to age and phenotype. A multidisciplinary approach includes respiratory and orthopedic care due to the risk for progressive respiratory insufficiency and joint and spinal deformities. Cardiac surveillance is necessary due to cardiomyopathy and cardiac conduction defects. Regular physical therapy for stretching limbs, shoulder and pelvic girdle, and spine is mandatory. Anti-seizure medication is used to treat seizures.
Recommended Surveillance for Individuals with
At least annually
More often during periods of rapid growth, loss of function, or respiratory compromise
For persons w/severe respiratory insufficiency: at least annually
For those w/palpitations, ↑ fatigue, or loss of consciousness w/o clear neurologic origin
If no cardiac symptoms: at age 5 yrs, 10 yrs, & then every 2 yrs
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
OT = occupational therapy; PT = physical therapy
Avoid the following:
Succinylcholine in induction of anesthesia because of risk of hyperkalemia and cardiac conduction abnormalities
Statins, cholesterol-lowering medications, because of the risk of muscle damage
See
New treatment strategies are being investigated for
Search
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Need for adaptive devices
• Need for PT (for improving gross motor skills) &/or OT (for improving fine motor skills)
• Nutritional status
• For GERD
• Constipation
• Secretion management, aspiration risk
• Optimal position for feeding
• Bone health (serum concentrations of vitamin D & calcium)
• Assess pulmonary function.
• Evaluate for evidence of nocturnal hypoventilation esp in children w/recurrent respiratory infections, FTT, poor cry, or feeding fatigue.
• To incl motor, speech/language eval, & general cognitive skills
• Eval for early intervention/special education in least restrictive educational environment
• Social work involvement to connect families w/local resources, respite, & support;
• Use of
• Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies;
• Need for palliative care.
• Low threshold for radiographic swallowing study if evidence of dysphagia
• Gastrostomy tube placement may be required for persistent feeding issues.
• Maintenance of function & mobility
• Prevention or treatment of joint & neck contractures & spine deformities
• Activities to improve respiratory function
• Adequate seating & wheelchair support
• Appropriate conservation vs surgical management of spine, hips, & ankles
• Goals are clearance of secretions & assisted ventilation as needed to maintain oxygenation & avoid hypercapnia.
• Aggressive treatment of respiratory infections
• Consider positive-pressure ventilation & tracheostomy in individuals w/severe bulbar involvement & chronic aspiration & pneumonia.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• At least annually
• More often during periods of rapid growth, loss of function, or respiratory compromise
• For persons w/severe respiratory insufficiency: at least annually
• For those w/palpitations, ↑ fatigue, or loss of consciousness w/o clear neurologic origin
• If no cardiac symptoms: at age 5 yrs, 10 yrs, & then every 2 yrs
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
• Succinylcholine in induction of anesthesia because of risk of hyperkalemia and cardiac conduction abnormalities
• Statins, cholesterol-lowering medications, because of the risk of muscle damage
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of a child diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Need for adaptive devices
Need for PT (for improving gross motor skills) &/or OT (for improving fine motor skills)
Nutritional status
For GERD
Constipation
Secretion management, aspiration risk
Optimal position for feeding
Bone health (serum concentrations of vitamin D & calcium)
Assess pulmonary function.
Evaluate for evidence of nocturnal hypoventilation esp in children w/recurrent respiratory infections, FTT, poor cry, or feeding fatigue.
To incl motor, speech/language eval, & general cognitive skills
Eval for early intervention/special education in least restrictive educational environment
Social work involvement to connect families w/local resources, respite, & support;
Use of
Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies;
Need for palliative care.
FTT = failure to thrive; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Need for adaptive devices
• Need for PT (for improving gross motor skills) &/or OT (for improving fine motor skills)
• Nutritional status
• For GERD
• Constipation
• Secretion management, aspiration risk
• Optimal position for feeding
• Bone health (serum concentrations of vitamin D & calcium)
• Assess pulmonary function.
• Evaluate for evidence of nocturnal hypoventilation esp in children w/recurrent respiratory infections, FTT, poor cry, or feeding fatigue.
• To incl motor, speech/language eval, & general cognitive skills
• Eval for early intervention/special education in least restrictive educational environment
• Social work involvement to connect families w/local resources, respite, & support;
• Use of
• Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies;
• Need for palliative care.
## Treatment of Manifestations
Management ideally involves multidisciplinary care by specialists in relevant fields (see
Treatment of Manifestations in Individuals with Congenital Muscular Dystrophy Type 1A
Low threshold for radiographic swallowing study if evidence of dysphagia
Gastrostomy tube placement may be required for persistent feeding issues.
Maintenance of function & mobility
Prevention or treatment of joint & neck contractures & spine deformities
Activities to improve respiratory function
Adequate seating & wheelchair support
Appropriate conservation vs surgical management of spine, hips, & ankles
Goals are clearance of secretions & assisted ventilation as needed to maintain oxygenation & avoid hypercapnia.
Aggressive treatment of respiratory infections
Consider positive-pressure ventilation & tracheostomy in individuals w/severe bulbar involvement & chronic aspiration & pneumonia.
ASM = anti-seizure medication; DD = developmental delay; FTT = failure to thrive; ID = intellectual disability; OT = occupational therapist; PT = physical therapist
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary significantly from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Consider evaluation for alternative means of communication (e.g.,
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications such as medication used to treat attention-deficit/hyperactivity disorder when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
The care measures are similar to those described for children but adapted to age and phenotype. A multidisciplinary approach includes respiratory and orthopedic care due to the risk for progressive respiratory insufficiency and joint and spinal deformities. Cardiac surveillance is necessary due to cardiomyopathy and cardiac conduction defects. Regular physical therapy for stretching limbs, shoulder and pelvic girdle, and spine is mandatory. Anti-seizure medication is used to treat seizures.
• Low threshold for radiographic swallowing study if evidence of dysphagia
• Gastrostomy tube placement may be required for persistent feeding issues.
• Maintenance of function & mobility
• Prevention or treatment of joint & neck contractures & spine deformities
• Activities to improve respiratory function
• Adequate seating & wheelchair support
• Appropriate conservation vs surgical management of spine, hips, & ankles
• Goals are clearance of secretions & assisted ventilation as needed to maintain oxygenation & avoid hypercapnia.
• Aggressive treatment of respiratory infections
• Consider positive-pressure ventilation & tracheostomy in individuals w/severe bulbar involvement & chronic aspiration & pneumonia.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary significantly from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Communication Issues
Consider evaluation for alternative means of communication (e.g.,
## Social/Behavioral Concerns
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications such as medication used to treat attention-deficit/hyperactivity disorder when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Late-Onset
The care measures are similar to those described for children but adapted to age and phenotype. A multidisciplinary approach includes respiratory and orthopedic care due to the risk for progressive respiratory insufficiency and joint and spinal deformities. Cardiac surveillance is necessary due to cardiomyopathy and cardiac conduction defects. Regular physical therapy for stretching limbs, shoulder and pelvic girdle, and spine is mandatory. Anti-seizure medication is used to treat seizures.
## Surveillance
Recommended Surveillance for Individuals with
At least annually
More often during periods of rapid growth, loss of function, or respiratory compromise
For persons w/severe respiratory insufficiency: at least annually
For those w/palpitations, ↑ fatigue, or loss of consciousness w/o clear neurologic origin
If no cardiac symptoms: at age 5 yrs, 10 yrs, & then every 2 yrs
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
OT = occupational therapy; PT = physical therapy
• At least annually
• More often during periods of rapid growth, loss of function, or respiratory compromise
• For persons w/severe respiratory insufficiency: at least annually
• For those w/palpitations, ↑ fatigue, or loss of consciousness w/o clear neurologic origin
• If no cardiac symptoms: at age 5 yrs, 10 yrs, & then every 2 yrs
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
## Agents/Circumstances to Avoid
Avoid the following:
Succinylcholine in induction of anesthesia because of risk of hyperkalemia and cardiac conduction abnormalities
Statins, cholesterol-lowering medications, because of the risk of muscle damage
• Succinylcholine in induction of anesthesia because of risk of hyperkalemia and cardiac conduction abnormalities
• Statins, cholesterol-lowering medications, because of the risk of muscle damage
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
New treatment strategies are being investigated for
Search
## Genetic Counseling
In most families, both parents of an affected child are carriers of one
Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
Appears to have homozygous
Has compound heterozygous
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
If only one parent is heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• In most families, both parents of an affected child are carriers of one
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
• Appears to have homozygous
• Has compound heterozygous
• Appears to have homozygous
• Has compound heterozygous
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Appears to have homozygous
• Has compound heterozygous
• If both parents are known to be heterozygous for a
• If only one parent is heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
In most families, both parents of an affected child are carriers of one
Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
Appears to have homozygous
Has compound heterozygous
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
If only one parent is heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• In most families, both parents of an affected child are carriers of one
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
• Appears to have homozygous
• Has compound heterozygous
• Appears to have homozygous
• Has compound heterozygous
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Appears to have homozygous
• Has compound heterozygous
• If both parents are known to be heterozygous for a
• If only one parent is heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
France
Japan
United Kingdom
CMDIR/Cure CMD
•
• France
•
•
•
•
•
•
• Japan
•
•
•
•
• United Kingdom
•
•
•
• CMDIR/Cure CMD
•
## Molecular Genetics
LAMA2 Muscular Dystrophy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for LAMA2 Muscular Dystrophy (
Laminins are a group of heterotrimeric glycoproteins, composed of a heavy α chain and two light chains, β and γ, each encoded by separate genes. To date, five α chains (designated α1 to α5), three β chains (β1 to β3), and three γ chains (γ1 to γ3) have been identified, which combine to form 15 laminin isoforms [
The link between the sarcolemma of muscle fibers and the extracellular matrix is established by laminin-211, being a major component of the extrasynaptic skeletal muscle basement membrane [
Partial laminin-211 deficiency, caused by missense or in-frame variants in at least one of the mutated disease alleles, is associated with later onset and a milder phenotype.
Notable
Variants listed in the table have been provided by the authors.
Deletion of exon 3
Deletion of exon 56
## Molecular Pathogenesis
Laminins are a group of heterotrimeric glycoproteins, composed of a heavy α chain and two light chains, β and γ, each encoded by separate genes. To date, five α chains (designated α1 to α5), three β chains (β1 to β3), and three γ chains (γ1 to γ3) have been identified, which combine to form 15 laminin isoforms [
The link between the sarcolemma of muscle fibers and the extracellular matrix is established by laminin-211, being a major component of the extrasynaptic skeletal muscle basement membrane [
Partial laminin-211 deficiency, caused by missense or in-frame variants in at least one of the mutated disease alleles, is associated with later onset and a milder phenotype.
Notable
Variants listed in the table have been provided by the authors.
Deletion of exon 3
Deletion of exon 56
## References
Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K,Cohn D, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, Nelson LL, Rahbek J, Quijano-Roy S, Sewry C, Storhaug K, Simonds A, Tseng B, Vajsar J, Vianello A, Zeller R. Consensus statement on standard of care for congenital muscular dystrophies. Available
• Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K,Cohn D, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, Nelson LL, Rahbek J, Quijano-Roy S, Sewry C, Storhaug K, Simonds A, Tseng B, Vajsar J, Vianello A, Zeller R. Consensus statement on standard of care for congenital muscular dystrophies. Available
## Published Guidelines / Consensus Statements
Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K,Cohn D, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, Nelson LL, Rahbek J, Quijano-Roy S, Sewry C, Storhaug K, Simonds A, Tseng B, Vajsar J, Vianello A, Zeller R. Consensus statement on standard of care for congenital muscular dystrophies. Available
• Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K,Cohn D, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, Nelson LL, Rahbek J, Quijano-Roy S, Sewry C, Storhaug K, Simonds A, Tseng B, Vajsar J, Vianello A, Zeller R. Consensus statement on standard of care for congenital muscular dystrophies. Available
## Literature Cited
## Chapter Notes
JO maintains the
The authors would like to thank the extensive list of collaborators who over the years contributed to improve the current scientific knowledge about
Teresa Coelho, MD, PhD (2020-present)Jorge Oliveira, MSc, PhD (2020-present)João Parente Freixo, MD (2020-present)Susana Quijano-Roy, MD, PhD; Hôpital Raymond Poincaré (2012-2020)Anne Rutkowski, MD; Kaiser Permanente Southern California (2012-2020)Manuela Santos, MD (2020-present)Susan E Sparks, MD, PhD; Sanofi Genzyme (2012-2020)
17 September 2020 (bp) Comprehensive update posted live
7 June 2012 (me) Review posted live
16 March 2010 (ss) Initial submission
• 17 September 2020 (bp) Comprehensive update posted live
• 7 June 2012 (me) Review posted live
• 16 March 2010 (ss) Initial submission
## Author Notes
JO maintains the
## Acknowledgments
The authors would like to thank the extensive list of collaborators who over the years contributed to improve the current scientific knowledge about
## Author History
Teresa Coelho, MD, PhD (2020-present)Jorge Oliveira, MSc, PhD (2020-present)João Parente Freixo, MD (2020-present)Susana Quijano-Roy, MD, PhD; Hôpital Raymond Poincaré (2012-2020)Anne Rutkowski, MD; Kaiser Permanente Southern California (2012-2020)Manuela Santos, MD (2020-present)Susan E Sparks, MD, PhD; Sanofi Genzyme (2012-2020)
## Revision History
17 September 2020 (bp) Comprehensive update posted live
7 June 2012 (me) Review posted live
16 March 2010 (ss) Initial submission
• 17 September 2020 (bp) Comprehensive update posted live
• 7 June 2012 (me) Review posted live
• 16 March 2010 (ss) Initial submission
|
[
"A Abdel Aleem, MF Elsaid, N Chalhoub, A Chakroun, KAS Mohamed, R AlShami, O Kuzu, RB Mohamed, K Ibrahim, N AlMudheki, O Osman, ME Ross. ELalamy O. Clinical and genomic characteristics of LAMA2 related congenital muscular dystrophy in a patients' cohort from Qatar. A population specific founder variant.. Neuromuscul Disord. 2020;30:457-71",
"V Allamand, P Guicheney. Merosin-deficient congenital muscular dystrophy, autosomal recessive (MDC1A, MIM#156225,. Eur J Hum Genet. 2002;10:91-4",
"RC Andrade, J Nevado, MA de Faria Domingues de Lima, T Saad, L Moraes, L Chimelli, P Lapunzina, FR Vargas. Segmental uniparental isodisomy of chromosome 6 causing transient diabetes mellitus and merosin-deficient congenital muscular dystrophy.. Am J Med Genet A. 2014;164A:2908-13",
"M Aumailley, L Bruckner-Tuderman, WG Carter, R Deutzmann, D Edgar, P Ekblom, J Engel, E Engvall, E Hohenester, JC Jones, HK Kleinman, MP Marinkovich, GR Martin, U Mayer, G Meneguzzi, JH Miner, K Miyazaki, M Patarroyo, M Paulsson, V Quaranta, JR Sanes, T Sasaki, K Sekiguchi, LM Sorokin, JF Talts, K Tryggvason, J Uitto, I Virtanen, K von der Mark, UM Wewer, Y Yamada, PD Yurchenco. A simplified laminin nomenclature.. Matrix Biol. 2005;24:326-32",
"G Bentley, F Haddad, TM Bull, D Seingry. The treatment of scoliosis in muscular dystrophy using modified Luque and Harrington-Luque instrumentation.. J Bone Joint Surg Br. 2001;83:22-8",
"CG Bönnemann, CH Wang, S Quijano-Roy, N Deconinck, E Bertini, A Ferreiro, F Muntoni, C Sewry, C Béroud, KD Mathews, SA Moore, J Bellini, A Rutkowski, KN North. Diagnostic approach to the congenital muscular dystrophies.. Neuromuscul Disord. 2014;24:289-311",
"N Carboni, G Marrosu, M Porcu, A Mateddu, E Solla, E Cocco, MA Maioli, V Oppo, R Piras, MG Marrosu. Dilated cardiomyopathy with conduction defects in a patient with partial merosin deficiency due to mutations in the laminin-α2-chain gene: a chance association or a novel phenotype?. Muscle Nerve. 2011;44:826-8",
"SH Chan, AR Foley, R Phadke, AA Mathew, M Pitt, C Sewry, F Muntoni. Limb girdle muscular dystrophy due to LAMA2 mutations: diagnostic difficulties due to associated peripheral neuropathy.. Neuromuscul Disord. 2014;24:677-83",
"N Darin, M Tulinius. Neuromuscular disorders in childhood: a descriptive epidemiological study from western Sweden.. Neuromuscul Disord. 2000;10:1-9",
"C Di Blasi, E Bellafiore, MA Salih, MC Manzini, SA Moore, MZ Seidahmed, MM Mukhtar, ZA Karrar, CA Walsh, KP Campbell, R Mantegazza, L Morandi, M Mora. Variable disease severity in Saudi Arabian and Sudanese families with c.3924 + 2 T > C mutation of LAMA2.. BMC Res Notes. 2011;4:534",
"C Di Blasi, D Piga, P Brioschi, I Moroni, A Pini, A Ruggieri, S Zanotti, G Uziel, L Jarre, E Della Giustina, C Scuderi, C Jonsrud, R Mantegazza, L Morandi, M Mora. Arch Neurol. 2005;62:1582-6",
"A Di Muzio, MV De Angelis, P Di Fulvio, A Ratti, A Pizzuti, L Stuppia, D Gambi, A Uncini. Dysmyelinating sensory-motor neuropathy in merosin-deficient congenital muscular dystrophy.. Muscle Nerve. 2003;27:500-6",
"M Durbeej. Laminin-α2 chain-deficient congenital muscular dystrophy: pathophysiology and development of treatment.. Curr Top Membr. 2015;76:31-60",
"T Endo. Glycobiology of α-dystroglycan and muscular dystrophy.. J Biochem. 2015;157:1-12",
"L Ge, C Zhang, Z Wang, SHS Chan, W Zhu, C Han, X Zhang, H Zheng, L Wu, B Jin, J Shan, B Mao, J Zhong, X Peng, Y Cheng, J Hu, Y Sun, J Lu, Y Hua, S Zhu, C Wei, S Wang, H Jiao, H Yang, X Fu, Y Fan, X Chang, S Wang, X Bao, Y Zhang, J Wang, Y Wu, Y Jiang, Y Yuan, A Rutkowski, CG Bönnemann, W Wei, X Wu, H Xiong. Congenital muscular dystrophies in China.. Clin Genet. 2019;96:207-15",
"F Geranmayeh, E Clement, LH Feng, C Sewry, J Pagan, R Mein, S Abbs, L Brueton, A-M Childs, H Jungbluth, CG De Goede, B Lynch, J-P Lin, G Chow, C de Sousa, O O'Mahony, A Majumdar, V Straub, K Bushby, F Muntoni. Genotype-phenotype correlation in a large population of muscular dystrophy patients with. Neuromuscul Disord. 2010;20:241-50",
"A Graziano, F Bianco, A D'Amico, I Moroni, S Messina, C Bruno, E Pegoraro, M Mora, G Astrea, F Magri, GP Comi, A Berardinelli, M Moggio, L Morandi, A Pini, R Petillo, G Tasca, M Monforte, C Minetti, T Mongini, E Ricci, K Gorni, R Battini, M Villanova, L Politano, F Gualandi, A Ferlini, F Muntoni, FM Santorelli, E Bertini, M Pane, E Mercuri. Prevalence of congenital muscular dystrophy in Italy: a population study.. Neurology. 2015;84:904-11",
"P Guicheney, N Vignier, X Zhang, Y He, C Cruaud, V Frey, A Helbling-Leclerc, P Richard, B Estournet, L Merlini, H Topaloglu, M Mora, JP Harpey, CA Haenggeli, A Barois, B Hainque, K Schwartz, FM Tomé, M Fardeau, K Tryggvason. PCR based mutation screening of the laminin alpha2 chain gene (. J Med Genet. 1998;35:211-7",
"E Harris, M McEntagart, A Topf, H Lochmüller, K Bushby, C Sewry, V Straub. Clinical and neuroimaging findings in two brothers with limb girdle muscular dystrophy due to LAMA2 mutations.. Neuromuscul Disord. 2017;27:170-4",
"YK Hayashi, Z Tezak, T Momoi, I Nonaka, CA Garcia, EP Hoffman, K Arahata. Massive muscle cell degeneration in the early stage of merosin-deficient congenital muscular dystrophy.. Neuromuscul Disord. 2001;11:350-9",
"Y He, KJ Jones, N Vignier, G Morgan, M Chevallay, A Barois, B Estournet-Mathiaud, H Hori, T Mizuta, FM Tomé, KN North, P Guicheney. Congenital muscular dystrophy with primary partial laminin alpha2 chain deficiency: molecular study.. Neurology. 2001;57:1319-22",
"JC Jones, GW Dehart, M Gonzales, LE Goldfinger. Laminins: an overview.. Microsc Res Tech. 2000;51:211-3",
"KJ Jones, G Morgan, H Johnston, V Tobias, RA Ouvrier, I Wilkinson, KN North. The expanding phenotype of laminin alpha2 chain (merosin) abnormalities: case series and review.. J Med Genet. 2001;38:649-57",
"CC Leite, UC Reed, MC Otaduy, MT Lacerda, MO Costa, LG Ferreira, MS Carvalho, MB Resende, SK Marie, GG Cerri. Congenital muscular dystrophy with merosin deficiency: 1H MR spectroscopy and diffusion-weighted MR imaging.. Radiology. 2005;235:190-6",
"J Marques, ST Duarte, S Costa, S Jacinto, J Oliveira, ME Oliveira, R Santos, E Bronze-da-Rocha, AR Silvestre, E Calado, T Evangelista. Atypical phenotype in two patients with LAMA2 mutations.. Neuromuscul Disord. 2014;24:419-24",
"MJ Menezes, FK McClenahan, CV Leiton, A Aranmolate, X Shan, H Colognato. The extracellular matrix protein laminin α2 regulates the maturation and function of the blood-brain barrier.. J Neurosci. 2014;34:15260-80",
"E Mercuri, J Gruter-Andrew, J Philpot, C Sewry, S Counsell, S Henderson, A Jensen, I Naom, G Bydder, V Dubowitz, F Muntoni. Cognitive abilities in children with congenital muscular dystrophy: correlation with brain MRI and merosin status.. Neuromuscul Disord. 1999;9:383-7",
"S Messina, C Bruno, I Moroni, E Pegoraro, A D'Amico, R Biancheri, A Berardinelli, P Boffi, D Cassandrini, L Farina, C Minetti, M Moggio, T Mongini, E Mottarelli, M Pane, C Pantaleoni, A Pichiecchio, A Pini, E Ricci, S Saredi, M Sframeli, G Tortorella, A Toscano, CP Trevisan, C Uggetti, G Vasco, GP Comi, FM Santorelli, E Bertini, E Mercuri. Congenital muscular dystrophies with cognitive impairment. A population study.. Neurology. 2010;75:898-903",
"D Natera-de Benito, J Muchart, D Itzep, C Ortez, L González-Quereda, P Gallano, A Ramirez, J Aparicio, J Domínguez-Carral, L Carrera-García, J Expósito-Escudero, N Pardo Cardozo, D Cuadras, A Codina, C Jou, C Jimenez-Mallebrera, F Palau, J Colomer, A Arzimanoglou, A Nascimento, V San Antonio-Arce. Epilepsy in LAMA2-related muscular dystrophy: an electro-clinico-radiological characterization.. Epilepsia. 2020;61:971-83",
"I Nelson, T Stojkovic, V Allamand, F Leturcq, HM Bécane, D Babuty, A Toutain, C Béroud, P Richard, NB Romero, B Eymard, R Ben Yaou, G Bonne. Laminin α2 deficiency-related muscular dystrophy mimicking emery-dreifuss and collagen vi related diseases.. J Neuromuscul Dis. 2015;2:229-40",
"Q Nguyen, KRQ Lim, T Yokota. Current understanding and treatment of cardiac and skeletal muscle pathology in laminin-α2 chain-deficient congenital muscular dystrophy.. Appl Clin Genet. 2019;12:113-30",
"GL O'Grady, M Lek, SR Lamande, L Waddell, EC Oates, J Punetha, R Ghaoui, SA Sandaradura, H Best, S Kaur, M Davis, NG Laing, F Muntoni, E Hoffman, DG MacArthur, NF Clarke, S Cooper, K North. Diagnosis and etiology of congenital muscular dystrophy: we are halfway there.. Ann Neurol. 2016;80:101-11",
"J Oliveira, A Gonçalves, ME Oliveira, I Fineza, RC Pavanello, M Vainzof, E Bronze-da-Rocha, R Santos, M Sousa. Reviewing large LAMA2 deletions and duplications in congenital muscular dystrophy patients.. J Neuromuscul Dis. 2014;1:169-79",
"J Oliveira, A Gruber, M Cardoso, R Taipa, I Fineza, A Gonçalves, A Laner, TL Winder, J Schroeder, J Rath, ME Oliveira, E Vieira, AP Sousa, JP Vieira, T Lourenço, L Almendra, L Negrão, M Santos, M Melo-Pires, T Coelho, JT den Dunnen, R Santos, M Sousa. LAMA2 gene mutation update: toward a more comprehensive picture of the laminin-α2 variome and its related phenotypes.. Hum Mutat. 2018;39:1314-37",
"J Oliveira, R Santos, I Soares-Silva, P Jorge, E Vieira, ME Oliveira, A Moreira, T Coelho, JC Ferreira, MJ Fonseca, C Barbosa, J Prats, ML Aríztegui, ML Martins, T Moreno, K Heinimann, C Barbot, SI Pascual-Pascual, A Cabral, I Fineza, M Santos, E Bronze-da-Rocha. Clin Genet. 2008;74:502-12",
"E Pegoraro, H Marks, CA Garcia, T Crawford, P Mancias, AM Connolly, M Fanin, F Martinello, CP Trevisan, C Angelini, A Stella, M Scavina, RL Munk, S Servidei, CC Bönnemann, T Bertorini, G Acsadi, CE Thompson, D Gagnon, G Hoganson, V Carver, RA Zimmerman, EP Hoffman. Laminin alpha2 muscular dystrophy: genotype/phenotype studies of 22 patients.. Neurology. 1998;51:101-10",
"J Philpot, A Bagnall, C King, V Dubowitz, F Muntoni. Feeding problems in merosin deficient congenital muscular dystrophy.. Arch Dis Child. 1999a;80:542-7",
"J Philpot, F Cowan, J Pennock, C Sewry, V Dubowitz, G Bydder, F Muntoni. Merosin-deficient congenital muscular dystrophy: the spectrum of brain involvement on magnetic resonance imaging.. Neuromuscul Disord. 1999b;9:81-5",
"A Pini, L Merlini, FM Tomé, M Chevallay, G Gobbi. Merosin-negative congenital muscular dystrophy, occipital epilepsy with periodic spasms and focal cortical dysplasia. Report of three Italian cases in two families.. Brain Dev. 1996;18:316-22",
"S Quijano-Roy, F Renault, N Romero, P Guicheney, M Fardeau, B Estournet. EMG and nerve conduction studies in children with congenital muscular dystrophy.. Muscle Nerve. 2004;29:292-9",
"S Rajakulendran, M Parton, JL Holton, MG Hanna. Clinical and pathological heterogeneity in late-onset partial merosin deficiency.. Muscle Nerve. 2011;44:590-3",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"S Saredi, S Gibertini, L Matalonga, L Farina, A Ardissone, I Moroni, M Mora. Exome sequencing detects compound heterozygous nonsense LAMA2 mutations in two siblings with atypical phenotype and nearly normal brain MRI.. Neuromuscul Disord. 2019;29:376-80",
"M Sframeli, A Sarkozy, M Bertoli, G Astrea, J Hudson, M Scoto, R Mein, M Yau, R Phadke, L Feng, C Sewry, ANS Fen, C Longman, G McCullagh, V Straub, S Robb, A Manzur, K Bushby, F Muntoni. Congenital muscular dystrophies in the UK population: clinical and molecular spectrum of a large cohort diagnosed over a 12-year period.. Neuromuscul Disord. 2017;27:793-803",
"V Straub, A Murphy, B Udd. 229th ENMC international workshop: limb girdle muscular dystrophies - nomenclature and reformed classification Naarden, the Netherlands, 17-19 March 2017.. Neuromuscul Disord. 2018;28:702-10",
"Y Sunada, TS Edgar, BP Lotz, RS Rust, KP Campbell. Merosin-negative congenital muscular dystrophy associated with extensive brain abnormalities.. Neurology. 1995;45:2084-9",
"N Suzuki, F Yokoyama, M Nomizu. Functional sites in the laminin alpha chains.. Connect Tissue Res. 2005;46:142-52",
"Z Tezak, P Prandini, M Boscaro, A Marin, J Devaney, M Marino, M Fanin, CP Trevisan, J Park, W Tyson, R Finkel, C Garcia, C Angelini, EP Hoffman, E Pegoraro. Clinical and molecular study in congenital muscular dystrophy with partial laminin alpha 2 (. Hum Mutat. 2003;21:103-11",
"M Tordjman, I Dabaj, P Laforet, A Felter, A Ferreiro, M Biyoukar, B Law-Ye, E Zanoteli, C Castiglioni, J Rendu, C Beroud, A Chamouni, P Richard, D Mompoint, S Quijano-Roy, RY Carlier. Muscular MRI-based algorithm to differentiate inherited myopathies presenting with spinal rigidity.. Eur Radiol. 2018;28:5293-303",
"P Vigliano, P Dassi, C Di Blasi, M Mora, L Jarre. Eur J Paediatr Neurol. 2009;13:72-6",
"C Wallgren-Pettersson, K Bushby, U Mellies, A Simonds. 117th ENMC workshop: ventilatory support in congenital neuromuscular disorders -- congenital myopathies, congenital muscular dystrophies, congenital myotonic dystrophy and SMA (II) 4-6 April 2003, Naarden, the Netherlands.. Neuromuscul Disord. 2004;14:56-69",
"CH Wang, CG Bonnemann, A Rutkowski, T Sejersen, J Bellini, V Battista, JM Florence, U Schara, PM Schuler, K Wahbi, A Aloysius, RO Bash, C Béroud, E Bertini, K Bushby, RD Cohn, AM Connolly, N Deconinck, I Desguerre, M Eagle, B Estournet-Mathiaud, A Ferreiro, A Fujak, N Goemans, ST Iannaccone, P Jouinot, M Main, P Melacini, W Mueller-Felber, F Muntoni, LL Nelson, J Rahbek, S Quijano-Roy, C Sewry, K Storhaug, A Simonds, B Tseng, J Vajsar, A Vianello, R Zeller. Consensus statement on standard of care for congenital muscular dystrophies.. J Child Neurol. 2010;25:1559-81",
"H Xiong, D Tan, S Wang, S Song, H Yang, K Gao, A Liu, H Jiao, B Mao, J Ding, X Chang, J Wang, Y Wu, Y Yuan, Y Jiang, F Zhang, H Wu, X Wu. Genotype/phenotype analysis in Chinese laminin-α2 deficient congenital muscular dystrophy patients.. Clin Genet. 2015;87:233-43",
"PD Yurchenco. Integrating activities of laminins that drive basement membrane assembly and function.. Curr Top Membr. 2015;76:1-30",
"PD Yurchenco, KK McKee, JR Reinhard, MA Rüegg. Laminin-deficient muscular dystrophy: molecular pathogenesis and structural repair strategies.. Matrix Biol. 2018;71-2:174-87",
"J Zhou, J Tan, D Ma, J Zhang, J Cheng, C Luo, G Liu, Y Wang, Z Xu. Identification of two novel LAMA2 mutations in a Chinese patient with congenital muscular dystrophy.. Front Genet. 2018;9:43"
] |
7/6/2012
|
17/9/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mdel15q13_3
|
mdel15q13_3
|
[
"Fanconi-associated nuclease 1",
"Inactive Rho GTPase-activating protein 11B",
"Krueppel-like factor 13",
"Neuronal acetylcholine receptor subunit alpha-7",
"OTU domain-containing protein 7A",
"Transient receptor potential cation channel subfamily M member 1",
"ARHGAP11B",
"CHRNA7",
"FAN1",
"KLF13",
"OTUD7A",
"TRPM1",
"15q13.3 Recurrent Deletion"
] |
15q13.3 Recurrent Deletion
|
Bregje WM van Bon, Heather C Mefford, Bert BA de Vries, Christian P Schaaf
|
Summary Individuals with the 15q13.3 recurrent deletion may have a wide range of clinical manifestations. The deletion itself may not lead to a clinically recognizable syndrome and a subset of persons with the recurrent deletion have no obvious clinical findings, implying that penetrance for the deletion is incomplete. A little over half of individuals diagnosed with this recurrent deletion have intellectual disability or developmental delay, mainly in the areas of speech acquisition and cognitive function. In the majority of individuals, cognitive impairment is mild. Other features reported in diagnosed individuals include epilepsy (in ~30%), mild hypotonia, and neuropsychiatric disorders (including autism spectrum disorder, attention-deficit/hyperactivity disorder, mood disorder, schizophrenia, and aggressive or self-injurious behavior). Congenital malformations are uncommon. The diagnosis of the 15q13.3 recurrent deletion is established in a proband by the presence of a heterozygous recurrent 2.0-Mb deletion at the approximate position of 30.5-32.5 Mb in the reference genome (chr15:30366247-32929476 [GRCh37/hg19]) that includes deletion of 1.5 Mb of unique sequence as well as an additional 500 kb or more of segmental duplications. The 15q13.3 recurrent deletion is inherited in an autosomal dominant manner. Approximately 15% are
|
## Diagnosis
No consensus clinical diagnostic criteria for the 15q13.3 recurrent deletion have been published.
Individuals with the 15q13.3 recurrent deletion may have a wide range of clinical manifestations. The deletion itself may not lead to a clinically recognizable syndrome and a subset of persons with the recurrent deletion have no obvious clinical findings, implying that penetrance for the deletion is incomplete.
The 15q13.3 recurrent deletion
Intellectual disability
Speech delay
Seizures
Autism
Schizophrenia
Behavioral findings including poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior
Some affected individuals have combinations of these findings, such as intellectual disability and seizures.
The diagnosis of the 15q13.3 recurrent deletion
Note: (1) For the purposes of this chapter, the term "15q13.3 recurrent deletion" is defined as heterozygous and by the genomic coordinates provided in
Although several genes of interest (e.g.,
Note: (1) Most individuals with the 15q13.3 recurrent deletion are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (2) Prior to 2008 some CMA platforms did not include coverage for this region and thus may not have detected the deletion.
Note: (1) Targeted deletion testing by FISH, quantitative PCR, or MLPA is not appropriate for an individual in whom the deletion was not detected by CMA designed to target the 15q13.3 region. (2) It is not possible to size the deletion routinely by use of FISH, quantitative PCR, or MLPA.
Genomic Testing Used in the 15q13.3 Recurrent Deletion
See
Standardized clinical annotation and interpretation for genomic variants from the Clinical Genome Resource (
Genomic coordinates represent the minimum deletion size associated with 15q13.3 recurrent deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the deletion as calculated from these genomic positions may differ from the expected deletion size due to the presence of segmental duplications near breakpoints. The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 15q13.3 recurrent deletion (see
See
The deletion occurs between the recurrent breakpoint (BP) regions BP4 and BP5 (see
CMA using oligonucleotide arrays or SNP genotyping arrays. CMA designs in current clinical use target the 15q13.3 region. Note: The 15q13.3 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms.
FISH, quantitative PCR, and MLPA are not appropriate as a diagnostic method for an individual in whom the 15q13.3 recurrent deletion was not detected by CMA designed to target this region.
• Intellectual disability
• Speech delay
• Seizures
• Autism
• Schizophrenia
• Behavioral findings including poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior
• Note: (1) Most individuals with the 15q13.3 recurrent deletion are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (2) Prior to 2008 some CMA platforms did not include coverage for this region and thus may not have detected the deletion.
• Note: (1) Targeted deletion testing by FISH, quantitative PCR, or MLPA is not appropriate for an individual in whom the deletion was not detected by CMA designed to target the 15q13.3 region. (2) It is not possible to size the deletion routinely by use of FISH, quantitative PCR, or MLPA.
## Suggestive Findings
The 15q13.3 recurrent deletion
Intellectual disability
Speech delay
Seizures
Autism
Schizophrenia
Behavioral findings including poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior
Some affected individuals have combinations of these findings, such as intellectual disability and seizures.
• Intellectual disability
• Speech delay
• Seizures
• Autism
• Schizophrenia
• Behavioral findings including poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior
## Establishing the Diagnosis
The diagnosis of the 15q13.3 recurrent deletion
Note: (1) For the purposes of this chapter, the term "15q13.3 recurrent deletion" is defined as heterozygous and by the genomic coordinates provided in
Although several genes of interest (e.g.,
Note: (1) Most individuals with the 15q13.3 recurrent deletion are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (2) Prior to 2008 some CMA platforms did not include coverage for this region and thus may not have detected the deletion.
Note: (1) Targeted deletion testing by FISH, quantitative PCR, or MLPA is not appropriate for an individual in whom the deletion was not detected by CMA designed to target the 15q13.3 region. (2) It is not possible to size the deletion routinely by use of FISH, quantitative PCR, or MLPA.
Genomic Testing Used in the 15q13.3 Recurrent Deletion
See
Standardized clinical annotation and interpretation for genomic variants from the Clinical Genome Resource (
Genomic coordinates represent the minimum deletion size associated with 15q13.3 recurrent deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the deletion as calculated from these genomic positions may differ from the expected deletion size due to the presence of segmental duplications near breakpoints. The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 15q13.3 recurrent deletion (see
See
The deletion occurs between the recurrent breakpoint (BP) regions BP4 and BP5 (see
CMA using oligonucleotide arrays or SNP genotyping arrays. CMA designs in current clinical use target the 15q13.3 region. Note: The 15q13.3 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms.
FISH, quantitative PCR, and MLPA are not appropriate as a diagnostic method for an individual in whom the 15q13.3 recurrent deletion was not detected by CMA designed to target this region.
• Note: (1) Most individuals with the 15q13.3 recurrent deletion are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (2) Prior to 2008 some CMA platforms did not include coverage for this region and thus may not have detected the deletion.
• Note: (1) Targeted deletion testing by FISH, quantitative PCR, or MLPA is not appropriate for an individual in whom the deletion was not detected by CMA designed to target the 15q13.3 region. (2) It is not possible to size the deletion routinely by use of FISH, quantitative PCR, or MLPA.
## Clinical Characteristics
More than 200 individuals with an approximately 2.0-Mb heterozygous recurrent deletion at 15q13.3 have been reported [
15q13.3 Recurrent Deletion: Frequency of Select Features
AHDH = attention-deficit/hyperactivity disorder
Derived from 125 known affected individuals specifically with BP4-BP5 deletions [
Individuals with developmental delay / intellectual disability are more likely to undergo advanced genetic testing, including chromosomal microarray analysis, than individuals without this finding [
Percentage of reported individuals with behavior problems ranges from 35% to 51%, although the report that found a high percentage of behavior problems excluded publications that contain fewer than three affected individuals and did not correct for ascertainment bias.
Some individuals with the 15q13.3 recurrent deletion have no discernible clinical features, including developmental or cognitive delays. However, data on 23,838 adult "controls" (individuals who did not undergo genetic testing for an indication of developmental concerns or other clinical features) detected no 15q13.3 deletions [
In three studies, the 15q13.3 recurrent deletion was enriched in cohorts of individuals with schizophrenia compared to controls [
No phenotype-genotype correlations are known; the phenotypic findings in individuals with the 15q13.3 recurrent deletion range from normal to significantly impaired.
The penetrance of the 15q13.3 recurrent deletion is incomplete and highly variable. In total, 80.5% of reported individuals with the recurrent deletion have at least one of the following neurodevelopmental or neuropsychiatric diagnoses [
Developmental delay / intellectual disability
Speech delays/impairment
Epilepsy
Autism spectrum disorder
Schizophrenia
Mood disorder
ADHD
Owing to the lack of a recognizable phenotype in persons with the 15q13.3 recurrent deletion, it has not been described eponymously. Although the 15q13.3 region includes other segmental duplication breakpoints [
The prevalence of the 15q13.3 recurrent deletion in the general population is estimated at 1:5,500 [
• Developmental delay / intellectual disability
• Speech delays/impairment
• Epilepsy
• Autism spectrum disorder
• Schizophrenia
• Mood disorder
• ADHD
## Clinical Description
More than 200 individuals with an approximately 2.0-Mb heterozygous recurrent deletion at 15q13.3 have been reported [
15q13.3 Recurrent Deletion: Frequency of Select Features
AHDH = attention-deficit/hyperactivity disorder
Derived from 125 known affected individuals specifically with BP4-BP5 deletions [
Individuals with developmental delay / intellectual disability are more likely to undergo advanced genetic testing, including chromosomal microarray analysis, than individuals without this finding [
Percentage of reported individuals with behavior problems ranges from 35% to 51%, although the report that found a high percentage of behavior problems excluded publications that contain fewer than three affected individuals and did not correct for ascertainment bias.
Some individuals with the 15q13.3 recurrent deletion have no discernible clinical features, including developmental or cognitive delays. However, data on 23,838 adult "controls" (individuals who did not undergo genetic testing for an indication of developmental concerns or other clinical features) detected no 15q13.3 deletions [
In three studies, the 15q13.3 recurrent deletion was enriched in cohorts of individuals with schizophrenia compared to controls [
## Genotype-Phenotype Correlations
No phenotype-genotype correlations are known; the phenotypic findings in individuals with the 15q13.3 recurrent deletion range from normal to significantly impaired.
## Penetrance
The penetrance of the 15q13.3 recurrent deletion is incomplete and highly variable. In total, 80.5% of reported individuals with the recurrent deletion have at least one of the following neurodevelopmental or neuropsychiatric diagnoses [
Developmental delay / intellectual disability
Speech delays/impairment
Epilepsy
Autism spectrum disorder
Schizophrenia
Mood disorder
ADHD
• Developmental delay / intellectual disability
• Speech delays/impairment
• Epilepsy
• Autism spectrum disorder
• Schizophrenia
• Mood disorder
• ADHD
## Nomenclature
Owing to the lack of a recognizable phenotype in persons with the 15q13.3 recurrent deletion, it has not been described eponymously. Although the 15q13.3 region includes other segmental duplication breakpoints [
## Prevalence
The prevalence of the 15q13.3 recurrent deletion in the general population is estimated at 1:5,500 [
## Genetically Related Disorders
Due to the limited number of published cases reporting on other clinical features in addition to those used for ascertainment, the associated phenotype of the 15q13.3 duplication is still uncertain. Phenotypic features of reported individuals include intellectual disability, ADHD, behavior problems, autism spectrum disorders, hypotonia, obesity, and recurrent ear infections. No dysmorphic features, recurrent congenital anomalies, or epileptic seizures were noted. The duplication can either be
## Differential Diagnosis
The differential diagnosis of the 15q13.3 recurrent deletion comprises an extensive and broad spectrum of disorders and includes any cause of intellectual disability / developmental delay, schizophrenia, autism spectrum disorders, and epilepsy without additional distinguishing clinical features. All chromosome anomalies and genes known to be associated with intellectual disability (see
## Management
No clinical practice guidelines for the 15q13.3 recurrent deletion have been published.
To establish the extent of disease and needs in an individual diagnosed with the 15q13.3 recurrent deletion, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with the 15q13.3 Recurrent Deletion
To incl adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
It is unclear whether renal anomalies are a component of this condition. However, as the diagnosis is often made early in life, particularly in those with developmental delay, signs/symptoms of urinary findings may be lacking at the time of diagnosis. Baseline renal imaging, which is not invasive, is therefore left to the discretion of the treating physician.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Ideally, treatment is tailored to the specific needs of the individual. Because of the high incidence of neurodevelopmental disability, referral to a clinical psychologist for neuropsychological and/or developmental assessment for treatment recommendations is suggested.
Additional management in healthy adults who have the 15q13.3 recurrent deletion is not necessary, although their medical care providers may benefit from being alerted to the possible increased risk for late-onset manifestations (e.g., schizophrenia).
Treatment of Manifestations in Individuals with 15q13.3 Recurrent Deletion
Use of valproate has been successful in some affected persons.
Oxcarbazepine led to clinical worsening in 1 affected person.
Ketogenic diet & cannabidiol have been tried in 1 person each, w/no efficacy.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
It is unclear whether renal anomalies are a component of this condition. However, if renal anomalies are present, treatment is the same as for those in the general population.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Recommended Surveillance for Individuals with the 15q13.3 Recurrent Deletion
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
About 11% of individuals with the 15q13.3 recurrent deletion develop schizophrenia. The use of cannabis has been reported as a risk factor for development of schizophrenia. Although no studies have been performed on the possible additional risk of the use of cannabis by persons with the 15q13.3 recurrent deletion, discouraging the use of cannabis may be considered.
It is unclear if oxcarbazepine should be avoided. In at least one affected individual with seizures, oxcarbazepine led to clinical worsening [
Using genomic testing that will detect the 15q13.3 recurrent deletion found in the proband, it is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from close assessment/monitoring of developmental milestones in childhood.
See
Search
• To incl adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support.
• Use of valproate has been successful in some affected persons.
• Oxcarbazepine led to clinical worsening in 1 affected person.
• Ketogenic diet & cannabidiol have been tried in 1 person each, w/no efficacy.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with the 15q13.3 recurrent deletion, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with the 15q13.3 Recurrent Deletion
To incl adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
It is unclear whether renal anomalies are a component of this condition. However, as the diagnosis is often made early in life, particularly in those with developmental delay, signs/symptoms of urinary findings may be lacking at the time of diagnosis. Baseline renal imaging, which is not invasive, is therefore left to the discretion of the treating physician.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Ideally, treatment is tailored to the specific needs of the individual. Because of the high incidence of neurodevelopmental disability, referral to a clinical psychologist for neuropsychological and/or developmental assessment for treatment recommendations is suggested.
Additional management in healthy adults who have the 15q13.3 recurrent deletion is not necessary, although their medical care providers may benefit from being alerted to the possible increased risk for late-onset manifestations (e.g., schizophrenia).
Treatment of Manifestations in Individuals with 15q13.3 Recurrent Deletion
Use of valproate has been successful in some affected persons.
Oxcarbazepine led to clinical worsening in 1 affected person.
Ketogenic diet & cannabidiol have been tried in 1 person each, w/no efficacy.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
It is unclear whether renal anomalies are a component of this condition. However, if renal anomalies are present, treatment is the same as for those in the general population.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Use of valproate has been successful in some affected persons.
• Oxcarbazepine led to clinical worsening in 1 affected person.
• Ketogenic diet & cannabidiol have been tried in 1 person each, w/no efficacy.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Recommended Surveillance for Individuals with the 15q13.3 Recurrent Deletion
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures.
## Agents/Circumstances to Avoid
About 11% of individuals with the 15q13.3 recurrent deletion develop schizophrenia. The use of cannabis has been reported as a risk factor for development of schizophrenia. Although no studies have been performed on the possible additional risk of the use of cannabis by persons with the 15q13.3 recurrent deletion, discouraging the use of cannabis may be considered.
It is unclear if oxcarbazepine should be avoided. In at least one affected individual with seizures, oxcarbazepine led to clinical worsening [
## Evaluation of Relatives at Risk
Using genomic testing that will detect the 15q13.3 recurrent deletion found in the proband, it is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from close assessment/monitoring of developmental milestones in childhood.
See
## Therapies Under Investigation
Search
## Genetic Counseling
The 15q13.3 recurrent deletion is inherited in an autosomal dominant manner.
About 85% of individuals with a 15q13.3 recurrent deletion inherited the genetic alteration from a parent. The parent with the 15q13.3 recurrent deletion may be phenotypically normal or have features associated with the 15q13.3 recurrent deletion.
The 15q13.3 recurrent deletion occurs
Genomic testing that will detect the 15q13.3 recurrent deletion present in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the 15q13.3 recurrent deletion identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered:
The proband has a
The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
If one of the parents has the 15q13.3 recurrent deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. It is not possible to predict the phenotype in sibs who inherit a 15q13.3 recurrent deletion because the penetrance of the deletion is incomplete and clinical manifestations are highly variable; phenotypic findings in individuals with the 15q13.3 recurrent deletion range from normal to significantly impaired.
If the 15q13.3 recurrent deletion identified in the proband cannot be detected in either of the parents, the chance of recurrence to sibs is low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 15q13.3 recurrent deletion.
Note: Regardless of whether a pregnancy is known or not known to be at increased risk for the 15q13.3 recurrent deletion, the prenatal finding of a 15q13.3 recurrent deletion cannot be used to predict the phenotype (see
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• About 85% of individuals with a 15q13.3 recurrent deletion inherited the genetic alteration from a parent. The parent with the 15q13.3 recurrent deletion may be phenotypically normal or have features associated with the 15q13.3 recurrent deletion.
• The 15q13.3 recurrent deletion occurs
• Genomic testing that will detect the 15q13.3 recurrent deletion present in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the 15q13.3 recurrent deletion identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If one of the parents has the 15q13.3 recurrent deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. It is not possible to predict the phenotype in sibs who inherit a 15q13.3 recurrent deletion because the penetrance of the deletion is incomplete and clinical manifestations are highly variable; phenotypic findings in individuals with the 15q13.3 recurrent deletion range from normal to significantly impaired.
• If the 15q13.3 recurrent deletion identified in the proband cannot be detected in either of the parents, the chance of recurrence to sibs is low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 15q13.3 recurrent deletion.
## Mode of Inheritance
The 15q13.3 recurrent deletion is inherited in an autosomal dominant manner.
## Risk to Family Members
About 85% of individuals with a 15q13.3 recurrent deletion inherited the genetic alteration from a parent. The parent with the 15q13.3 recurrent deletion may be phenotypically normal or have features associated with the 15q13.3 recurrent deletion.
The 15q13.3 recurrent deletion occurs
Genomic testing that will detect the 15q13.3 recurrent deletion present in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the 15q13.3 recurrent deletion identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered:
The proband has a
The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
If one of the parents has the 15q13.3 recurrent deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. It is not possible to predict the phenotype in sibs who inherit a 15q13.3 recurrent deletion because the penetrance of the deletion is incomplete and clinical manifestations are highly variable; phenotypic findings in individuals with the 15q13.3 recurrent deletion range from normal to significantly impaired.
If the 15q13.3 recurrent deletion identified in the proband cannot be detected in either of the parents, the chance of recurrence to sibs is low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
• About 85% of individuals with a 15q13.3 recurrent deletion inherited the genetic alteration from a parent. The parent with the 15q13.3 recurrent deletion may be phenotypically normal or have features associated with the 15q13.3 recurrent deletion.
• The 15q13.3 recurrent deletion occurs
• Genomic testing that will detect the 15q13.3 recurrent deletion present in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the 15q13.3 recurrent deletion identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If one of the parents has the 15q13.3 recurrent deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. It is not possible to predict the phenotype in sibs who inherit a 15q13.3 recurrent deletion because the penetrance of the deletion is incomplete and clinical manifestations are highly variable; phenotypic findings in individuals with the 15q13.3 recurrent deletion range from normal to significantly impaired.
• If the 15q13.3 recurrent deletion identified in the proband cannot be detected in either of the parents, the chance of recurrence to sibs is low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 15q13.3 recurrent deletion.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 15q13.3 recurrent deletion.
## Prenatal Testing and Preimplantation Genetic Testing
Note: Regardless of whether a pregnancy is known or not known to be at increased risk for the 15q13.3 recurrent deletion, the prenatal finding of a 15q13.3 recurrent deletion cannot be used to predict the phenotype (see
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
15q13.3 Recurrent Deletion: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for 15q13.3 Recurrent Deletion (
The proximal 15q region is characterized by a high density of low copy repeats [
The 2.0-Mb deletion arises when the flanking low copy repeats are positioned in a direct orientation, most probably through a common inversion of the BP4-BP5 region, which generates a configuration predisposing to nonallelic homologous recombination [
Smaller 15q13.3 deletions overlapping only
## Molecular Pathogenesis
The proximal 15q region is characterized by a high density of low copy repeats [
The 2.0-Mb deletion arises when the flanking low copy repeats are positioned in a direct orientation, most probably through a common inversion of the BP4-BP5 region, which generates a configuration predisposing to nonallelic homologous recombination [
Smaller 15q13.3 deletions overlapping only
## Chapter Notes
17 November 2022 (ma) Comprehensive update posted live
23 July 2015 (me) Comprehensive update posted live
23 December 2010 (me) Review posted live
18 May 2010 (bvb) Original submission
• 17 November 2022 (ma) Comprehensive update posted live
• 23 July 2015 (me) Comprehensive update posted live
• 23 December 2010 (me) Review posted live
• 18 May 2010 (bvb) Original submission
## Revision History
17 November 2022 (ma) Comprehensive update posted live
23 July 2015 (me) Comprehensive update posted live
23 December 2010 (me) Review posted live
18 May 2010 (bvb) Original submission
• 17 November 2022 (ma) Comprehensive update posted live
• 23 July 2015 (me) Comprehensive update posted live
• 23 December 2010 (me) Review posted live
• 18 May 2010 (bvb) Original submission
## References
## Literature Cited
|
[
"JA Bailey, Z Gu, RA Clark, K Reinert, RV Samonte, S Schwartz, MD Adams, EW Myers, PW Li, EE Eichler. Recent segmental duplications in the human genome.. Science. 2002;297:1003-7",
"S Ben-Shachar, B Lanpher, JR German, M Qasaymeh, L Potocki, SC Nagamani, LM Franco, A Malphrus, GW Bottenfield, JE Spence, S Amato, JA Rousseau, B Moghaddam, C Skinner, SA Skinner, S Bernes, N Armstrong, M Shinawi, P Stankiewicz, A Patel, SW Cheung, JR Lupski, AL Beaudet, T Sahoo. Microdeletion 15q13.3: a locus with incomplete pentrance for autism, mental retardation, and psychiatric disorders.. J Med Genet. 2009;46:382-8",
"P Garret, F Ebstein, G Delplancq, B Dozieres-Puyravel, A Boughalem, S Auvin, Y Duffourd, S Klafack, BA Zieba, S Mahmoudi, KK Singh, L Duplomb, C Thauvin-Robinet, JM Costa, E Krüger, D Trost, A Verloes, L Faivre, A Vitobello. Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction.. Clin Genet. 2020;97:567-75",
"MA Gillentine, PJ Lupo, P Stankiewicz, CP Schaaf. An estimation of the prevalence of genomic disorders using chromosomal microarray data.. J Hum Genet. 2018;63:795-801",
"MA Gillentine, CP Schaaf. The human clinical phenotypes of altered CHRNA7 copy number.. Biochem Pharmacol. 2015;97:352-62",
"CJ Hong, IC Lai, LL Liou, SJ Tsai. Association study of the human partially duplicated alpha7 nicotinic acetylcholine receptor genetic variant with bipolar disorder.. Neurosci Lett. 2004;355:69-72",
"N Hoppman-Chaney, K Wain, PR Seger, DW Superneau, JC Hodge. Identification of single gene deletions at 15q13.3: further evidence that CHRNA7 causes the 15q13.3 microdeletion syndrome phenotype.. Clin Genet. 2013;83:345-51",
"Rare chromosomal deletions and duplications increase risk of schizophrenia.. Nature. 2008;455:237-41",
"Y Iwata, M Nakajima, K Yamada, K Nakamura, Y Sekine, KJ Tsuchiya, G Sugihara, H Matsuzaki, S Suda, K Suzuki, N Takei, N Mori, Y Iwayama, H Takao, T Yoshikawa, B Riley, A Makoff, P Sham, R Chen, D Collier. Linkage disequilibrium analysis of the CHRNA7 gene and its partially duplicated region in schizophrenia.. Neurosci Res. 2007;57:194-202",
"A Kozlova, S Zhang, AV Kotlar, B Jamison, H Zhang, S Shi, MP Forrest, J McDaid, DJ Cutler, MP Epstein, ME Zwick, ZP Pang, AR Sanders, ST Warren, PV Gejman, JG Mulle, J Duan. Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons.. Am J Hum Genet. 2022;109:1500-19",
"S Leonard, R Freedman. Genetics of chromosome 15q13-q14 in schizophrenia.. Biol Psychiatry. 2006;60:115-22",
"C Lowther, G Costain, DJ Stavropoulos, R Melvin, CK Silversides, DM Andrade, J So, H Faghfoury, AC Lionel, CR Marshall, SW Scherer, AS Bassett. Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature.. Genet Med. 2015;17:149-57",
"AJ Makoff, RH Flomen. Detailed analysis of 15q11-q14 sequence corrects errors and gaps in the public access sequence to fully reveal large segmental duplications at breakpoints for Prader-Willi, Angelman, and inv dup(15) syndromes. Genome Biol. 2007;8:R114",
"C Mignon-Ravix, D Depetris, JJ Luciani, C Cuoco, M Krajewska-Walasek, C Missirian, P Collignon, B Delobel, MF Croquette, A Moncla, PM Kroisel, MG Mattei. Recurrent rearrangements in the proximal 15q11-q14 region: a new breakpoint cluster specific to unbalanced translocations.. Eur J Hum Genet. 2007;15:432-40",
"P Pavone, M Ruggieri, SD Marino, G Corsello, X Pappalardo, A Polizzi, E Parano, C Romano, S Marino, AD Praticò, R Falsaperla. Chromosome 15q BP3 to BP5 deletion is a likely locus for speech delay and language impairment: Report on a four-member family and an unrelated boy.. Mol Genet Genomic Med. 2020;8",
"AJ Sharp, HC Mefford, K Li, C Baker, C Skinner, RE Stevenson, RJ Schroer, F Novara, M De Gregori, R Ciccone, A Broomer, I Casuga, Y Wang, C Xiao, C Barbacioru, G Gimelli, BD Bernardina, C Torniero, R Giorda, R Regan, V Murday, S Mansour, M Fichera, L Castiglia, P Failla, M Ventura, Z Jiang, GM Cooper, SJ Knight, C Romano, O Zuffardi, C Chen, CE Schwartz, EE Eichler. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures.. Nat Genet. 2008;40:322-8",
"M Shinawi, CP Schaaf, SS Bhatt, Z Xia, A Patel, SW Cheung, B Lanpher, S Nagl, HS Herding, C Nevinny-Stickel, LL Immken, GS Patel, JR German, AL Beaudet, P Stankiewicz. A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes.. Nat Genet. 2009;41:1269-71",
"J Simon, K Stoll, R Fick, J Mott, A. Lawson-Yuen. Homozygous 15q13.3 microdeletion in a child with hypotonia and impaired vision: A new report and review of the literature.. Clin Case Rep. 2019;7:2311-5",
"H Stefansson, A Meyer-Lindenberg, S Steinberg, B Magnusdottir, K Morgen, S Arnarsdottir, G Bjornsdottir, GB Walters, GA Jonsdottir, OM Doyle, H Tost, O Grimm, S Kristjansdottir, H Snorrason, SR Davidsdottir, LJ Gudmundsson, GF Jonsson, B Stefansdottir, I Helgadottir, M Haraldsson, B Jonsdottir, JH Thygesen, AJ Schwarz, M Didriksen, TB Stensbøl, M Brammer, S Kapur, JG Halldorsson, S Hreidarsson, E Saemundsen, E Sigurdsson, K Stefansson. CNVs conferring risk of autism or schizophrenia affect cognition in controls.. Nature. 2014;505:361-6",
"H Stefansson, D Rujescu, S Cichon, OP Pietiläinen, A Ingason, S Steinberg, R Fossdal, E Sigurdsson, T Sigmundsson, JE Buizer-Voskamp, T Hansen, KD Jakobsen, P Muglia, C Francks, PM Matthews, A Gylfason, BV Halldorsson, D Gudbjartsson, TE Thorgeirsson, A Sigurdsson, A Jonasdottir, A Jonasdottir, A Bjornsson, S Mattiasdottir, T Blondal, M Haraldsson, BB Magnusdottir, I Giegling, HJ Möller, A Hartmann, KV Shianna, D Ge, AC Need, C Crombie, G Fraser, N Walker, J Lonnqvist, J Suvisaari, A Tuulio-Henriksson, T Paunio, T Toulopoulou, E Bramon, M Di Forti, R Murray, M Ruggeri, E Vassos, S Tosato, M Walshe, T Li, C Vasilescu, TW Mühleisen, AG Wang, H Ullum, S Djurovic, I Melle, J Olesen, LA Kiemeney, B Franke. GROUP, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K. Large recurrent microdeletions associated with schizophrenia.. Nature. 2008;455:232-6",
"H Suzuki, M Inaba, M Yamada, T Uehara, T Takenouchi, S Mizuno, K Kosaki, M. Doi. Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures.. Am J Med Genet A. 2021;185:1182-6",
"P Szafranski, CP Schaaf, RE Person, IB Gibson, Z Xia, S Mahadevan, J Wiszniewska, CA Bacino, S Lalani, L Potocki, SH Kang, A Patel, SW Cheung, FJ Probst, BH Graham, M Shinawi, AL Beaudet, P Stankiewicz. Structures and molecular mechanisms for common 15q13.3 microduplications involving CHRNA7: benign or pathological?. Hum Mutat. 2010;31:840-50",
"NL Taske, MP Williamson, A Makoff, L Bate, D Curtis, M Kerr, MJ Kjeldsen, KA Pang, A Sundqvist, ML Friis, D Chadwick, A Richens, A Covanis, M Santos, A Arzimanoglou, CP Panayiotopoulos, WP Whitehouse, M Rees, RM Gardiner. Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14.. Epilepsy Res. 2002;49:157-72",
"M Uddin, BK Unda, V Kwan, NT Holzapfel, SH White, L Chalil, M Woodbury-Smith, KS Ho, E Harward, N Murtaza, B Dave, G Pellecchia, L D'Abate, T Nalpathamkalam, S Lamoureux, J Wei, M Speevak, J Stavropoulos, KJ Hope, BW Doble, J Nielsen, ER Wassman, SW Scherer, KK Singh. OTUD7A regulates neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.. Am J Hum Genet. 2018;102:278-95",
"BW van Bon, HC Mefford, B Menten, DA Koolen, AJ Sharp, WM Nillesen, JW Innis, TJ de Ravel, CL Mercer, M Fichera, H Stewart, LE Connell, K Ounap, K Lachlan, B Castle, N Van der Aa, C van Ravenswaaij, MA Nobrega, C Serra-Juhé, I Simonic, N de Leeuw, R Pfundt, EM Bongers, C Baker, P Finnemore, S Huang, VK Maloney, JA Crolla, M van Kalmthout, M Elia, G Vandeweyer, JP Fryns, S Janssens, N Foulds, S Reitano, K Smith, S Parkel, B Loeys, CG Woods, A Oostra, F Speleman, AC Pereira, A Kurg, L Willatt, SJ Knight, JR Vermeesch, C Romano, JC Barber, G Mortier, LA Pérez-Jurado, F Kooy, HG Brunner, EE Eichler, T Kleefstra, BB de Vries. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome.. J Med Genet. 2009;46:511-23",
"R Whitney, A Nair, E McCready, AE Keller, IS Adil, AS Aziz, O Borys, K Siu, C Shah, BF Meaney, K Jones. RamachandranNair R. The spectrum of epilepsy in children with 15q13.3 microdeletion syndrome.. Seizure. 2021;92:221-9",
"NM Williams, B Franke, E Mick, RJ Anney, CM Freitag, M Gill, A Thapar, MC O'Donovan, MJ Owen, P Holmans, L Kent, F Middleton, Y Zhang-James, L Liu, J Meyer, TT Nguyen, J Romanos, M Romanos, C Seitz, TJ Renner, S Walitza, A Warnke, H Palmason, J Buitelaar, N Rommelse, AA Vasquez, Z Hawi, K Langley, J Sergeant, HC Steinhausen, H Roeyers, J Biederman, I Zaharieva, H Hakonarson, J Elia, AC Lionel, J Crosbie, CR Marshall, R Schachar, SW Scherer, A Todorov, SL Smalley, S Loo, S Nelson, C Shtir, P Asherson, A Reif, KP Lesch, SV Faraone. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3.. Am J Psychiatry. 2012;169:195-204",
"MN Ziats, RP Goin-Kochel, LN Berry, M Ali, J Ge, D Guffey, JA Rosenfeld, P Bader, MJ Gambello, V Wolf, LS Penney, R Miller, RR Lebel, J Kane, K Bachman, R Troxell, G Clark, CG Minard, P Stankiewicz, A Beaudet, CP Schaaf. The complex behavioral phenotype of 15q13.3 microdeletion syndrome.. Genet Med. 2016;18:1111-8"
] |
23/12/2010
|
17/11/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mdel15q24
|
mdel15q24
|
[
"15q24 Microdeletion"
] |
15q24 Microdeletion Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Heather Mefford, Natasha Shur, Jill Rosenfeld
|
Summary The 15q24 microdeletion syndrome is characterized by global developmental delay; mild to severe (usually at least moderate) intellectual disability; facial dysmorphisms; congenital malformations of the hands and feet, eye, and genitalia; joint laxity; and growth retardation and failure to thrive. Less common findings include: seizures; conductive and sensorineural hearing loss; hypospadias and/ or micropenis. Males and females are affected equally. The diagnosis is established by demonstration of a heterozygous deletion at chromosome 15q24, most often involving a 1.1-Mb region between 72.2 and 73.3 Mb of the reference genome (NCBI Build 36 / hg18) using whole-genome and targeted molecular methods that determine the copy number of sequences within the deleted region. The 15q24 microdeletion syndrome is inherited in an autosomal dominant manner; however, all known cases have resulted from a
|
## Diagnosis
The clinical spectrum of the 15q24 microdeletion syndrome is variable. Developmental delay and intellectual disability are the most consistent features; however, no single clinical feature is required to establish the diagnosis.
Features that should prompt consideration of this diagnosis in an individual with developmental delay or intellectual disability include:
Dysmorphic facial features, especially a high anterior hairline, deep-set eyes, and a triangular shaped face (see
Markedly delayed or absent speech
Hypotonia
Joint laxity
Ocular abnormalities, especially strabismus
Hand and foot abnormalities: short fifth fingers; significant shortening of the fourth metacarpals and short fifth metacarpals; thumb anomalies such as proximally implanted thumbs
Growth retardation and failure to thrive
Hearing: conductive and sensorineural hearing loss
Genital anomalies: hypospadias or micropenis in males, labial adhesions in females
Notably, the critical region continues to be refined as patients with “atypical” deletions are identified, some of which involve only part or none of the proposed 1.1-Mb critical region but still appear to be pathogenic.
Two individuals with
Two patients with large deletions that involve only 800 kb [
Future identification of smaller, atypical deletions will continue to refine the critical region and genotype-phenotype correlations.
Whether or not it is possible to size the deletion depends on the number and distribution of probes in the 15q24 region. It is not possible to size the deletion routinely by use of FISH.
Molecular Genetic Testing Used in 15q24 Microdeletion
The ability of the test method used to detect a deletion or duplication that is present in the indicated chromosomal region
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
Most microdeletions are detected by genomic microarray analysis performed as part of the evaluation of developmental delay or intellectual disability.
If the 15q24 microdeletion is suspected based on the clinical features, a targeted technique (e.g., FISH, MLPA) can be employed.
Note: The deletion cannot be identified by routine chromosome analysis.
• Dysmorphic facial features, especially a high anterior hairline, deep-set eyes, and a triangular shaped face (see
• Markedly delayed or absent speech
• Hypotonia
• Joint laxity
• Ocular abnormalities, especially strabismus
• Hand and foot abnormalities: short fifth fingers; significant shortening of the fourth metacarpals and short fifth metacarpals; thumb anomalies such as proximally implanted thumbs
• Growth retardation and failure to thrive
• Hearing: conductive and sensorineural hearing loss
• Genital anomalies: hypospadias or micropenis in males, labial adhesions in females
• Two individuals with
• Two patients with large deletions that involve only 800 kb [
• Whether or not it is possible to size the deletion depends on the number and distribution of probes in the 15q24 region. It is not possible to size the deletion routinely by use of FISH.
• Most microdeletions are detected by genomic microarray analysis performed as part of the evaluation of developmental delay or intellectual disability.
• If the 15q24 microdeletion is suspected based on the clinical features, a targeted technique (e.g., FISH, MLPA) can be employed.
## Clinical Diagnosis
The clinical spectrum of the 15q24 microdeletion syndrome is variable. Developmental delay and intellectual disability are the most consistent features; however, no single clinical feature is required to establish the diagnosis.
Features that should prompt consideration of this diagnosis in an individual with developmental delay or intellectual disability include:
Dysmorphic facial features, especially a high anterior hairline, deep-set eyes, and a triangular shaped face (see
Markedly delayed or absent speech
Hypotonia
Joint laxity
Ocular abnormalities, especially strabismus
Hand and foot abnormalities: short fifth fingers; significant shortening of the fourth metacarpals and short fifth metacarpals; thumb anomalies such as proximally implanted thumbs
Growth retardation and failure to thrive
Hearing: conductive and sensorineural hearing loss
Genital anomalies: hypospadias or micropenis in males, labial adhesions in females
• Dysmorphic facial features, especially a high anterior hairline, deep-set eyes, and a triangular shaped face (see
• Markedly delayed or absent speech
• Hypotonia
• Joint laxity
• Ocular abnormalities, especially strabismus
• Hand and foot abnormalities: short fifth fingers; significant shortening of the fourth metacarpals and short fifth metacarpals; thumb anomalies such as proximally implanted thumbs
• Growth retardation and failure to thrive
• Hearing: conductive and sensorineural hearing loss
• Genital anomalies: hypospadias or micropenis in males, labial adhesions in females
## Testing
Notably, the critical region continues to be refined as patients with “atypical” deletions are identified, some of which involve only part or none of the proposed 1.1-Mb critical region but still appear to be pathogenic.
Two individuals with
Two patients with large deletions that involve only 800 kb [
Future identification of smaller, atypical deletions will continue to refine the critical region and genotype-phenotype correlations.
Whether or not it is possible to size the deletion depends on the number and distribution of probes in the 15q24 region. It is not possible to size the deletion routinely by use of FISH.
Molecular Genetic Testing Used in 15q24 Microdeletion
The ability of the test method used to detect a deletion or duplication that is present in the indicated chromosomal region
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
• Two individuals with
• Two patients with large deletions that involve only 800 kb [
• Whether or not it is possible to size the deletion depends on the number and distribution of probes in the 15q24 region. It is not possible to size the deletion routinely by use of FISH.
## Molecular Genetic Testing
Notably, the critical region continues to be refined as patients with “atypical” deletions are identified, some of which involve only part or none of the proposed 1.1-Mb critical region but still appear to be pathogenic.
Two individuals with
Two patients with large deletions that involve only 800 kb [
Future identification of smaller, atypical deletions will continue to refine the critical region and genotype-phenotype correlations.
Whether or not it is possible to size the deletion depends on the number and distribution of probes in the 15q24 region. It is not possible to size the deletion routinely by use of FISH.
Molecular Genetic Testing Used in 15q24 Microdeletion
The ability of the test method used to detect a deletion or duplication that is present in the indicated chromosomal region
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
• Two individuals with
• Two patients with large deletions that involve only 800 kb [
• Whether or not it is possible to size the deletion depends on the number and distribution of probes in the 15q24 region. It is not possible to size the deletion routinely by use of FISH.
## Testing Strategy
Most microdeletions are detected by genomic microarray analysis performed as part of the evaluation of developmental delay or intellectual disability.
If the 15q24 microdeletion is suspected based on the clinical features, a targeted technique (e.g., FISH, MLPA) can be employed.
Note: The deletion cannot be identified by routine chromosome analysis.
• Most microdeletions are detected by genomic microarray analysis performed as part of the evaluation of developmental delay or intellectual disability.
• If the 15q24 microdeletion is suspected based on the clinical features, a targeted technique (e.g., FISH, MLPA) can be employed.
## Clinical Characteristics
The 15q24 microdeletion syndrome has a clinically recognizable phenotype that includes developmental delay/intellectual disability, facial dysmorphisms (
Features of 15q24 Microdeletion Syndrome
Distinctive facial features (see
Developmental delay/intellectual disability
Significant speech delay
Hypotonia (childhood)
Eye abnormalities, most frequently strabismus
Digital anomalies
Ear anomalies (most frequently dysplastic ears)
Joint laxity
Hearing loss
Abnormalities on brain MRI incl heterotopia, corpus callosum cysts, enlarged ventricles, cerebral atrophy, hypoplastic olfactory bulbs
Hypospadias &/or micropenis
Seizures
Sensorineural hearing loss
Conductive hearing loss
Heart defects
Diaphragmatic hernia
Bowel atresia
Pierre Robin syndrome
Data from 32 individuals (24 male, 8 female) [
No genotype-phenotype correlations are known.
Penetrance is 100%: clinical features of 15q24 microdeletion syndrome are apparent in all individuals with the microdeletion, although the extent and severity of clinical findings vary among individuals.
The exact prevalence of the 15q24 microdeletion syndrome is unknown; though it is clearly rare. To date, about 30 affected individuals have been reported worldwide.
Large-scale surveys of the novel 15q24 microdeletion syndrome estimate the frequency to be 0.1-0.2% in individuals with autism spectrum disorders [
In one large series, 15q24 microdeletions were identified in 3:10,000-4:10,000 individuals in clinical array CGH studies [
• Distinctive facial features (see
• Developmental delay/intellectual disability
• Significant speech delay
• Hypotonia (childhood)
• Eye abnormalities, most frequently strabismus
• Digital anomalies
• Ear anomalies (most frequently dysplastic ears)
• Joint laxity
• Hearing loss
• Abnormalities on brain MRI incl heterotopia, corpus callosum cysts, enlarged ventricles, cerebral atrophy, hypoplastic olfactory bulbs
• Hypospadias &/or micropenis
• Seizures
• Sensorineural hearing loss
• Conductive hearing loss
• Heart defects
• Diaphragmatic hernia
• Bowel atresia
• Pierre Robin syndrome
## Clinical Description
The 15q24 microdeletion syndrome has a clinically recognizable phenotype that includes developmental delay/intellectual disability, facial dysmorphisms (
Features of 15q24 Microdeletion Syndrome
Distinctive facial features (see
Developmental delay/intellectual disability
Significant speech delay
Hypotonia (childhood)
Eye abnormalities, most frequently strabismus
Digital anomalies
Ear anomalies (most frequently dysplastic ears)
Joint laxity
Hearing loss
Abnormalities on brain MRI incl heterotopia, corpus callosum cysts, enlarged ventricles, cerebral atrophy, hypoplastic olfactory bulbs
Hypospadias &/or micropenis
Seizures
Sensorineural hearing loss
Conductive hearing loss
Heart defects
Diaphragmatic hernia
Bowel atresia
Pierre Robin syndrome
Data from 32 individuals (24 male, 8 female) [
• Distinctive facial features (see
• Developmental delay/intellectual disability
• Significant speech delay
• Hypotonia (childhood)
• Eye abnormalities, most frequently strabismus
• Digital anomalies
• Ear anomalies (most frequently dysplastic ears)
• Joint laxity
• Hearing loss
• Abnormalities on brain MRI incl heterotopia, corpus callosum cysts, enlarged ventricles, cerebral atrophy, hypoplastic olfactory bulbs
• Hypospadias &/or micropenis
• Seizures
• Sensorineural hearing loss
• Conductive hearing loss
• Heart defects
• Diaphragmatic hernia
• Bowel atresia
• Pierre Robin syndrome
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
## Penetrance
Penetrance is 100%: clinical features of 15q24 microdeletion syndrome are apparent in all individuals with the microdeletion, although the extent and severity of clinical findings vary among individuals.
## Prevalence
The exact prevalence of the 15q24 microdeletion syndrome is unknown; though it is clearly rare. To date, about 30 affected individuals have been reported worldwide.
Large-scale surveys of the novel 15q24 microdeletion syndrome estimate the frequency to be 0.1-0.2% in individuals with autism spectrum disorders [
In one large series, 15q24 microdeletions were identified in 3:10,000-4:10,000 individuals in clinical array CGH studies [
## Genetically Related Disorders
15q24 duplications of the region distal to the 1.1-Mb critical deletion region have also been reported and may also contribute to variable abnormal phenotypes. Two reported families have multiple affected individuals with this duplication; persons heterozygous for this duplication showed varying degrees of developmental delay, hypotonia, and dysmorphic features; one of the families also had individuals with autism spectrum disorders [
## Differential Diagnosis
The most common findings in 15q24 microdeletion syndrome, developmental delay and childhood hypotonia, are frequent and relatively nonspecific indications for molecular cytogenetic analysis. However, the concurrent finding of characteristic facial dysmorphic features and hand and genital anomalies may prompt special consideration of 15q24 microdeletion syndrome.
Other diagnoses that may be considered in affected individuals include the following:
## Management
To establish the extent of disease and needs of an individual diagnosed with the 15q24 microdeletion syndrome, the following evaluations should be considered:
Ophthalmologic examination
Formal audiology evaluation to assess for sensorineural hearing loss
Cardiac evaluation
Brain imaging in individuals with microcephaly and/or neurologic findings
Examination for genitourinary abnormalities (e.g., hypospadias or cryptorchidism in males)
Comprehensive developmental assessment
Consideration of neurologic referral for any unusual movements or concern for seizures
Discussion of results with a clinical geneticist or genetic counselor
The following are indicated:
Routine treatment of ophthalmologic, cardiac, neurologic findings
Speech, occupational, and physical therapies
Specialized learning programs to meet individual needs
No specific antiepileptic or antipsychotic medications are indicated
Appropriate surveillance includes:
Routine pediatric care
Routine developmental assessments
Monitoring of specific identified medical issues
See
If a fetus is known to have 15q24 microdeletion syndrome, fetal echocardiogram and ultrasound examination with an attempt to visualize the palate and look for diaphragmatic hernia are recommended. Close monitoring for intrauterine growth retardation is warranted. Counseling with regard to the developmental outcomes and medical complications of the 15q24 microdeletion syndrome is appropriate. Delivery at a center with a good neonatal intensive care team is optimal, as respiratory complications and feeding difficulties may occur after delivery.
Search
• Ophthalmologic examination
• Formal audiology evaluation to assess for sensorineural hearing loss
• Cardiac evaluation
• Brain imaging in individuals with microcephaly and/or neurologic findings
• Examination for genitourinary abnormalities (e.g., hypospadias or cryptorchidism in males)
• Comprehensive developmental assessment
• Consideration of neurologic referral for any unusual movements or concern for seizures
• Discussion of results with a clinical geneticist or genetic counselor
• Routine treatment of ophthalmologic, cardiac, neurologic findings
• Speech, occupational, and physical therapies
• Specialized learning programs to meet individual needs
• Routine pediatric care
• Routine developmental assessments
• Monitoring of specific identified medical issues
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with the 15q24 microdeletion syndrome, the following evaluations should be considered:
Ophthalmologic examination
Formal audiology evaluation to assess for sensorineural hearing loss
Cardiac evaluation
Brain imaging in individuals with microcephaly and/or neurologic findings
Examination for genitourinary abnormalities (e.g., hypospadias or cryptorchidism in males)
Comprehensive developmental assessment
Consideration of neurologic referral for any unusual movements or concern for seizures
Discussion of results with a clinical geneticist or genetic counselor
• Ophthalmologic examination
• Formal audiology evaluation to assess for sensorineural hearing loss
• Cardiac evaluation
• Brain imaging in individuals with microcephaly and/or neurologic findings
• Examination for genitourinary abnormalities (e.g., hypospadias or cryptorchidism in males)
• Comprehensive developmental assessment
• Consideration of neurologic referral for any unusual movements or concern for seizures
• Discussion of results with a clinical geneticist or genetic counselor
## Treatment of Manifestations
The following are indicated:
Routine treatment of ophthalmologic, cardiac, neurologic findings
Speech, occupational, and physical therapies
Specialized learning programs to meet individual needs
No specific antiepileptic or antipsychotic medications are indicated
• Routine treatment of ophthalmologic, cardiac, neurologic findings
• Speech, occupational, and physical therapies
• Specialized learning programs to meet individual needs
## Surveillance
Appropriate surveillance includes:
Routine pediatric care
Routine developmental assessments
Monitoring of specific identified medical issues
• Routine pediatric care
• Routine developmental assessments
• Monitoring of specific identified medical issues
## Evaluation of Relatives at Risk
See
## Pregnancy Management
If a fetus is known to have 15q24 microdeletion syndrome, fetal echocardiogram and ultrasound examination with an attempt to visualize the palate and look for diaphragmatic hernia are recommended. Close monitoring for intrauterine growth retardation is warranted. Counseling with regard to the developmental outcomes and medical complications of the 15q24 microdeletion syndrome is appropriate. Delivery at a center with a good neonatal intensive care team is optimal, as respiratory complications and feeding difficulties may occur after delivery.
## Therapies Under Investigation
Search
## Genetic Counseling
The 15q24 microdeletion syndrome is inherited in an autosomal dominant manner; however, all known cases have resulted from a
All known cases have been
Recurrence risk for future pregnancies is low (probably <1%) but greater than that of the general population because parents may have one of the following:
Germline mosaicism
Low-level somatic mosaicism that also includes the germline
A balanced chromosomal rearrangement involving the 15q24 region
The risk to the sibs of the proband depends on the status of the parents. In the unlikely event that a parent has germline mosaicism for a 15q24 deletion or a balanced structural chromosome rearrangement involving the 15q24 region, the risk to sibs is increased and depends on the specific chromosome rearrangement.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low because recurrence has not yet been reported in a family with the 15q24 microdeletion syndrome.
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 15q24 microdeletion syndrome.
Prenatal testing may be offered to unaffected parents who have had a child with the 15q24 microdeletion syndrome because of the recurrence risk (probably <1%) associated with the possibility of germline mosaicism.
Prenatal testing is technically feasible. Fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using array comparative genomic hybridization or targeted deletion analysis methods in the manner described in
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
• All known cases have been
• Recurrence risk for future pregnancies is low (probably <1%) but greater than that of the general population because parents may have one of the following:
• Germline mosaicism
• Low-level somatic mosaicism that also includes the germline
• A balanced chromosomal rearrangement involving the 15q24 region
• Germline mosaicism
• Low-level somatic mosaicism that also includes the germline
• A balanced chromosomal rearrangement involving the 15q24 region
• Germline mosaicism
• Low-level somatic mosaicism that also includes the germline
• A balanced chromosomal rearrangement involving the 15q24 region
• The risk to the sibs of the proband depends on the status of the parents. In the unlikely event that a parent has germline mosaicism for a 15q24 deletion or a balanced structural chromosome rearrangement involving the 15q24 region, the risk to sibs is increased and depends on the specific chromosome rearrangement.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low because recurrence has not yet been reported in a family with the 15q24 microdeletion syndrome.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 15q24 microdeletion syndrome.
## Mode of Inheritance
The 15q24 microdeletion syndrome is inherited in an autosomal dominant manner; however, all known cases have resulted from a
## Risk to Family Members
All known cases have been
Recurrence risk for future pregnancies is low (probably <1%) but greater than that of the general population because parents may have one of the following:
Germline mosaicism
Low-level somatic mosaicism that also includes the germline
A balanced chromosomal rearrangement involving the 15q24 region
The risk to the sibs of the proband depends on the status of the parents. In the unlikely event that a parent has germline mosaicism for a 15q24 deletion or a balanced structural chromosome rearrangement involving the 15q24 region, the risk to sibs is increased and depends on the specific chromosome rearrangement.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low because recurrence has not yet been reported in a family with the 15q24 microdeletion syndrome.
• All known cases have been
• Recurrence risk for future pregnancies is low (probably <1%) but greater than that of the general population because parents may have one of the following:
• Germline mosaicism
• Low-level somatic mosaicism that also includes the germline
• A balanced chromosomal rearrangement involving the 15q24 region
• Germline mosaicism
• Low-level somatic mosaicism that also includes the germline
• A balanced chromosomal rearrangement involving the 15q24 region
• Germline mosaicism
• Low-level somatic mosaicism that also includes the germline
• A balanced chromosomal rearrangement involving the 15q24 region
• The risk to the sibs of the proband depends on the status of the parents. In the unlikely event that a parent has germline mosaicism for a 15q24 deletion or a balanced structural chromosome rearrangement involving the 15q24 region, the risk to sibs is increased and depends on the specific chromosome rearrangement.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low because recurrence has not yet been reported in a family with the 15q24 microdeletion syndrome.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 15q24 microdeletion syndrome.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 15q24 microdeletion syndrome.
## Prenatal Testing and Preimplantation Genetic Diagnosis
Prenatal testing may be offered to unaffected parents who have had a child with the 15q24 microdeletion syndrome because of the recurrence risk (probably <1%) associated with the possibility of germline mosaicism.
Prenatal testing is technically feasible. Fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using array comparative genomic hybridization or targeted deletion analysis methods in the manner described in
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
## Resources
PO Box 724
Boca Raton FL 33429-0724
G1 The Stables
Station Road West
Oxted Surrey RH8 9EE
United Kingdom
•
•
•
• PO Box 724
• Boca Raton FL 33429-0724
•
•
• G1 The Stables
• Station Road West
• Oxted Surrey RH8 9EE
• United Kingdom
•
## Molecular Genetics
15q24 Microdeletion: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for 15q24 Microdeletion (
The 15q24 region is characterized by several segmental duplication (SD) blocks or low copy repeats [
The 1.1-Mb critical region between blocks B and C contains 26 genes that are well characterized in the
## Molecular Genetic Pathogenesis
The 15q24 region is characterized by several segmental duplication (SD) blocks or low copy repeats [
The 1.1-Mb critical region between blocks B and C contains 26 genes that are well characterized in the
## References
## Literature Cited
## Chapter Notes
Dr Mefford’s Laboratory website:
OMIM
9 May 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population
23 February 2012 (me) Review posted live
1 September 2011 (hm) Original submission
• 9 May 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population
• 23 February 2012 (me) Review posted live
• 1 September 2011 (hm) Original submission
## Author Notes
Dr Mefford’s Laboratory website:
## Acknowledgments
OMIM
## Revision History
9 May 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population
23 February 2012 (me) Review posted live
1 September 2011 (hm) Original submission
• 9 May 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population
• 23 February 2012 (me) Review posted live
• 1 September 2011 (hm) Original submission
Eight individuals with deletions in the 15q24 region. Those in panels A-F each have a deletion that includes the 1.1-Mb critical region. The individual in panel G has a large atypical deletion that includes only the proximal ~250 kb of the critical region; the individual in panel H has a small atypical deletion that is just distal to the critical region. Note the high forehead, widely spaced eyes, and pointed chin in most.
A schematic representation of the structure of the 15q24 region and the most common deletions identified in the region. Orange rectangles represent segmental duplication blocks A-E, which are though to facilitate nonallelic homologous recombination (NAHR). Red bars represent the recurrent deletions that have been reported with both breakpoints in segmental duplication blocks. For each, the percentage of all deletions reported to date is indicated. The vast majority of deletions reported in the literature include the shaded region between blocks B and C, though at least three individuals have deletions involving only part of this region [
|
[
"H al Kandari, N Katsumata, S Alexander, MA Rasoul. Homozygous mutation of P450 side-chain cleavage enzyme gene (CYP11A1) in 46,XY patient with adrenal insufficiency, complete sex reversal, and agenesis of corpus callosum.. J Clin Endocr Metab. 2006;91:2821-6",
"J Andrieux, C Dubourg, M Rio, T Attie-Bitach, E Delaby, M Mathieu, H Journel, H Copin, E Blondeel, M Doco-Fenzy, E Landais, B Delobel, S Odent, S Manouvrier-Hanu, M. Holder-Espinasse. Genotype-phenotype correlation in four 15q24 deleted patients identified by array-CGH.. Am J Med Genet A. 2009;149A:2813-9",
"JA Bailey, Z Gu, RA Clark, K Reinert, RV Samonte, S Schwartz, MD Adams, EW Myers, PW Li, EE Eichler. Recent segmental duplications in the human genome.. Science. 2002;297:1003-7",
"AW El-Hattab, TA Smolarek, ME Walker, EK Schorry, LL Immken, G Patel, MA Abbott, BC Lanpher, Z Ou, SH Kang, A Patel, F Scaglia, JR Lupski, SW Cheung, P Stankiewicz. Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping.. Hum Genet. 2009;126:589-602",
"AW El-Hattab, F Zhang, R Maxim, KM Christensen, JC Ward, S Hines-Dowell, F Scaglia, JR Lupski, SW Cheung. Deletion and duplication of 15q24: molecular mechanisms and potential modification by additional copy number variants.. Genet Med. 2010;12:573-86",
"C Golzio, J Martinovic-Bouriel, S Thomas, S Mougou-Zrelli, B Grattagliano-Bessieres, M Bonniere, S Delahaye, A Munnich, F Encha-Razavi, S Lyonnet, M Vekemans, T Attie-Batich, HC Etchevers. Matthew-Wood syndrome is caused by truncating mutations in the retinol-binding protein receptor gene STRA6.. Am J Hum Genet. 2007;80:1179-87",
"O Hiort, PM Holterhus, R Werner, C Marschke, U Hoppe, CJ Partsch, FG Riepe, JC Achermann, D Struve. Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46,XY sex reversal, and severe adrenal failure.. J Clin Endocrinol Metab. 2005;90:538-41",
"J Jaeken, G Matthijs, J-M Saudubray, C Dionisi-Vici, E Bertini, P de Lonlay, H Henri, H Carchon, E Schollen, E Van Schaftingen. Phosphomannose isomerase deficiency: a carbohydrate-deficient glycoprotein syndrome with hepatic-intestinal presentation.. Am J Hum Genet. 1998;62:1535-9",
"N Katsumata, M Ohtake, T Hojo, E Ogawa, T Hara, N Sato, T Tanaka. Compound heterozygous mutations in the cholesterol side-chain cleavage enzyme gene (CYP11A) cause congenital adrenal insufficiency in humans.. J Clin Endocr Metab. 2002;87:3808-13",
"AB Kiholm Lund, HD Hove, M. A Kirchhoff. 15q24 microduplication, reciprocal to the recently described 15q24 microdeletion, in a boy sharing clinical features with 15q24 microdeletion syndrome patients.. Eur J Med Genet. 2008;51:520-6",
"CJ Kim, L Lin, N Huang, CA Quigley. AvRuskin TW, Achermann JC, Miller WL. Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc.. J Clin Endocr Metab. 2008;93:696-702",
"E Klopocki, LM Graul-Neumann, U Grieben, H Tönnies, HH Ropers, D Horn, S Mundlos, R Ullmann. A further case of the recurrent 15q24 microdeletion syndrome, detected by array CGH.. Eur J Pediatr. 2008;167:903-8",
"ISL Ng, WH Chin, ECP Lim, EC Tan. An additional case of the recurrent 15q24.1 microdeletion syndrome and review of the literature.. Twin Res Hum Genet. 2011;14:333-9",
"CR Marshall, A Noor, JB Vincent, AC Lionel, L Feuk, J Skaug, M Shago, R Moessner, D Pinto, Y Ren, B Thiruvahindrapduram, A Fiebig, S Schreiber, J Friedman, CE Ketelaars, YJ Vos, C Ficicioglu, S Kirkpatrick, R Nicolson, L Sloman, A Summers, CA Gibbons, A Teebi, D Chitayat, R Weksberg, A Thompson, C Vardy, V Crosbie, S Luscombe, R Baatjes, L Zwaigenbaum, W Roberts, B Fernandez, P Szatmari, SW Scherer. Structural variation of chromosomes in autism spectrum disorder.. Am J Hum Genet. 2008;82:477-88",
"A Masurel-Paulet, P Callier, C Thauvin-Robinet, M Chouchane, N Mejean, N Marle, AL Mosca, D Ben Salem, M Giroud, L Guibaud, F Huet, F Mugneret, L Faivre. Multiple cysts of the corpus callosum and psychomotor delay in a patient with a 3.1 Mb 15q24.1q24.2 interstitial deletion identified by array-CGH.. Am J Med Genet A. 2009;149A:1504-10",
"LA McInnes, A Nakamine, M Pilorge, T Brandt, P Jiménez González, M Fallas, ER Manghi, L Edelmann, J Glessner, H Hakonarson, C Betancur, JD Buxbaum. A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region.. Mol Autism. 2010;1:5",
"HC Mefford, JA Rosenfeld, N Shur, AM Slavotinek, VA Cox, RC Hennekam, HV Firth, L Willatt, P Wheeler, EM Morrow, J Cook, R Sullivan, A Oh, MT McDonald, J Zonana, K Keller, MC Hannibal, S Ball, J Kussmann, J Gorski, S Zelewski, V Banks, W Smith, R Smith, L Paull, KN Rosenbaum, DJ Amor, J Silva, A Lamb, EE Eichler. Further clinical and molecular delineation of the 15q24 microdeletion syndrome.. J Med Genet. 2012;49:110-8",
"ISL Ng, WH Chin, ECP Lim, EC Tan. An additional case of the recurrent 15q24.1 microdeletion syndrome and review of the literature.. Twin Res Hum Genet. 2011;14:333-9",
"F Pasutto, H Sticht, G Hammersen, G Gillessen-Kaesbach, DR Fitzpatrick, G Nürnberg, F Brasch, H Schirmer-Zimmermann, JL Tolmie, D Chitayat, G Houge, L Fernández-Martínez, S Keating, G Mortier, RC Hennekam, A von der Wense, A Slavotinek, P Meinecke, P Bitoun, C Becker, P Nürnberg, A Reis, A Rauch. Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation.. Am J Hum Genet. 2007;80:550-60",
"KM Roetzer, T Schwarzbraun, AC Obenauf, E Hauser, MR Speicher. Further evidence for the pathogenicity of 15q24 microduplications distal to the minimal critical regions.. Am J Med Genet A. 2010;152A:3173-8",
"P Rubtsov, M Karmanov, P Sverdlova, P Spirin, A. Tiulpakov. A novel homozygous mutation in CYP11A1 gene is associated with late-onset adrenal insufficiency and hypospadias in a 46,XY patient.. J Clin Endocr Metab. 2009;94:936-9",
"E Schollen, L Dorland, TJ de Koning, OP Van Diggelen, JGM Huijmans, T Marquardt, D Babovic-Vuksanovic, M Patterson, F Imtiaz, B Winchester, M Adamowicz, E Pronicka, H Freeze, G Matthijs. Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG-Ib).. Hum Mutat. 2000;16:247-52",
"AJ Sharp, RR Selzer, JA Veltman, S Gimelli, G Gimelli, P Striano, A Coppola, R Regan, SM Price, NV Knoers, PS Eis, HG Brunner, RC Hennekam, SJ Knight, BB de Vries, O Zuffardi, EE Eichler. Characterization of a recurrent 15q24 microdeletion syndrome.. Hum Mol Genet. 2007;16:567-72",
"T Tajima, K Fujieda, N Kouda, J Nakae, WL Miller. Heterozygous mutation in the cholesterol side chain cleavage enzyme (P450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency.. J Clin Endocr Metab. 2001;86:3820-5",
"H Van Esch, L Backx, E Pijkels, JP Fryns. Congenital diaphragmatic hernia is part of the new 15q24 microdeletion syndrome.. Eur J Med Genet. 2009;52:153-6"
] |
23/2/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mdel16p12_2
|
mdel16p12_2
|
[
"16p12.1 Microdeletion",
"16p12.1 Microdeletion",
"16p12.2 Recurrent Deletion"
] |
16p12.2 Recurrent Deletion
|
Santhosh Girirajan, Lucilla Pizzo, John Moeschler, Jill Rosenfeld
|
Summary 16p12.2 recurrent deletion is characterized by variable clinical findings that do not constitute a recognizable syndrome. Of note, the significant bias in ascertainment of individuals undergoing clinical chromosomal microarray analysis (i.e., children with intellectual disability and developmental delay; individuals with schizophrenia) makes it difficult to accurately associate specific phenotypes with the 16p12.2 recurrent deletion. Findings commonly observed in children (probands) with this deletion include: developmental delay, cognitive impairment (ranging from mild to profound), growth impairment (including short stature), cardiac malformations, epilepsy, and psychiatric and/or behavioral issues. Other findings can include: hearing loss, dental abnormalities, renal and genital anomalies (the latter in males), and cleft palate ± cleft lip. The diagnosis of 16p12.2 recurrent deletion is established by identification of a 520-kb heterozygous deletion on chromosome 16p12.2 on chromosomal microarray analysis or other genomic analyses. The 16p12.2 recurrent deletion is inherited in an autosomal dominant manner. The majority (~95%) of individuals with this recurrent deletion inherited the deletion from a parent (who may or may not have clinical features related to the recurrent deletion). If a parent is heterozygous for the 16p12.2 recurrent deletion, the risk that the sibs of a proband would inherit the deletion is 50%; however, the risk that sibs would be affected is less than 50% because of reduced penetrance for the deletion. Children with a family history of neurodevelopmental and psychiatric disease are more likely to present with severe clinical features of the deletion. If a 16p12.2 recurrent deletion has been identified in a family member, prenatal testing for pregnancies at increased risk is possible; however, it is not possible to reliably predict phenotype based on the laboratory finding of a 16p12.2 recurrent deletion.
|
## Diagnosis
No formal diagnostic criteria have been established for 16p12.2 recurrent deletion.
Because of the variable clinical presentation of 16p12.2 recurrent deletion, the diagnosis is made by detection of 16p12.2 recurrent deletion on chromosomal microarray analysis (CMA) or other genomic analyses.
The 16p12.2 recurrent deletion
Developmental delays
Mild-to-moderate intellectual disability
Speech delays
Psychiatric and behavioral abnormalities including autism, bipolar disorder, depression, and schizophrenia
Mild dysmorphic facial features without a consistent pattern
Congenital cardiac defects
Sleep disturbance
Epilepsy
A positive family history of learning disorders or psychiatric issues
Of note, most individuals with the 16p12.2 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, and/or autism spectrum disorder.
The diagnosis of the 16p12.2 recurrent deletion is established by detection of the 520-kb heterozygous deletion at chromosome 16p12.2 (see
For this
ISCN nomenclature for this deletion is: seq[GRCh37] del(16)(p12.2) chr16:g.21,948,445-22,430,805del. Note: Since this deletion is recurrent and mediated by segmental duplications, the unique genetic sequence that is deleted is the same in all individuals with the syndrome; however, the reported size of the deletion may: (1) be larger if adjacent segmental duplications are included in the size and (2) vary based on the design of the microarray used to detect it (see
Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 16p12.2 recurrent deletion (see
Although seven genes of interest (
Note: (1) Most individuals with a 16p12.2 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2010 several CMA platforms did not include coverage for this region and thus may not have detected this deletion. (3) The deletion would not have been detected using BAC arrays.
Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 16p12.2 recurrent deletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.
Genomic Testing Used in 16p12.2 Recurrent Deletion
See
Standardized ISCN annotation and interpretation for genomic variants from the
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 16p12.2 region. Note: The 16p12.2 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms.
Targeted deletion analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods.
Targeted deletion analysis is not appropriate for an individual in whom the 16p12.2 recurrent deletion was not detected by CMA designed to target this region.
Targeted deletion analysis may be used to test at-risk relatives of a proband who is known to have the 16p12.2 recurrent deletion.
• Developmental delays
• Mild-to-moderate intellectual disability
• Speech delays
• Psychiatric and behavioral abnormalities including autism, bipolar disorder, depression, and schizophrenia
• Mild dysmorphic facial features without a consistent pattern
• Congenital cardiac defects
• Sleep disturbance
• Epilepsy
• A positive family history of learning disorders or psychiatric issues
## Suggestive Findings
The 16p12.2 recurrent deletion
Developmental delays
Mild-to-moderate intellectual disability
Speech delays
Psychiatric and behavioral abnormalities including autism, bipolar disorder, depression, and schizophrenia
Mild dysmorphic facial features without a consistent pattern
Congenital cardiac defects
Sleep disturbance
Epilepsy
A positive family history of learning disorders or psychiatric issues
Of note, most individuals with the 16p12.2 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, and/or autism spectrum disorder.
• Developmental delays
• Mild-to-moderate intellectual disability
• Speech delays
• Psychiatric and behavioral abnormalities including autism, bipolar disorder, depression, and schizophrenia
• Mild dysmorphic facial features without a consistent pattern
• Congenital cardiac defects
• Sleep disturbance
• Epilepsy
• A positive family history of learning disorders or psychiatric issues
## Establishing the Diagnosis
The diagnosis of the 16p12.2 recurrent deletion is established by detection of the 520-kb heterozygous deletion at chromosome 16p12.2 (see
For this
ISCN nomenclature for this deletion is: seq[GRCh37] del(16)(p12.2) chr16:g.21,948,445-22,430,805del. Note: Since this deletion is recurrent and mediated by segmental duplications, the unique genetic sequence that is deleted is the same in all individuals with the syndrome; however, the reported size of the deletion may: (1) be larger if adjacent segmental duplications are included in the size and (2) vary based on the design of the microarray used to detect it (see
Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 16p12.2 recurrent deletion (see
Although seven genes of interest (
Note: (1) Most individuals with a 16p12.2 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2010 several CMA platforms did not include coverage for this region and thus may not have detected this deletion. (3) The deletion would not have been detected using BAC arrays.
Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 16p12.2 recurrent deletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.
Genomic Testing Used in 16p12.2 Recurrent Deletion
See
Standardized ISCN annotation and interpretation for genomic variants from the
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 16p12.2 region. Note: The 16p12.2 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms.
Targeted deletion analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods.
Targeted deletion analysis is not appropriate for an individual in whom the 16p12.2 recurrent deletion was not detected by CMA designed to target this region.
Targeted deletion analysis may be used to test at-risk relatives of a proband who is known to have the 16p12.2 recurrent deletion.
## Clinical Characteristics
Due to the variable expressivity of deletion 16p12.2, this variant was not known prior to the use of chromosomal microarray testing in genetic diagnosis. The significant bias in ascertainment of children with intellectual disability and developmental delay [
Clinical Features in Probands with 16p12.2 Recurrent Deletion
Some probands had additional genetic abnormalities identified that likely contributed to their phenotypes; frequencies therefore likely represent an ascertainment bias.
A study including 23 unrelated probands with 16p12.2 recurrent deletion from a (postnatal) clinical genetic testing cohort yielded the following phenotypic findings [
In contrast, individuals with the recurrent deletion who were specifically ascertained for heart defects did not show delayed development [
Microcephaly was present in seven of 22 pediatric probands [
Recurrent deletions of 16p12.2 have also been reported to be significantly enriched among individuals with schizophrenia, with an associated odds ratio of 2.72 (95% confidence interval, 1.48-5.02) relative to a control population [
Hypotonia was reported in 34%-45% of individuals assessed for this feature [
Either a sacral dimple or tethered cord was present in four of 24 individuals assessed [
Abnormal brain imaging was reported in 56%-63% of individuals, with features including cerebellar and cerebral atrophy, decreased white matter, unspecified periventricular changes, and agenesis of the corpus callosum [
One individual with a 16p12.2 recurrent deletion had postnatal onset of hydrocephalus due to cervicomedullary spinal stenosis [
Four children had absence of canine teeth with duplication of incisors bilaterally, pegged incisors, crowded teeth, and/or dental caries.
Three children had renal abnormalities (small kidneys, horseshoe kidney, or hydronephrosis).
Three males had genital anomalies including chordee, hypospadias, and cryptorchidism [
Two had cleft palate, one with cleft lip.
Two had clubfoot or bowed legs.
Single individuals have been reported with craniosynostosis, inguinal hernia, and tracheal agenesis, although the last was in an individual who had an additional rare copy number variant [
Probands with 16p12.2 recurrent deletion manifesting abnormal phenotypes are significantly more likely than controls to have a second rare, unrelated, large (>500 kb) copy number variant (CNV) [
Penetrance for 16p12.2 recurrent deletions is incomplete.
The 16p12.2 recurrent deletion was documented to be enriched in a population undergoing clinical chromosomal microarray analysis [
Based on data from children undergoing clinical chromosome microarray analysis and adult controls, estimates for intellectual disability / developmental delay and/or congenital malformations in those with a 16p12.2 recurrent deletion were 12.3% (95% confidence interval, 7.91%-18.8%) [
In addition, individuals with a 16p12.2 recurrent deletion are more likely to have a family history of neuropsychiatric phenotypes, suggesting segregation of neuropsychiatric risk factors other than 16p12.2 recurrent deletion. Of note, ten (~25%) of 42 probands with 16p12.2 recurrent deletion also had another large (>500-kb) CNV elsewhere in the genome. The "second hit" was frequently
The proportion of males is higher among all individuals with a CNV associated with reduced penetrance and variable expressivity (like a 16p12.2 recurrent deletion) as compared to those with syndromic CNVs (like
While almost all reports describe identification of the 16p12.2 recurrent deletion in individuals who are more severely affected than a parent with the deletion, this is more likely to reflect an ascertainment bias than genetic anticipation. Changes in the size of a 16p12.2 recurrent deletion on transmission from one generation to the next have not been described [
The chromosomal location of the recurrent deletion originally described at 16p12.1 (from coordinates ~21850000-~22370000, genome build hg18/NCB136) has changed to 16p12.2 (from coordinates ~21948445-~22430805, genome build hg19/GRCh37). Clinical reports and descriptions now use the 16p12.2 location/nomenclature.
The estimated frequency of 16p12.2 recurrent deletion – on the order of 0.19% of individuals undergoing clinical microarray-based testing [
However, this estimate does not account for healthy or mildly affected individuals who are heterozygous for the deletion.
Control studies show the frequency of the 16p12.2 recurrent deletion to be 0.050%-0.072%, or approximately one in 1,400-2,000 individuals [
One study estimated the prevalence of the 16p12.2 recurrent deletion in the general population (including healthy and affected individuals) at 0.057% (95% confidence interval, 0.032%-0.10%) [
• Four children had absence of canine teeth with duplication of incisors bilaterally, pegged incisors, crowded teeth, and/or dental caries.
• Three children had renal abnormalities (small kidneys, horseshoe kidney, or hydronephrosis).
• Three males had genital anomalies including chordee, hypospadias, and cryptorchidism [
• Two had cleft palate, one with cleft lip.
• Two had clubfoot or bowed legs.
• Single individuals have been reported with craniosynostosis, inguinal hernia, and tracheal agenesis, although the last was in an individual who had an additional rare copy number variant [
• Control studies show the frequency of the 16p12.2 recurrent deletion to be 0.050%-0.072%, or approximately one in 1,400-2,000 individuals [
• One study estimated the prevalence of the 16p12.2 recurrent deletion in the general population (including healthy and affected individuals) at 0.057% (95% confidence interval, 0.032%-0.10%) [
## Clinical Description
Due to the variable expressivity of deletion 16p12.2, this variant was not known prior to the use of chromosomal microarray testing in genetic diagnosis. The significant bias in ascertainment of children with intellectual disability and developmental delay [
Clinical Features in Probands with 16p12.2 Recurrent Deletion
Some probands had additional genetic abnormalities identified that likely contributed to their phenotypes; frequencies therefore likely represent an ascertainment bias.
A study including 23 unrelated probands with 16p12.2 recurrent deletion from a (postnatal) clinical genetic testing cohort yielded the following phenotypic findings [
In contrast, individuals with the recurrent deletion who were specifically ascertained for heart defects did not show delayed development [
Microcephaly was present in seven of 22 pediatric probands [
Recurrent deletions of 16p12.2 have also been reported to be significantly enriched among individuals with schizophrenia, with an associated odds ratio of 2.72 (95% confidence interval, 1.48-5.02) relative to a control population [
Hypotonia was reported in 34%-45% of individuals assessed for this feature [
Either a sacral dimple or tethered cord was present in four of 24 individuals assessed [
Abnormal brain imaging was reported in 56%-63% of individuals, with features including cerebellar and cerebral atrophy, decreased white matter, unspecified periventricular changes, and agenesis of the corpus callosum [
One individual with a 16p12.2 recurrent deletion had postnatal onset of hydrocephalus due to cervicomedullary spinal stenosis [
Four children had absence of canine teeth with duplication of incisors bilaterally, pegged incisors, crowded teeth, and/or dental caries.
Three children had renal abnormalities (small kidneys, horseshoe kidney, or hydronephrosis).
Three males had genital anomalies including chordee, hypospadias, and cryptorchidism [
Two had cleft palate, one with cleft lip.
Two had clubfoot or bowed legs.
Single individuals have been reported with craniosynostosis, inguinal hernia, and tracheal agenesis, although the last was in an individual who had an additional rare copy number variant [
• Four children had absence of canine teeth with duplication of incisors bilaterally, pegged incisors, crowded teeth, and/or dental caries.
• Three children had renal abnormalities (small kidneys, horseshoe kidney, or hydronephrosis).
• Three males had genital anomalies including chordee, hypospadias, and cryptorchidism [
• Two had cleft palate, one with cleft lip.
• Two had clubfoot or bowed legs.
• Single individuals have been reported with craniosynostosis, inguinal hernia, and tracheal agenesis, although the last was in an individual who had an additional rare copy number variant [
## Genotype-Phenotype Correlations
Probands with 16p12.2 recurrent deletion manifesting abnormal phenotypes are significantly more likely than controls to have a second rare, unrelated, large (>500 kb) copy number variant (CNV) [
## Penetrance
Penetrance for 16p12.2 recurrent deletions is incomplete.
The 16p12.2 recurrent deletion was documented to be enriched in a population undergoing clinical chromosomal microarray analysis [
Based on data from children undergoing clinical chromosome microarray analysis and adult controls, estimates for intellectual disability / developmental delay and/or congenital malformations in those with a 16p12.2 recurrent deletion were 12.3% (95% confidence interval, 7.91%-18.8%) [
In addition, individuals with a 16p12.2 recurrent deletion are more likely to have a family history of neuropsychiatric phenotypes, suggesting segregation of neuropsychiatric risk factors other than 16p12.2 recurrent deletion. Of note, ten (~25%) of 42 probands with 16p12.2 recurrent deletion also had another large (>500-kb) CNV elsewhere in the genome. The "second hit" was frequently
The proportion of males is higher among all individuals with a CNV associated with reduced penetrance and variable expressivity (like a 16p12.2 recurrent deletion) as compared to those with syndromic CNVs (like
## Anticipation
While almost all reports describe identification of the 16p12.2 recurrent deletion in individuals who are more severely affected than a parent with the deletion, this is more likely to reflect an ascertainment bias than genetic anticipation. Changes in the size of a 16p12.2 recurrent deletion on transmission from one generation to the next have not been described [
## Nomenclature
The chromosomal location of the recurrent deletion originally described at 16p12.1 (from coordinates ~21850000-~22370000, genome build hg18/NCB136) has changed to 16p12.2 (from coordinates ~21948445-~22430805, genome build hg19/GRCh37). Clinical reports and descriptions now use the 16p12.2 location/nomenclature.
## Prevalence
The estimated frequency of 16p12.2 recurrent deletion – on the order of 0.19% of individuals undergoing clinical microarray-based testing [
However, this estimate does not account for healthy or mildly affected individuals who are heterozygous for the deletion.
Control studies show the frequency of the 16p12.2 recurrent deletion to be 0.050%-0.072%, or approximately one in 1,400-2,000 individuals [
One study estimated the prevalence of the 16p12.2 recurrent deletion in the general population (including healthy and affected individuals) at 0.057% (95% confidence interval, 0.032%-0.10%) [
• Control studies show the frequency of the 16p12.2 recurrent deletion to be 0.050%-0.072%, or approximately one in 1,400-2,000 individuals [
• One study estimated the prevalence of the 16p12.2 recurrent deletion in the general population (including healthy and affected individuals) at 0.057% (95% confidence interval, 0.032%-0.10%) [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The differential diagnosis of the 16p12.2 recurrent deletion is broad due to the variable spectrum and presence of relatively common abnormal phenotypes that occur in affected individuals including developmental delay, learning problems, and neuropsychiatric disorders. All manifestations of the 16p12.2 recurrent deletion can also be seen in individuals with other genomic disorders.
## Management
To establish the extent of disease and needs of an individual diagnosed with the 16p12.2 recurrent deletion, the following evaluations are recommended if they have not already been completed:
Consultation with a clinical geneticist and/or genetic counselor
Measurement of height and weight
Broad review of all organ systems
Developmental assessment with cognitive and behavioral testing
To consider:
Consultation with a neurologist and EEG testing if history suggests the possibility of seizures
Evaluation and echocardiogram by a cardiologist
Because manifestations of 16p12.2 recurrent deletion are variable, treatment should be targeted to the specific problems identified. Early diagnosis and treatment facilitate the best outcome. Referral to other appropriate medical specialists is recommended based on specific signs and symptoms. Specialists may include a developmental/behavioral pediatrician, pediatric neurologist, and/or clinical geneticist.
Periodic:
Developmental evaluations because of the increased incidence of developmental delay, intellectual disability, autism spectrum disorders, and other behavioral features
Monitoring of cardiac, renal, urologic, and/or dental abnormalities, as needed
Reevaluation by a clinical geneticist who can apprise the family of new recommendations for monitoring for medical or mental health concerns.
Older and younger sibs of a proband should be tested for a 16p12.2 recurrent deletion to encourage close assessment/monitoring of developmental milestones and monitoring for neuropsychiatric and congenital manifestations in children with the deletion.
See
Search
• Consultation with a clinical geneticist and/or genetic counselor
• Measurement of height and weight
• Broad review of all organ systems
• Developmental assessment with cognitive and behavioral testing
• Consultation with a neurologist and EEG testing if history suggests the possibility of seizures
• Evaluation and echocardiogram by a cardiologist
• Developmental evaluations because of the increased incidence of developmental delay, intellectual disability, autism spectrum disorders, and other behavioral features
• Monitoring of cardiac, renal, urologic, and/or dental abnormalities, as needed
• Reevaluation by a clinical geneticist who can apprise the family of new recommendations for monitoring for medical or mental health concerns.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with the 16p12.2 recurrent deletion, the following evaluations are recommended if they have not already been completed:
Consultation with a clinical geneticist and/or genetic counselor
Measurement of height and weight
Broad review of all organ systems
Developmental assessment with cognitive and behavioral testing
To consider:
Consultation with a neurologist and EEG testing if history suggests the possibility of seizures
Evaluation and echocardiogram by a cardiologist
• Consultation with a clinical geneticist and/or genetic counselor
• Measurement of height and weight
• Broad review of all organ systems
• Developmental assessment with cognitive and behavioral testing
• Consultation with a neurologist and EEG testing if history suggests the possibility of seizures
• Evaluation and echocardiogram by a cardiologist
## Treatment of Manifestations
Because manifestations of 16p12.2 recurrent deletion are variable, treatment should be targeted to the specific problems identified. Early diagnosis and treatment facilitate the best outcome. Referral to other appropriate medical specialists is recommended based on specific signs and symptoms. Specialists may include a developmental/behavioral pediatrician, pediatric neurologist, and/or clinical geneticist.
## Surveillance
Periodic:
Developmental evaluations because of the increased incidence of developmental delay, intellectual disability, autism spectrum disorders, and other behavioral features
Monitoring of cardiac, renal, urologic, and/or dental abnormalities, as needed
Reevaluation by a clinical geneticist who can apprise the family of new recommendations for monitoring for medical or mental health concerns.
• Developmental evaluations because of the increased incidence of developmental delay, intellectual disability, autism spectrum disorders, and other behavioral features
• Monitoring of cardiac, renal, urologic, and/or dental abnormalities, as needed
• Reevaluation by a clinical geneticist who can apprise the family of new recommendations for monitoring for medical or mental health concerns.
## Evaluation of Relatives at Risk
Older and younger sibs of a proband should be tested for a 16p12.2 recurrent deletion to encourage close assessment/monitoring of developmental milestones and monitoring for neuropsychiatric and congenital manifestations in children with the deletion.
See
## Therapies Under Investigation
Search
## Genetic Counseling
The 16p12.2 recurrent deletion is inherited in an autosomal dominant manner, with an estimated 95% of deletions inherited from a parent and 5% occurring
A single, apparently
Evaluation of the parents by genomic testing that will detect the 16p12.2 recurrent deletion present in the proband is recommended.
Note: Germline mosaicism, somatic mosaicism, and balanced chromosomal rearrangements involving the 16p12.2 region have not been reported with 16p12.2 recurrent deletions.
The family history of some individuals diagnosed with a 16p12.2 recurrent deletion may appear to be negative because of reduced penetrance and variable expressivity. Therefore, an apparently negative family history cannot be confirmed unless appropriate genomic testing followed by detailed clinical evaluation has been performed on the parents of the proband. Even in individuals with a
The risk to the sibs of the proband depends on the genetic status of the parents.
If the 16p12.2 recurrent deletion identified in the proband is not identified in a parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism for the deletion.
If one of the parents has the 16p12.2 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the expressivity of 16p12.2 recurrent deletion in sibs of a proband.
The presence of neuropsychiatric phenotypes in a parent with the deletion may indicate higher penetrance within a family (see
Offspring of an individual with a 16p12.2 recurrent deletion have a 50% chance of inheriting the deletion.
The risk to offspring of being affected is less than 50% because of reduced penetrance (see
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 16p12.2 recurrent deletion.
Prenatal testing using targeted deletion analysis that will detect the 16p12.2 recurrent deletion found in the proband may be offered when:
A parent has the recurrent deletion; or
The parents do not have the recurrent deletion but have had a child with the 16p12.2 recurrent deletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is probably slightly greater than that of the general population (though still <1%).
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Note: Regardless of whether a pregnancy is known or not known to be at increased risk for 16p12.2 recurrent deletion, prenatal test results cannot reliably predict the phenotype.
• Evaluation of the parents by genomic testing that will detect the 16p12.2 recurrent deletion present in the proband is recommended.
• Note: Germline mosaicism, somatic mosaicism, and balanced chromosomal rearrangements involving the 16p12.2 region have not been reported with 16p12.2 recurrent deletions.
• The family history of some individuals diagnosed with a 16p12.2 recurrent deletion may appear to be negative because of reduced penetrance and variable expressivity. Therefore, an apparently negative family history cannot be confirmed unless appropriate genomic testing followed by detailed clinical evaluation has been performed on the parents of the proband. Even in individuals with a
• The risk to the sibs of the proband depends on the genetic status of the parents.
• If the 16p12.2 recurrent deletion identified in the proband is not identified in a parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism for the deletion.
• If one of the parents has the 16p12.2 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the expressivity of 16p12.2 recurrent deletion in sibs of a proband.
• The presence of neuropsychiatric phenotypes in a parent with the deletion may indicate higher penetrance within a family (see
• Offspring of an individual with a 16p12.2 recurrent deletion have a 50% chance of inheriting the deletion.
• The risk to offspring of being affected is less than 50% because of reduced penetrance (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 16p12.2 recurrent deletion.
• A parent has the recurrent deletion; or
• The parents do not have the recurrent deletion but have had a child with the 16p12.2 recurrent deletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is probably slightly greater than that of the general population (though still <1%).
## Mode of Inheritance
The 16p12.2 recurrent deletion is inherited in an autosomal dominant manner, with an estimated 95% of deletions inherited from a parent and 5% occurring
A single, apparently
## Risk to Family Members
Evaluation of the parents by genomic testing that will detect the 16p12.2 recurrent deletion present in the proband is recommended.
Note: Germline mosaicism, somatic mosaicism, and balanced chromosomal rearrangements involving the 16p12.2 region have not been reported with 16p12.2 recurrent deletions.
The family history of some individuals diagnosed with a 16p12.2 recurrent deletion may appear to be negative because of reduced penetrance and variable expressivity. Therefore, an apparently negative family history cannot be confirmed unless appropriate genomic testing followed by detailed clinical evaluation has been performed on the parents of the proband. Even in individuals with a
The risk to the sibs of the proband depends on the genetic status of the parents.
If the 16p12.2 recurrent deletion identified in the proband is not identified in a parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism for the deletion.
If one of the parents has the 16p12.2 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the expressivity of 16p12.2 recurrent deletion in sibs of a proband.
The presence of neuropsychiatric phenotypes in a parent with the deletion may indicate higher penetrance within a family (see
Offspring of an individual with a 16p12.2 recurrent deletion have a 50% chance of inheriting the deletion.
The risk to offspring of being affected is less than 50% because of reduced penetrance (see
• Evaluation of the parents by genomic testing that will detect the 16p12.2 recurrent deletion present in the proband is recommended.
• Note: Germline mosaicism, somatic mosaicism, and balanced chromosomal rearrangements involving the 16p12.2 region have not been reported with 16p12.2 recurrent deletions.
• The family history of some individuals diagnosed with a 16p12.2 recurrent deletion may appear to be negative because of reduced penetrance and variable expressivity. Therefore, an apparently negative family history cannot be confirmed unless appropriate genomic testing followed by detailed clinical evaluation has been performed on the parents of the proband. Even in individuals with a
• The risk to the sibs of the proband depends on the genetic status of the parents.
• If the 16p12.2 recurrent deletion identified in the proband is not identified in a parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism for the deletion.
• If one of the parents has the 16p12.2 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the expressivity of 16p12.2 recurrent deletion in sibs of a proband.
• The presence of neuropsychiatric phenotypes in a parent with the deletion may indicate higher penetrance within a family (see
• Offspring of an individual with a 16p12.2 recurrent deletion have a 50% chance of inheriting the deletion.
• The risk to offspring of being affected is less than 50% because of reduced penetrance (see
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 16p12.2 recurrent deletion.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 16p12.2 recurrent deletion.
## Prenatal Testing and Preimplantation Genetic Testing
Prenatal testing using targeted deletion analysis that will detect the 16p12.2 recurrent deletion found in the proband may be offered when:
A parent has the recurrent deletion; or
The parents do not have the recurrent deletion but have had a child with the 16p12.2 recurrent deletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is probably slightly greater than that of the general population (though still <1%).
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Note: Regardless of whether a pregnancy is known or not known to be at increased risk for 16p12.2 recurrent deletion, prenatal test results cannot reliably predict the phenotype.
• A parent has the recurrent deletion; or
• The parents do not have the recurrent deletion but have had a child with the 16p12.2 recurrent deletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is probably slightly greater than that of the general population (though still <1%).
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
OMIM Entries for 16p12.2 Recurrent Deletion (
The 520-kb deletion at chromosome 16p12.2 (coordinates ~21948445-~22430805, genome build
The 16p12.2 recurrent deletion is mediated by recombination between flanking 68-kb low-copy segmental duplications with 99.5% sequence identity [
African (97.5%)
European (83.1%)
Asian (71.6%)
Therefore, African and European populations likely have a higher risk for 16p12.2 recurrent deletions than Asian populations [
Functional information on
• African (97.5%)
• European (83.1%)
• Asian (71.6%)
## Molecular Pathogenesis
The 520-kb deletion at chromosome 16p12.2 (coordinates ~21948445-~22430805, genome build
The 16p12.2 recurrent deletion is mediated by recombination between flanking 68-kb low-copy segmental duplications with 99.5% sequence identity [
African (97.5%)
European (83.1%)
Asian (71.6%)
Therefore, African and European populations likely have a higher risk for 16p12.2 recurrent deletions than Asian populations [
Functional information on
• African (97.5%)
• European (83.1%)
• Asian (71.6%)
## Chapter Notes
I am interested in understanding the causes and consequences of genome structure and function as related to human neurodevelopmental disorders such as intellectual disability and developmental delay, autism, schizophrenia, and epilepsy. My graduate work on Smith-Magenis syndrome (SMS) trained me in understanding how all individuals carrying a deletion encompassing the retinoic acid induced 1 gene (
13 September 2018 (sw) Comprehensive update posted live
26 February 2015 (me) Review posted live
9 September 2014 (sg) Original submission
• 13 September 2018 (sw) Comprehensive update posted live
• 26 February 2015 (me) Review posted live
• 9 September 2014 (sg) Original submission
## Author Notes
I am interested in understanding the causes and consequences of genome structure and function as related to human neurodevelopmental disorders such as intellectual disability and developmental delay, autism, schizophrenia, and epilepsy. My graduate work on Smith-Magenis syndrome (SMS) trained me in understanding how all individuals carrying a deletion encompassing the retinoic acid induced 1 gene (
## Revision History
13 September 2018 (sw) Comprehensive update posted live
26 February 2015 (me) Review posted live
9 September 2014 (sg) Original submission
• 13 September 2018 (sw) Comprehensive update posted live
• 26 February 2015 (me) Review posted live
• 9 September 2014 (sg) Original submission
## References
## Literature Cited
|
[] |
26/2/2015
|
13/9/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mdel17q12
|
mdel17q12
|
[
"Hepatocyte nuclear factor 1-beta",
"LIM/homeobox protein Lhx1",
"HNF1B",
"LHX1",
"17q12 Recurrent Deletion Syndrome"
] |
17q12 Recurrent Deletion Syndrome
|
Marissa W Mitchel, Daniel Moreno-De-Luca, Scott M Myers, Rebecca V Levy, Stefanie Turner, David H Ledbetter, Christa L Martin
|
Summary 17q12 recurrent deletion syndrome is characterized by variable combinations of the three following findings: structural or functional abnormalities of the kidney and urinary tract, maturity-onset diabetes of the young type 5 (MODY5), and neurodevelopmental or neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder [ASD], attention-deficit/hyperactivity disorder [ADHD], schizophrenia, anxiety, and bipolar disorder). Using a method of data analysis that avoids ascertainment bias, the authors determined that multicystic kidneys and other structural and functional kidney anomalies occur in 85%-90% of affected individuals, MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%. MODY5 is most often diagnosed before age 25 years (range: age 10-50 years). The diagnosis is established in a proband by detection of the 1.4-Mb heterozygous recurrent deletion at chromosome 17q12 by chromosomal microarray testing or other genomic methods. 17q12 recurrent deletion syndrome is inherited in an autosomal dominant manner, with approximately 75% of deletions occurring
|
## Diagnosis
No consensus clinical diagnostic criteria for 17q12 recurrent deletion syndrome have been published.
17q12 recurrent deletion syndrome
Note: Identification of an intragenic
The diagnosis of 17q12 recurrent deletion syndrome
Note: (1) For the purposes of this chapter, the term "17q12 recurrent deletion" is defined as heterozygous and by the genomic coordinates provided in
Although several genes of interest are within the 1.4-Mb deletion, no single gene has been identified to be causative of the overall phenotype of this recurrent deletion syndrome (see
Note: (1) Most individuals with the 17q12 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2007, many CMA platforms did not include coverage for this region and thus may not have detected this deletion.
Genomic Testing Used in 17q12 Recurrent Deletion Syndrome
NA = not applicable
See
Standardized clinical annotation and interpretation for genomic variants from the
Genomic coordinates represent the minimum deletion size associated with the 17q12 recurrent deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the deletion as calculated from these genomic positions may differ from the expected deletion size due to the presence of segmental duplications near breakpoints. The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the recurrent 17q12 deletion (see
See
CMA using oligonucleotide arrays or SNP genotyping arrays. CMA designs in current clinical use target the 17q12 region. Note: The 17q12 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms.
CNV-calling algorithms need to be utilized to detect the 17q12 recurrent deletion.
Targeted deletion analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA), as well as other targeted quantitative methods.
Targeted deletion analysis is not appropriate for an individual in whom the 17q12 recurrent deletion was not detected by CMA designed to target this region.
Targeted deletion analysis may be used to test at-risk relatives of a proband known to have the 17q12 recurrent deletion.
•
• Note: (1) Most individuals with the 17q12 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2007, many CMA platforms did not include coverage for this region and thus may not have detected this deletion.
## Suggestive Findings
17q12 recurrent deletion syndrome
Note: Identification of an intragenic
•
## Establishing the Diagnosis
The diagnosis of 17q12 recurrent deletion syndrome
Note: (1) For the purposes of this chapter, the term "17q12 recurrent deletion" is defined as heterozygous and by the genomic coordinates provided in
Although several genes of interest are within the 1.4-Mb deletion, no single gene has been identified to be causative of the overall phenotype of this recurrent deletion syndrome (see
Note: (1) Most individuals with the 17q12 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2007, many CMA platforms did not include coverage for this region and thus may not have detected this deletion.
Genomic Testing Used in 17q12 Recurrent Deletion Syndrome
NA = not applicable
See
Standardized clinical annotation and interpretation for genomic variants from the
Genomic coordinates represent the minimum deletion size associated with the 17q12 recurrent deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the deletion as calculated from these genomic positions may differ from the expected deletion size due to the presence of segmental duplications near breakpoints. The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the recurrent 17q12 deletion (see
See
CMA using oligonucleotide arrays or SNP genotyping arrays. CMA designs in current clinical use target the 17q12 region. Note: The 17q12 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms.
CNV-calling algorithms need to be utilized to detect the 17q12 recurrent deletion.
Targeted deletion analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA), as well as other targeted quantitative methods.
Targeted deletion analysis is not appropriate for an individual in whom the 17q12 recurrent deletion was not detected by CMA designed to target this region.
Targeted deletion analysis may be used to test at-risk relatives of a proband known to have the 17q12 recurrent deletion.
• Note: (1) Most individuals with the 17q12 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2007, many CMA platforms did not include coverage for this region and thus may not have detected this deletion.
## Clinical Characteristics
17q12 recurrent deletion syndrome is characterized by variable combinations of the following three most common findings: kidney abnormalities – including congenital abnormalities of the kidney and urinary tract (CAKUT) and tubulointerstitial disease – maturity-onset diabetes of the young (MODY), and neurodevelopmental/neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder [ASD], attention-deficit/hyperactivity disorder [ADHD], schizophrenia, anxiety, and bipolar disorder). In families with more than one affected individual, significant intrafamilial variability has been reported.
To calculate the frequency rates for these features reported in 17q12 recurrent deletion syndrome, the authors reviewed phenotypic information for 282 individuals on whom sufficiently detailed phenotypic information was reported in 42 studies (see
To minimize ascertainment bias, studies involving disease-specific cohorts were not included in the prevalence calculations of that particular phenotypic manifestation (e.g., kidney anomalies).
Individuals with
17q12 Recurrent Deletion Syndrome: Frequency of Select Features
Kidney structural or functional defects
Neurodevelopmental/neuropsychiatric disorders
Mild dysmorphic features
Maturity-onset diabetes of the young type 5
Female & male genital abnormalities
Structural & functional liver abnormalities
Hyperparathyroidism
Eye abnormalities
Structural & exocrine abnormalities of the pancreas
Prematurity
Nonspecific structural brain findings
Congenital cardiac anomalies
Musculoskeletal features
Other gastrointestinal features
Seizures
Clinical data summarized from 42 studies, including 282 individuals in whom the 17q12 recurrent deletion was identified [
Cystic dysplasia is the most common kidney finding; other structural kidney and urinary tract abnormalities include poor corticomedullary differentiation, collecting system abnormalities (duplicated collecting system, hydronephrosis, pyelectasis, vesicoureteral reflux, dilated ureter), single kidney (due to unilateral agenesis or involution of a cystic dysplastic kidney), and horseshoe kidney. Prenatal imaging most often shows kidney cysts or echogenic kidneys, but in many individuals (35%) findings may not develop until childhood or later [
Individuals may also present with tubulointerstitial disease, which is characterized by reduced urine-concentrating ability, bland urinary sediment, absent-to-minimal albuminuria/proteinuria, hyperuricemia, hypomagnesemia, hypokalemia, and slowly progressive kidney disease; interstitial fibrosis and tubular atrophy are seen on biopsy (although biopsy is not routinely indicated) [
Renal tubular wasting of magnesium resulting in hypomagnesemia is common and can be the initial and predominant manifestation of kidney disease in individuals with
The spectrum of severity and range in age of detection of
Progression to ESKD in childhood appears to be uncommon among individuals with
A recent large phenotype-first population study has established that, out of all recurrent deletions studied, deletions in 17q12 have the strongest association with ASD (hazard ratio [HR] 7.79, 95% CI 2.71-22.43) and ADHD (HR 4.24, 95% CI 1.29-13.92), and show a very strong trend toward increasing the chances of developing schizophrenia spectrum disorders (HR 4.84, 95% CI 0.81-28.85) [
Genotype-first studies have shown that ASD and schizophrenia are among the clinical features most strongly associated with 17q12 deletions and can be observed more frequently in people with this deletion compared to the general population. While not routinely assessed, ASD or autistic features are described in 13% of individuals ascertained for other clinical findings [
Moreover, speech and motor delay are common findings, reported in 56% and 64% of individuals, respectively. Overall, about half (41/89) of individuals with 17q12 recurrent deletion syndrome are reported to have some degree of learning disability, although phenotypic information about cognitive skills was limited in most studies. Learning difficulties, when noted, are most often described as mild.
Some studies suggest that genes other than
Hypoplastic nails and 2-3 finger/toe syndactyly are also frequently reported [
Overt diabetes mellitus and abnormal blood glucose levels and/or insulin response are reported in 58/155 (37%) individuals with 17q12 recurrent deletion syndrome not ascertained from cohorts with diabetes mellitus; however, this is almost certainly an underestimate of the lifetime prevalence, since many individuals described in the literature are children and young adults who may not yet have developed manifestations of diabetes. When cohorts with diabetes mellitus are considered, prevalence of MODY5 among individuals with 17q12 recurrent deletion syndrome is 50%.
While many individuals with 17q12 recurrent deletion syndrome with MODY5 have some residual insulin secretion at the time of diagnosis, one study found that 79% required insulin therapy by ten-year follow up [
In females, the most commonly reported finding is partial or complete absence of the upper part of the vagina, cervix, and uterus, often referred to as müllerian aplasia or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome [
In males, genital abnormalities include cryptorchidism, shawl scrotum, phimosis, urethral stenosis or obstruction, hypospadias, epididymal cysts, prostate cyst, and enlarged scrotum [
Ventricular dilatation with and without diffuse brain atrophy [
Mild cerebellar atrophy [
White matter abnormality [
Atrophy of the hippocampus [
Hypotonia (6 persons)
Macrocephaly (6)
Prenatal oligohydramnios (4)
Sensorineural hearing loss (4)
Deep vein thrombosis / vascular calcifications (2)
Ovarian carcinoma (1)
Dyslipidemia (1)
17q12 recurrent deletion syndrome is highly penetrant. Although it is inherited about 25% of the time, there have been no clear reports of unaffected parents with 17q12 recurrent deletion syndrome.
The reported prevalence of 17q12 recurrent deletion syndrome in a large, unbiased population not selected on the basis of disease was 1:6,250 [
• To minimize ascertainment bias, studies involving disease-specific cohorts were not included in the prevalence calculations of that particular phenotypic manifestation (e.g., kidney anomalies).
• Individuals with
• Kidney structural or functional defects
• Neurodevelopmental/neuropsychiatric disorders
• Mild dysmorphic features
• Maturity-onset diabetes of the young type 5
• Female & male genital abnormalities
• Structural & functional liver abnormalities
• Hyperparathyroidism
• Eye abnormalities
• Structural & exocrine abnormalities of the pancreas
• Prematurity
• Nonspecific structural brain findings
• Congenital cardiac anomalies
• Musculoskeletal features
• Other gastrointestinal features
• Seizures
• Ventricular dilatation with and without diffuse brain atrophy [
• Mild cerebellar atrophy [
• White matter abnormality [
• Atrophy of the hippocampus [
• Hypotonia (6 persons)
• Macrocephaly (6)
• Prenatal oligohydramnios (4)
• Sensorineural hearing loss (4)
• Deep vein thrombosis / vascular calcifications (2)
• Ovarian carcinoma (1)
• Dyslipidemia (1)
## Clinical Description
17q12 recurrent deletion syndrome is characterized by variable combinations of the following three most common findings: kidney abnormalities – including congenital abnormalities of the kidney and urinary tract (CAKUT) and tubulointerstitial disease – maturity-onset diabetes of the young (MODY), and neurodevelopmental/neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder [ASD], attention-deficit/hyperactivity disorder [ADHD], schizophrenia, anxiety, and bipolar disorder). In families with more than one affected individual, significant intrafamilial variability has been reported.
To calculate the frequency rates for these features reported in 17q12 recurrent deletion syndrome, the authors reviewed phenotypic information for 282 individuals on whom sufficiently detailed phenotypic information was reported in 42 studies (see
To minimize ascertainment bias, studies involving disease-specific cohorts were not included in the prevalence calculations of that particular phenotypic manifestation (e.g., kidney anomalies).
Individuals with
17q12 Recurrent Deletion Syndrome: Frequency of Select Features
Kidney structural or functional defects
Neurodevelopmental/neuropsychiatric disorders
Mild dysmorphic features
Maturity-onset diabetes of the young type 5
Female & male genital abnormalities
Structural & functional liver abnormalities
Hyperparathyroidism
Eye abnormalities
Structural & exocrine abnormalities of the pancreas
Prematurity
Nonspecific structural brain findings
Congenital cardiac anomalies
Musculoskeletal features
Other gastrointestinal features
Seizures
Clinical data summarized from 42 studies, including 282 individuals in whom the 17q12 recurrent deletion was identified [
Cystic dysplasia is the most common kidney finding; other structural kidney and urinary tract abnormalities include poor corticomedullary differentiation, collecting system abnormalities (duplicated collecting system, hydronephrosis, pyelectasis, vesicoureteral reflux, dilated ureter), single kidney (due to unilateral agenesis or involution of a cystic dysplastic kidney), and horseshoe kidney. Prenatal imaging most often shows kidney cysts or echogenic kidneys, but in many individuals (35%) findings may not develop until childhood or later [
Individuals may also present with tubulointerstitial disease, which is characterized by reduced urine-concentrating ability, bland urinary sediment, absent-to-minimal albuminuria/proteinuria, hyperuricemia, hypomagnesemia, hypokalemia, and slowly progressive kidney disease; interstitial fibrosis and tubular atrophy are seen on biopsy (although biopsy is not routinely indicated) [
Renal tubular wasting of magnesium resulting in hypomagnesemia is common and can be the initial and predominant manifestation of kidney disease in individuals with
The spectrum of severity and range in age of detection of
Progression to ESKD in childhood appears to be uncommon among individuals with
A recent large phenotype-first population study has established that, out of all recurrent deletions studied, deletions in 17q12 have the strongest association with ASD (hazard ratio [HR] 7.79, 95% CI 2.71-22.43) and ADHD (HR 4.24, 95% CI 1.29-13.92), and show a very strong trend toward increasing the chances of developing schizophrenia spectrum disorders (HR 4.84, 95% CI 0.81-28.85) [
Genotype-first studies have shown that ASD and schizophrenia are among the clinical features most strongly associated with 17q12 deletions and can be observed more frequently in people with this deletion compared to the general population. While not routinely assessed, ASD or autistic features are described in 13% of individuals ascertained for other clinical findings [
Moreover, speech and motor delay are common findings, reported in 56% and 64% of individuals, respectively. Overall, about half (41/89) of individuals with 17q12 recurrent deletion syndrome are reported to have some degree of learning disability, although phenotypic information about cognitive skills was limited in most studies. Learning difficulties, when noted, are most often described as mild.
Some studies suggest that genes other than
Hypoplastic nails and 2-3 finger/toe syndactyly are also frequently reported [
Overt diabetes mellitus and abnormal blood glucose levels and/or insulin response are reported in 58/155 (37%) individuals with 17q12 recurrent deletion syndrome not ascertained from cohorts with diabetes mellitus; however, this is almost certainly an underestimate of the lifetime prevalence, since many individuals described in the literature are children and young adults who may not yet have developed manifestations of diabetes. When cohorts with diabetes mellitus are considered, prevalence of MODY5 among individuals with 17q12 recurrent deletion syndrome is 50%.
While many individuals with 17q12 recurrent deletion syndrome with MODY5 have some residual insulin secretion at the time of diagnosis, one study found that 79% required insulin therapy by ten-year follow up [
In females, the most commonly reported finding is partial or complete absence of the upper part of the vagina, cervix, and uterus, often referred to as müllerian aplasia or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome [
In males, genital abnormalities include cryptorchidism, shawl scrotum, phimosis, urethral stenosis or obstruction, hypospadias, epididymal cysts, prostate cyst, and enlarged scrotum [
Ventricular dilatation with and without diffuse brain atrophy [
Mild cerebellar atrophy [
White matter abnormality [
Atrophy of the hippocampus [
Hypotonia (6 persons)
Macrocephaly (6)
Prenatal oligohydramnios (4)
Sensorineural hearing loss (4)
Deep vein thrombosis / vascular calcifications (2)
Ovarian carcinoma (1)
Dyslipidemia (1)
• To minimize ascertainment bias, studies involving disease-specific cohorts were not included in the prevalence calculations of that particular phenotypic manifestation (e.g., kidney anomalies).
• Individuals with
• Kidney structural or functional defects
• Neurodevelopmental/neuropsychiatric disorders
• Mild dysmorphic features
• Maturity-onset diabetes of the young type 5
• Female & male genital abnormalities
• Structural & functional liver abnormalities
• Hyperparathyroidism
• Eye abnormalities
• Structural & exocrine abnormalities of the pancreas
• Prematurity
• Nonspecific structural brain findings
• Congenital cardiac anomalies
• Musculoskeletal features
• Other gastrointestinal features
• Seizures
• Ventricular dilatation with and without diffuse brain atrophy [
• Mild cerebellar atrophy [
• White matter abnormality [
• Atrophy of the hippocampus [
• Hypotonia (6 persons)
• Macrocephaly (6)
• Prenatal oligohydramnios (4)
• Sensorineural hearing loss (4)
• Deep vein thrombosis / vascular calcifications (2)
• Ovarian carcinoma (1)
• Dyslipidemia (1)
## Most Common Features (>50%)
Cystic dysplasia is the most common kidney finding; other structural kidney and urinary tract abnormalities include poor corticomedullary differentiation, collecting system abnormalities (duplicated collecting system, hydronephrosis, pyelectasis, vesicoureteral reflux, dilated ureter), single kidney (due to unilateral agenesis or involution of a cystic dysplastic kidney), and horseshoe kidney. Prenatal imaging most often shows kidney cysts or echogenic kidneys, but in many individuals (35%) findings may not develop until childhood or later [
Individuals may also present with tubulointerstitial disease, which is characterized by reduced urine-concentrating ability, bland urinary sediment, absent-to-minimal albuminuria/proteinuria, hyperuricemia, hypomagnesemia, hypokalemia, and slowly progressive kidney disease; interstitial fibrosis and tubular atrophy are seen on biopsy (although biopsy is not routinely indicated) [
Renal tubular wasting of magnesium resulting in hypomagnesemia is common and can be the initial and predominant manifestation of kidney disease in individuals with
The spectrum of severity and range in age of detection of
Progression to ESKD in childhood appears to be uncommon among individuals with
A recent large phenotype-first population study has established that, out of all recurrent deletions studied, deletions in 17q12 have the strongest association with ASD (hazard ratio [HR] 7.79, 95% CI 2.71-22.43) and ADHD (HR 4.24, 95% CI 1.29-13.92), and show a very strong trend toward increasing the chances of developing schizophrenia spectrum disorders (HR 4.84, 95% CI 0.81-28.85) [
Genotype-first studies have shown that ASD and schizophrenia are among the clinical features most strongly associated with 17q12 deletions and can be observed more frequently in people with this deletion compared to the general population. While not routinely assessed, ASD or autistic features are described in 13% of individuals ascertained for other clinical findings [
Moreover, speech and motor delay are common findings, reported in 56% and 64% of individuals, respectively. Overall, about half (41/89) of individuals with 17q12 recurrent deletion syndrome are reported to have some degree of learning disability, although phenotypic information about cognitive skills was limited in most studies. Learning difficulties, when noted, are most often described as mild.
Some studies suggest that genes other than
Hypoplastic nails and 2-3 finger/toe syndactyly are also frequently reported [
## Common Features (25%-50%)
Overt diabetes mellitus and abnormal blood glucose levels and/or insulin response are reported in 58/155 (37%) individuals with 17q12 recurrent deletion syndrome not ascertained from cohorts with diabetes mellitus; however, this is almost certainly an underestimate of the lifetime prevalence, since many individuals described in the literature are children and young adults who may not yet have developed manifestations of diabetes. When cohorts with diabetes mellitus are considered, prevalence of MODY5 among individuals with 17q12 recurrent deletion syndrome is 50%.
While many individuals with 17q12 recurrent deletion syndrome with MODY5 have some residual insulin secretion at the time of diagnosis, one study found that 79% required insulin therapy by ten-year follow up [
In females, the most commonly reported finding is partial or complete absence of the upper part of the vagina, cervix, and uterus, often referred to as müllerian aplasia or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome [
In males, genital abnormalities include cryptorchidism, shawl scrotum, phimosis, urethral stenosis or obstruction, hypospadias, epididymal cysts, prostate cyst, and enlarged scrotum [
Ventricular dilatation with and without diffuse brain atrophy [
Mild cerebellar atrophy [
White matter abnormality [
Atrophy of the hippocampus [
• Ventricular dilatation with and without diffuse brain atrophy [
• Mild cerebellar atrophy [
• White matter abnormality [
• Atrophy of the hippocampus [
## Less Common Features (<25%)
Hypotonia (6 persons)
Macrocephaly (6)
Prenatal oligohydramnios (4)
Sensorineural hearing loss (4)
Deep vein thrombosis / vascular calcifications (2)
Ovarian carcinoma (1)
Dyslipidemia (1)
• Hypotonia (6 persons)
• Macrocephaly (6)
• Prenatal oligohydramnios (4)
• Sensorineural hearing loss (4)
• Deep vein thrombosis / vascular calcifications (2)
• Ovarian carcinoma (1)
• Dyslipidemia (1)
## Penetrance
17q12 recurrent deletion syndrome is highly penetrant. Although it is inherited about 25% of the time, there have been no clear reports of unaffected parents with 17q12 recurrent deletion syndrome.
## Prevalence
The reported prevalence of 17q12 recurrent deletion syndrome in a large, unbiased population not selected on the basis of disease was 1:6,250 [
## Genetically Related Disorders
Intragenic
## Differential Diagnosis
Genetic Disorders with Kidney Structural or Functional Defects in the Differential Diagnosis of 17q12 Recurrent Deletion Syndrome
Polyuria & polydipsia resulting from ↓ urine-concentrating ability
Chronic tubulointerstitial nephritis
Progression to ESKD
Note: NPH is suspected in absence of CAKUT & signs/symptoms of glomerular kidney disease.
Chronic anemia resistant to therapy
Growth restriction
Note: NPH may be isolated or part of a syndrome, such as
Numerous bilateral cysts
Kidney enlargement
Early-onset hypertension
Nephrolithiasis
Acute or chronic abdominal/flank pain
Kidney insufficiency
~50% have ESKD by age 60 yrs
Polycystic liver disease
Cysts in pancreas, seminal vesicles, & arachnoid membrane
↑ risk of intracranial aneurysms; dilatation of aortic root, & dissection of thoracic aorta; mitral valve prolapse
Abdominal wall hernias
Cystic renal dysplasia
VUR
Skeletal anomalies (small chest, abnormal vertebral segmentation, & posterior rib gaps)
Craniofacial anomalies (hypertelorism, epicanthal folds, depressed nasal bridge w/short nose, & low-set ears)
Dilated cerebral ventricles
Postaxial polydactyly
Ventricular septal defect
Enlarged hyperechogenic kidneys
Variable CKD
Oligo- or anhydramnios & related lung disease often cause most significant complications.
Enlarged hyperechogenic kidneys
Micro- & macrocysts
Variable CKD
Enlarged kidneys w/multiple macrocysts
↑ echogenicity
↓ cortex-medulla differentiation
Possible variable CKD
Inhomogeneous liver parenchyma due to congenital hepatic fibrosis, hepatomegaly, bile duct dilatation / cystic changes
Progressive liver fibrosis & portal hypertension; bile duct dilatation
Predominance of liver disease in some persons w/only mild functional & structural kidney disease
Renal agenesis, hypoplasia, or dysplasia
Ureteropelvic junction obstruction
Calyceal cyst/diverticulum
Caliectasis, pelviectasis, hydronephrosis, VUR
Malformations of outer, middle, & inner ear & hearing impairment
2nd branchial arch anomalies (sinus tract, cyst)
Structural involvement: small hyperechoic kidney, ureteropelvic obstruction, renal cysts
Functional involvement: most commonly renal tubular acidosis
Cholestasis
Congenital cardiac defects
Butterfly vertebrae
Ophthalmologic abnormalities
Characteristic facial features
Tubulointerstitial disease
Few small corticomedullary cysts in 50%
Normal or small-sized kidneys
CKD w/highly variable progression to ESKD
Polycystic kidneys in females
Risk for significant kidney disease appears to be >60% after age 18 yrs
Cleft palate
Dental anomalies
Facial dysmorphology
Digital anomalies
ID
Hypoplastic, dysplastic, multicystic kidneys
Oligomeganephronia
Renal insufficiency & ESKD
VUR
FSGS
Antenatal or childhood-onset enlarged hyperechogenic kidneys w/multiple cysts
Variable progression of CKD to ESKD from infancy to early adulthood
Infantile hyperinsulinemic hypoglycemia
Liver cysts
Childhood/adolescent-onset: ↓ estimated glomerular filtration rate, acidosis, hyperkalemia, & anemia early in life, followed by slowly progressive CKD & gout
Adult onset: gout or mild, slowly progressive CKD beginning in 3rd decade
Bilateral small cysts in 50%
Normal or small-sized kidneys
CKD
Benign renal angiomyolipomas
Epithelial cysts
Oncocytoma
Renal cell carcinoma
Characteristic skin lesions
CNS manifestations (e.g., TAND)
Cardiac rhabdomyomas, arrhythmias
LAM, multifocal micronodular pneumonocyte hyperplasia
Normal urinalysis & slowly progressive CKD, usually 1st noted in teen yrs & progressing to ESKD between 3rd & 7th decades
Hyperuricemia
Gout
Bilateral cysts
Renal cell carcinoma
Hemangioblastomas of brain, spinal cord, & retina
Pheochromocytoma & paraganglioma
Pancreatic cysts & neuroendocrine tumors
Endolymphatic sac tumors
Epididymal & broad ligament cystadenomas
Adapted from
AD = autosomal dominant; ADPKD = autosomal dominant polycystic kidney disease; ADPLD = autosomal dominant polycystic liver disease; ADTKD = autosomal dominant tubulointerstitial kidney disease; AR = autosomal recessive; ARPKD = autosomal recessive polycystic kidney disease; CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; CNS = central nervous system; COACH =
Among individuals with ARPKD,
Although
The differential diagnosis of kidney cysts also includes, in children, idiopathic cystic dysplasia and obstructive dysplasia; and, in adults, acquired kidney cysts (related to chronic kidney disease and/or dialysis) or simple cortical cysts [
An atypical type 2 diabetes-like condition that occurs in the absence of the usual predisposing factors (obesity, hypertension, and dyslipidemia) and often without acanthosis nigricans; OR
An atypical type 1 diabetes-like condition that occurs in the absence of the usual clinical and laboratory manifestations (islet cell autoantibodies, persistence of measurable C peptide levels, and diabetic ketoacidosis) [
• Polyuria & polydipsia resulting from ↓ urine-concentrating ability
• Chronic tubulointerstitial nephritis
• Progression to ESKD
• Note: NPH is suspected in absence of CAKUT & signs/symptoms of glomerular kidney disease.
• Chronic anemia resistant to therapy
• Growth restriction
• Note: NPH may be isolated or part of a syndrome, such as
• Numerous bilateral cysts
• Kidney enlargement
• Early-onset hypertension
• Nephrolithiasis
• Acute or chronic abdominal/flank pain
• Kidney insufficiency
• ~50% have ESKD by age 60 yrs
• Polycystic liver disease
• Cysts in pancreas, seminal vesicles, & arachnoid membrane
• ↑ risk of intracranial aneurysms; dilatation of aortic root, & dissection of thoracic aorta; mitral valve prolapse
• Abdominal wall hernias
• Cystic renal dysplasia
• VUR
• Skeletal anomalies (small chest, abnormal vertebral segmentation, & posterior rib gaps)
• Craniofacial anomalies (hypertelorism, epicanthal folds, depressed nasal bridge w/short nose, & low-set ears)
• Dilated cerebral ventricles
• Postaxial polydactyly
• Ventricular septal defect
• Enlarged hyperechogenic kidneys
• Variable CKD
• Oligo- or anhydramnios & related lung disease often cause most significant complications.
• Enlarged hyperechogenic kidneys
• Micro- & macrocysts
• Variable CKD
• Enlarged kidneys w/multiple macrocysts
• ↑ echogenicity
• ↓ cortex-medulla differentiation
• Possible variable CKD
• Inhomogeneous liver parenchyma due to congenital hepatic fibrosis, hepatomegaly, bile duct dilatation / cystic changes
• Progressive liver fibrosis & portal hypertension; bile duct dilatation
• Predominance of liver disease in some persons w/only mild functional & structural kidney disease
• Renal agenesis, hypoplasia, or dysplasia
• Ureteropelvic junction obstruction
• Calyceal cyst/diverticulum
• Caliectasis, pelviectasis, hydronephrosis, VUR
• Malformations of outer, middle, & inner ear & hearing impairment
• 2nd branchial arch anomalies (sinus tract, cyst)
• Structural involvement: small hyperechoic kidney, ureteropelvic obstruction, renal cysts
• Functional involvement: most commonly renal tubular acidosis
• Cholestasis
• Congenital cardiac defects
• Butterfly vertebrae
• Ophthalmologic abnormalities
• Characteristic facial features
• Tubulointerstitial disease
• Few small corticomedullary cysts in 50%
• Normal or small-sized kidneys
• CKD w/highly variable progression to ESKD
• Polycystic kidneys in females
• Risk for significant kidney disease appears to be >60% after age 18 yrs
• Cleft palate
• Dental anomalies
• Facial dysmorphology
• Digital anomalies
• ID
• Hypoplastic, dysplastic, multicystic kidneys
• Oligomeganephronia
• Renal insufficiency & ESKD
• VUR
• FSGS
• Antenatal or childhood-onset enlarged hyperechogenic kidneys w/multiple cysts
• Variable progression of CKD to ESKD from infancy to early adulthood
• Infantile hyperinsulinemic hypoglycemia
• Liver cysts
• Childhood/adolescent-onset: ↓ estimated glomerular filtration rate, acidosis, hyperkalemia, & anemia early in life, followed by slowly progressive CKD & gout
• Adult onset: gout or mild, slowly progressive CKD beginning in 3rd decade
• Bilateral small cysts in 50%
• Normal or small-sized kidneys
• CKD
• Benign renal angiomyolipomas
• Epithelial cysts
• Oncocytoma
• Renal cell carcinoma
• Characteristic skin lesions
• CNS manifestations (e.g., TAND)
• Cardiac rhabdomyomas, arrhythmias
• LAM, multifocal micronodular pneumonocyte hyperplasia
• Normal urinalysis & slowly progressive CKD, usually 1st noted in teen yrs & progressing to ESKD between 3rd & 7th decades
• Hyperuricemia
• Gout
• Bilateral cysts
• Renal cell carcinoma
• Hemangioblastomas of brain, spinal cord, & retina
• Pheochromocytoma & paraganglioma
• Pancreatic cysts & neuroendocrine tumors
• Endolymphatic sac tumors
• Epididymal & broad ligament cystadenomas
• An atypical type 2 diabetes-like condition that occurs in the absence of the usual predisposing factors (obesity, hypertension, and dyslipidemia) and often without acanthosis nigricans; OR
• An atypical type 1 diabetes-like condition that occurs in the absence of the usual clinical and laboratory manifestations (islet cell autoantibodies, persistence of measurable C peptide levels, and diabetic ketoacidosis) [
•
•
•
•
•
## Management
No clinical practice guidelines for 17q12 recurrent deletion syndrome have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
To establish the extent of disease and needs in an individual diagnosed with 17q12 recurrent deletion syndrome, the evaluations summarized in
17q12 Recurrent Deletion Syndrome: Recommended Evaluations Following Initial Diagnosis
Blood pressure
Kidney & bladder ultrasound
Serum BUN, creatinine, electrolytes (incl calcium, Mg, phosphorus) & uric acid
Urine protein, Mg, & creatinine
Consultation w/nephrologist
Random urine Mg/creatinine is needed to calculate fractional excretion of Mg.
↑ FEMg (>2%) is diagnostic of tubular Mg wasting in those w/normal kidney function.
Assessment of speech & language
Cognitive, motor, & social development
Perceptual anomalies
Mood
Behavior
Fasting glucose & hemoglobin A1c levels
Consultation w/endocrinologist
Males: clinical exam
Females: pelvic ultrasound & gynecologic exam to evaluate for possible müllerian abnormalities
Serum calcium, phosphorus, & intact parathyroid hormone
Urine calcium-to-creatinine ratio
Consultation w/endocrinologist
Measure fecal elastase-1 level to test for EPI in those w/chronic abdominal pain, loose stools, steatorrhea, bloating, excessive flatulence, unintentional weight loss, or poor growth.
Also consider fecal elastase-1 measurement in those w/behavior changes who are unable to communicate discomfort effectively.
Clinical assessment
Consultation w/cardiologist & echocardiography if warranted
Community or
Social work involvement for parental support;
Home nursing referral;
Home psychotherapy or behavioral support.
BUN = blood urea nitrogen; FEMg = fractional excretion of magnesium; GGT = gamma-glutamyl transferase; Mg = magnesium; MODY5 = maturity-onset diabetes of the young type 5; MOI = mode of inheritance
See
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Treatment is symptomatic and depends on an individual's specific needs. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
17q12 Recurrent Deletion Syndrome: Treatment of Manifestations
Treatment should follow standard practice. Established guidelines for mgmt of CKD, incl that related to CAKUT or ADTKD, are available for children & adults.
Some persons have normal kidney function; others may progress to ESKD & require dialysis or kidney transplantation.
In those developing ESKD, transplantation is a good option, as kidney disease is not expected to recur. For those who also have diabetes mellitus, simultaneous pancreas & kidney transplantation has been successful & should be considered.
Provide specialized educational instruction, habilitative therapies (e.g., OT, PT, ST), & psychosocial interventions (e.g., behavioral services, social skills instruction) as warranted, beginning in early childhood.
Consultation w/subspecialists in developmental/behavioral pediatrics or neurodevelopmental disabilities, child & adolescent psychiatry, &/or pediatric psychology in childhood, depending on the needs of the child. Important roles incl educating families, guiding them to evidence-based interventions & accurate information resources, & helping them navigate the multiple systems of care & transitions that are typically involved in the mgmt of neurodevelopmental disabilities.
Psychiatric consultation & therapy for those w/mental health concerns, incl mood & anxiety disorders & psychosis
Intervention involves a multimodal approach to habilitative, educational, social, & emotional needs & assoc impairments, incl behavior problems & coexisting mental health diagnoses. Specific targets of intervention vary w/age, diagnoses, severity, current abilities (e.g., language, cognitive, & functional adaptive skill levels), & family circumstances & preferences.
AACAP has published guidelines for assessment & treatment of psychiatric disorders in children & adolescents w/ID.
There are no published controlled trials of treatment for monogenic diabetes due to 17q12 deletion or
Initial response to oral antihyperglycemic agents appears to be common,
Nonsurgical & surgical intervention may be considered for those w/genital tract anomalies, incl müllerian agenesis.
All persons w/müllerian agenesis should be offered counseling & encouraged to connect w/peer support groups.
Primary vaginal dilation is successful for >90%-96% of those w/müllerian agenesis.
Uterus transplantation can restore fertility in women w/uterine agenesis;
Many ASMs may be effective (none demonstrated effective specifically for this disorder).
Education of parents/caregivers
AACAP = American Academy of Child and Adolescent Psychiatrists; AAP = American Academy of Pediatrics; ADTKD = autosomal dominant tubulointerstitial kidney disease; AGA = American Gastroenterological Association; ASD = autism spectrum disorder; ASM = anti-seizure medication; CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; ERT = enzyme replacement therapy; ESKD = end-stage kidney disease; MODY5 = maturity-onset diabetes of the young type 5; OT = occupational therapy; PT = physical therapy; SGLT2 = sodium-glucose cotransporter 2; ST = speech therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
17q12 Recurrent Deletion Syndrome: Recommended Surveillance
In those w/o known structural defects: 12 mos after establishing diagnosis, then every 2-3 yrs in childhood/adolescence & every 3-5 yrs in adulthood
If an abnormality is detected, more frequent ultrasound may be warranted.
Blood pressure
Kidney function
Serum concentration of Mg, potassium, uric acid
Urine Mg & creatinine
Urine protein-to-creatinine ratio
Periodic, preferably under guidance of nephrologist
Annual or more frequent monitoring may be advised for those who: (1) have lab findings suggestive of kidney disease; (2) are taking potentially nephrotoxic medications (e.g., NSAIDs); (3) have genitourinary structural abnormalities.
Consider reevaluation for uterine & vaginal abnormalities related to müllerian duct aplasia.
Note: Rudimentary müllerian structures are commonly found on MRI. On ultrasound, these rudimentary structures are difficult to interpret & may be particularly misleading before puberty.
Hepatic function panel (or comprehensive metabolic panel) & GGT
Consider lipid panel given case reports of hepatic steatosis.
US may be indicated if labs are abnormal.
Periodic
Consider annually w/kidney function tests & electrolytes as described above.
Fecal elastase-1 level to assess for EPI in persons w/chronic abdominal pain, loose stools, steatorrhea, bloating, excessive flatulence, unintentional weight loss, or poor growth
Also consider fecal elastase-1 measurement in persons w/behavior changes who are unable to communicate discomfort effectively.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GGT = gamma-glutamyl transferase; Mg = magnesium; MODY5 = maturity-onset diabetes of the young type 5; NSAIDs = nonsteroidal anti-inflammatory drugs
Individuals with
Nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory drugs) should be avoided by those with kidney abnormalities. Hepatotoxic medications and alcohol should be avoided by those with liver abnormalities.
For individuals with mental health conditions such as autism spectrum disorder, schizophrenia, or bipolar disorder, the authors recommend caution when considering the use of antipsychotic agents that may lead to weight gain and increased risk of metabolic syndrome and diabetes mellitus, since individuals with 17q12 deletions are already at increased risk for diabetes mellitus. Likewise, the use of mood stabilizers that can affect kidney function in the long term, such as lithium, should be carefully considered in the setting of potential underlying anatomic and functional abnormalities in individuals with 17q12 deletions. These recommendations stem from empirically grounded clinical reasoning based on the underlying phenotypes associated with 17q12 deletions, as large studies assessing the efficacy of these interventions have not yet been performed.
If the 17q12 recurrent deletion is identified in one of the proband's parents on targeted deletion analysis,* it is appropriate to clarify the genetic status of older and younger sibs of the proband and other relatives at risk in order to identify those who would benefit from close assessment/monitoring for evidence of kidney structural or functional defects, maturity-onset diabetes of the young, and developmental delays / intellectual disability.
See
Search
• Blood pressure
• Kidney & bladder ultrasound
• Serum BUN, creatinine, electrolytes (incl calcium, Mg, phosphorus) & uric acid
• Urine protein, Mg, & creatinine
• Consultation w/nephrologist
• Random urine Mg/creatinine is needed to calculate fractional excretion of Mg.
• ↑ FEMg (>2%) is diagnostic of tubular Mg wasting in those w/normal kidney function.
• Assessment of speech & language
• Cognitive, motor, & social development
• Perceptual anomalies
• Mood
• Behavior
• Fasting glucose & hemoglobin A1c levels
• Consultation w/endocrinologist
• Males: clinical exam
• Females: pelvic ultrasound & gynecologic exam to evaluate for possible müllerian abnormalities
• Serum calcium, phosphorus, & intact parathyroid hormone
• Urine calcium-to-creatinine ratio
• Consultation w/endocrinologist
• Measure fecal elastase-1 level to test for EPI in those w/chronic abdominal pain, loose stools, steatorrhea, bloating, excessive flatulence, unintentional weight loss, or poor growth.
• Also consider fecal elastase-1 measurement in those w/behavior changes who are unable to communicate discomfort effectively.
• Clinical assessment
• Consultation w/cardiologist & echocardiography if warranted
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Home psychotherapy or behavioral support.
• Treatment should follow standard practice. Established guidelines for mgmt of CKD, incl that related to CAKUT or ADTKD, are available for children & adults.
• Some persons have normal kidney function; others may progress to ESKD & require dialysis or kidney transplantation.
• In those developing ESKD, transplantation is a good option, as kidney disease is not expected to recur. For those who also have diabetes mellitus, simultaneous pancreas & kidney transplantation has been successful & should be considered.
• Provide specialized educational instruction, habilitative therapies (e.g., OT, PT, ST), & psychosocial interventions (e.g., behavioral services, social skills instruction) as warranted, beginning in early childhood.
• Consultation w/subspecialists in developmental/behavioral pediatrics or neurodevelopmental disabilities, child & adolescent psychiatry, &/or pediatric psychology in childhood, depending on the needs of the child. Important roles incl educating families, guiding them to evidence-based interventions & accurate information resources, & helping them navigate the multiple systems of care & transitions that are typically involved in the mgmt of neurodevelopmental disabilities.
• Psychiatric consultation & therapy for those w/mental health concerns, incl mood & anxiety disorders & psychosis
• Intervention involves a multimodal approach to habilitative, educational, social, & emotional needs & assoc impairments, incl behavior problems & coexisting mental health diagnoses. Specific targets of intervention vary w/age, diagnoses, severity, current abilities (e.g., language, cognitive, & functional adaptive skill levels), & family circumstances & preferences.
• AACAP has published guidelines for assessment & treatment of psychiatric disorders in children & adolescents w/ID.
• There are no published controlled trials of treatment for monogenic diabetes due to 17q12 deletion or
• Initial response to oral antihyperglycemic agents appears to be common,
• Nonsurgical & surgical intervention may be considered for those w/genital tract anomalies, incl müllerian agenesis.
• All persons w/müllerian agenesis should be offered counseling & encouraged to connect w/peer support groups.
• Primary vaginal dilation is successful for >90%-96% of those w/müllerian agenesis.
• Uterus transplantation can restore fertility in women w/uterine agenesis;
• Many ASMs may be effective (none demonstrated effective specifically for this disorder).
• Education of parents/caregivers
• In those w/o known structural defects: 12 mos after establishing diagnosis, then every 2-3 yrs in childhood/adolescence & every 3-5 yrs in adulthood
• If an abnormality is detected, more frequent ultrasound may be warranted.
• Blood pressure
• Kidney function
• Serum concentration of Mg, potassium, uric acid
• Urine Mg & creatinine
• Urine protein-to-creatinine ratio
• Periodic, preferably under guidance of nephrologist
• Annual or more frequent monitoring may be advised for those who: (1) have lab findings suggestive of kidney disease; (2) are taking potentially nephrotoxic medications (e.g., NSAIDs); (3) have genitourinary structural abnormalities.
• Consider reevaluation for uterine & vaginal abnormalities related to müllerian duct aplasia.
• Note: Rudimentary müllerian structures are commonly found on MRI. On ultrasound, these rudimentary structures are difficult to interpret & may be particularly misleading before puberty.
• Hepatic function panel (or comprehensive metabolic panel) & GGT
• Consider lipid panel given case reports of hepatic steatosis.
• US may be indicated if labs are abnormal.
• Periodic
• Consider annually w/kidney function tests & electrolytes as described above.
• Fecal elastase-1 level to assess for EPI in persons w/chronic abdominal pain, loose stools, steatorrhea, bloating, excessive flatulence, unintentional weight loss, or poor growth
• Also consider fecal elastase-1 measurement in persons w/behavior changes who are unable to communicate discomfort effectively.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with 17q12 recurrent deletion syndrome, the evaluations summarized in
17q12 Recurrent Deletion Syndrome: Recommended Evaluations Following Initial Diagnosis
Blood pressure
Kidney & bladder ultrasound
Serum BUN, creatinine, electrolytes (incl calcium, Mg, phosphorus) & uric acid
Urine protein, Mg, & creatinine
Consultation w/nephrologist
Random urine Mg/creatinine is needed to calculate fractional excretion of Mg.
↑ FEMg (>2%) is diagnostic of tubular Mg wasting in those w/normal kidney function.
Assessment of speech & language
Cognitive, motor, & social development
Perceptual anomalies
Mood
Behavior
Fasting glucose & hemoglobin A1c levels
Consultation w/endocrinologist
Males: clinical exam
Females: pelvic ultrasound & gynecologic exam to evaluate for possible müllerian abnormalities
Serum calcium, phosphorus, & intact parathyroid hormone
Urine calcium-to-creatinine ratio
Consultation w/endocrinologist
Measure fecal elastase-1 level to test for EPI in those w/chronic abdominal pain, loose stools, steatorrhea, bloating, excessive flatulence, unintentional weight loss, or poor growth.
Also consider fecal elastase-1 measurement in those w/behavior changes who are unable to communicate discomfort effectively.
Clinical assessment
Consultation w/cardiologist & echocardiography if warranted
Community or
Social work involvement for parental support;
Home nursing referral;
Home psychotherapy or behavioral support.
BUN = blood urea nitrogen; FEMg = fractional excretion of magnesium; GGT = gamma-glutamyl transferase; Mg = magnesium; MODY5 = maturity-onset diabetes of the young type 5; MOI = mode of inheritance
See
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Blood pressure
• Kidney & bladder ultrasound
• Serum BUN, creatinine, electrolytes (incl calcium, Mg, phosphorus) & uric acid
• Urine protein, Mg, & creatinine
• Consultation w/nephrologist
• Random urine Mg/creatinine is needed to calculate fractional excretion of Mg.
• ↑ FEMg (>2%) is diagnostic of tubular Mg wasting in those w/normal kidney function.
• Assessment of speech & language
• Cognitive, motor, & social development
• Perceptual anomalies
• Mood
• Behavior
• Fasting glucose & hemoglobin A1c levels
• Consultation w/endocrinologist
• Males: clinical exam
• Females: pelvic ultrasound & gynecologic exam to evaluate for possible müllerian abnormalities
• Serum calcium, phosphorus, & intact parathyroid hormone
• Urine calcium-to-creatinine ratio
• Consultation w/endocrinologist
• Measure fecal elastase-1 level to test for EPI in those w/chronic abdominal pain, loose stools, steatorrhea, bloating, excessive flatulence, unintentional weight loss, or poor growth.
• Also consider fecal elastase-1 measurement in those w/behavior changes who are unable to communicate discomfort effectively.
• Clinical assessment
• Consultation w/cardiologist & echocardiography if warranted
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Home psychotherapy or behavioral support.
## Treatment of Manifestations
Treatment is symptomatic and depends on an individual's specific needs. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
17q12 Recurrent Deletion Syndrome: Treatment of Manifestations
Treatment should follow standard practice. Established guidelines for mgmt of CKD, incl that related to CAKUT or ADTKD, are available for children & adults.
Some persons have normal kidney function; others may progress to ESKD & require dialysis or kidney transplantation.
In those developing ESKD, transplantation is a good option, as kidney disease is not expected to recur. For those who also have diabetes mellitus, simultaneous pancreas & kidney transplantation has been successful & should be considered.
Provide specialized educational instruction, habilitative therapies (e.g., OT, PT, ST), & psychosocial interventions (e.g., behavioral services, social skills instruction) as warranted, beginning in early childhood.
Consultation w/subspecialists in developmental/behavioral pediatrics or neurodevelopmental disabilities, child & adolescent psychiatry, &/or pediatric psychology in childhood, depending on the needs of the child. Important roles incl educating families, guiding them to evidence-based interventions & accurate information resources, & helping them navigate the multiple systems of care & transitions that are typically involved in the mgmt of neurodevelopmental disabilities.
Psychiatric consultation & therapy for those w/mental health concerns, incl mood & anxiety disorders & psychosis
Intervention involves a multimodal approach to habilitative, educational, social, & emotional needs & assoc impairments, incl behavior problems & coexisting mental health diagnoses. Specific targets of intervention vary w/age, diagnoses, severity, current abilities (e.g., language, cognitive, & functional adaptive skill levels), & family circumstances & preferences.
AACAP has published guidelines for assessment & treatment of psychiatric disorders in children & adolescents w/ID.
There are no published controlled trials of treatment for monogenic diabetes due to 17q12 deletion or
Initial response to oral antihyperglycemic agents appears to be common,
Nonsurgical & surgical intervention may be considered for those w/genital tract anomalies, incl müllerian agenesis.
All persons w/müllerian agenesis should be offered counseling & encouraged to connect w/peer support groups.
Primary vaginal dilation is successful for >90%-96% of those w/müllerian agenesis.
Uterus transplantation can restore fertility in women w/uterine agenesis;
Many ASMs may be effective (none demonstrated effective specifically for this disorder).
Education of parents/caregivers
AACAP = American Academy of Child and Adolescent Psychiatrists; AAP = American Academy of Pediatrics; ADTKD = autosomal dominant tubulointerstitial kidney disease; AGA = American Gastroenterological Association; ASD = autism spectrum disorder; ASM = anti-seizure medication; CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; ERT = enzyme replacement therapy; ESKD = end-stage kidney disease; MODY5 = maturity-onset diabetes of the young type 5; OT = occupational therapy; PT = physical therapy; SGLT2 = sodium-glucose cotransporter 2; ST = speech therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
• Treatment should follow standard practice. Established guidelines for mgmt of CKD, incl that related to CAKUT or ADTKD, are available for children & adults.
• Some persons have normal kidney function; others may progress to ESKD & require dialysis or kidney transplantation.
• In those developing ESKD, transplantation is a good option, as kidney disease is not expected to recur. For those who also have diabetes mellitus, simultaneous pancreas & kidney transplantation has been successful & should be considered.
• Provide specialized educational instruction, habilitative therapies (e.g., OT, PT, ST), & psychosocial interventions (e.g., behavioral services, social skills instruction) as warranted, beginning in early childhood.
• Consultation w/subspecialists in developmental/behavioral pediatrics or neurodevelopmental disabilities, child & adolescent psychiatry, &/or pediatric psychology in childhood, depending on the needs of the child. Important roles incl educating families, guiding them to evidence-based interventions & accurate information resources, & helping them navigate the multiple systems of care & transitions that are typically involved in the mgmt of neurodevelopmental disabilities.
• Psychiatric consultation & therapy for those w/mental health concerns, incl mood & anxiety disorders & psychosis
• Intervention involves a multimodal approach to habilitative, educational, social, & emotional needs & assoc impairments, incl behavior problems & coexisting mental health diagnoses. Specific targets of intervention vary w/age, diagnoses, severity, current abilities (e.g., language, cognitive, & functional adaptive skill levels), & family circumstances & preferences.
• AACAP has published guidelines for assessment & treatment of psychiatric disorders in children & adolescents w/ID.
• There are no published controlled trials of treatment for monogenic diabetes due to 17q12 deletion or
• Initial response to oral antihyperglycemic agents appears to be common,
• Nonsurgical & surgical intervention may be considered for those w/genital tract anomalies, incl müllerian agenesis.
• All persons w/müllerian agenesis should be offered counseling & encouraged to connect w/peer support groups.
• Primary vaginal dilation is successful for >90%-96% of those w/müllerian agenesis.
• Uterus transplantation can restore fertility in women w/uterine agenesis;
• Many ASMs may be effective (none demonstrated effective specifically for this disorder).
• Education of parents/caregivers
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
17q12 Recurrent Deletion Syndrome: Recommended Surveillance
In those w/o known structural defects: 12 mos after establishing diagnosis, then every 2-3 yrs in childhood/adolescence & every 3-5 yrs in adulthood
If an abnormality is detected, more frequent ultrasound may be warranted.
Blood pressure
Kidney function
Serum concentration of Mg, potassium, uric acid
Urine Mg & creatinine
Urine protein-to-creatinine ratio
Periodic, preferably under guidance of nephrologist
Annual or more frequent monitoring may be advised for those who: (1) have lab findings suggestive of kidney disease; (2) are taking potentially nephrotoxic medications (e.g., NSAIDs); (3) have genitourinary structural abnormalities.
Consider reevaluation for uterine & vaginal abnormalities related to müllerian duct aplasia.
Note: Rudimentary müllerian structures are commonly found on MRI. On ultrasound, these rudimentary structures are difficult to interpret & may be particularly misleading before puberty.
Hepatic function panel (or comprehensive metabolic panel) & GGT
Consider lipid panel given case reports of hepatic steatosis.
US may be indicated if labs are abnormal.
Periodic
Consider annually w/kidney function tests & electrolytes as described above.
Fecal elastase-1 level to assess for EPI in persons w/chronic abdominal pain, loose stools, steatorrhea, bloating, excessive flatulence, unintentional weight loss, or poor growth
Also consider fecal elastase-1 measurement in persons w/behavior changes who are unable to communicate discomfort effectively.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GGT = gamma-glutamyl transferase; Mg = magnesium; MODY5 = maturity-onset diabetes of the young type 5; NSAIDs = nonsteroidal anti-inflammatory drugs
• In those w/o known structural defects: 12 mos after establishing diagnosis, then every 2-3 yrs in childhood/adolescence & every 3-5 yrs in adulthood
• If an abnormality is detected, more frequent ultrasound may be warranted.
• Blood pressure
• Kidney function
• Serum concentration of Mg, potassium, uric acid
• Urine Mg & creatinine
• Urine protein-to-creatinine ratio
• Periodic, preferably under guidance of nephrologist
• Annual or more frequent monitoring may be advised for those who: (1) have lab findings suggestive of kidney disease; (2) are taking potentially nephrotoxic medications (e.g., NSAIDs); (3) have genitourinary structural abnormalities.
• Consider reevaluation for uterine & vaginal abnormalities related to müllerian duct aplasia.
• Note: Rudimentary müllerian structures are commonly found on MRI. On ultrasound, these rudimentary structures are difficult to interpret & may be particularly misleading before puberty.
• Hepatic function panel (or comprehensive metabolic panel) & GGT
• Consider lipid panel given case reports of hepatic steatosis.
• US may be indicated if labs are abnormal.
• Periodic
• Consider annually w/kidney function tests & electrolytes as described above.
• Fecal elastase-1 level to assess for EPI in persons w/chronic abdominal pain, loose stools, steatorrhea, bloating, excessive flatulence, unintentional weight loss, or poor growth
• Also consider fecal elastase-1 measurement in persons w/behavior changes who are unable to communicate discomfort effectively.
## Agents/Circumstances to Avoid
Individuals with
Nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory drugs) should be avoided by those with kidney abnormalities. Hepatotoxic medications and alcohol should be avoided by those with liver abnormalities.
For individuals with mental health conditions such as autism spectrum disorder, schizophrenia, or bipolar disorder, the authors recommend caution when considering the use of antipsychotic agents that may lead to weight gain and increased risk of metabolic syndrome and diabetes mellitus, since individuals with 17q12 deletions are already at increased risk for diabetes mellitus. Likewise, the use of mood stabilizers that can affect kidney function in the long term, such as lithium, should be carefully considered in the setting of potential underlying anatomic and functional abnormalities in individuals with 17q12 deletions. These recommendations stem from empirically grounded clinical reasoning based on the underlying phenotypes associated with 17q12 deletions, as large studies assessing the efficacy of these interventions have not yet been performed.
## Evaluation of Relatives at Risk
If the 17q12 recurrent deletion is identified in one of the proband's parents on targeted deletion analysis,* it is appropriate to clarify the genetic status of older and younger sibs of the proband and other relatives at risk in order to identify those who would benefit from close assessment/monitoring for evidence of kidney structural or functional defects, maturity-onset diabetes of the young, and developmental delays / intellectual disability.
See
## Therapies Under Investigation
Search
## Genetic Counseling
17q12 recurrent deletion syndrome is inherited in an autosomal dominant manner.
Most studies examining the 17q12 recurrent deletion have not reported whether the parents were tested; therefore, inheritance status is often unknown or the data are limited. However, in 109 individuals with the 17q12 deletion from 26 studies for which this information is available, the deletion was
In reported families with parent-to-child transmission of the 17q12 recurrent deletion, significant intrafamilial variability has been observed in clinical manifestations [
Genomic testing that will detect the 17q12 recurrent deletion present in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and assess their risk of kidney structural or functional defects, maturity-onset diabetes of the young, and other features associated with the 17q12 recurrent deletion. Because features range in severity, it is possible for parents who are mildly affected to be unaware of any clinical manifestations (diabetes and kidney problems may not be evident until adulthood).
If the 17q12 recurrent deletion identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a deletion from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only.
If one of the parents has the 17q12 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the full phenotypic expression in a sib who inherits the deletion because significant intrafamilial variability may be observed.
If the 17q12 recurrent deletion identified in the proband is not identified in a parent, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental gonadal mosaicism.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having a child with 17q12 recurrent deletion syndrome.
Note: Regardless of whether the pregnancy is known or not known to be at increased risk for 17q12 recurrent deletion syndrome, prenatal test results cannot reliably predict the phenotype.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most studies examining the 17q12 recurrent deletion have not reported whether the parents were tested; therefore, inheritance status is often unknown or the data are limited. However, in 109 individuals with the 17q12 deletion from 26 studies for which this information is available, the deletion was
• In reported families with parent-to-child transmission of the 17q12 recurrent deletion, significant intrafamilial variability has been observed in clinical manifestations [
• Genomic testing that will detect the 17q12 recurrent deletion present in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and assess their risk of kidney structural or functional defects, maturity-onset diabetes of the young, and other features associated with the 17q12 recurrent deletion. Because features range in severity, it is possible for parents who are mildly affected to be unaware of any clinical manifestations (diabetes and kidney problems may not be evident until adulthood).
• If the 17q12 recurrent deletion identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a deletion from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a deletion from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a deletion from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only.
• If one of the parents has the 17q12 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the full phenotypic expression in a sib who inherits the deletion because significant intrafamilial variability may be observed.
• If the 17q12 recurrent deletion identified in the proband is not identified in a parent, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental gonadal mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having a child with 17q12 recurrent deletion syndrome.
## Mode of Inheritance
17q12 recurrent deletion syndrome is inherited in an autosomal dominant manner.
## Risk to Family Members
Most studies examining the 17q12 recurrent deletion have not reported whether the parents were tested; therefore, inheritance status is often unknown or the data are limited. However, in 109 individuals with the 17q12 deletion from 26 studies for which this information is available, the deletion was
In reported families with parent-to-child transmission of the 17q12 recurrent deletion, significant intrafamilial variability has been observed in clinical manifestations [
Genomic testing that will detect the 17q12 recurrent deletion present in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and assess their risk of kidney structural or functional defects, maturity-onset diabetes of the young, and other features associated with the 17q12 recurrent deletion. Because features range in severity, it is possible for parents who are mildly affected to be unaware of any clinical manifestations (diabetes and kidney problems may not be evident until adulthood).
If the 17q12 recurrent deletion identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a deletion from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only.
If one of the parents has the 17q12 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the full phenotypic expression in a sib who inherits the deletion because significant intrafamilial variability may be observed.
If the 17q12 recurrent deletion identified in the proband is not identified in a parent, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental gonadal mosaicism.
• Most studies examining the 17q12 recurrent deletion have not reported whether the parents were tested; therefore, inheritance status is often unknown or the data are limited. However, in 109 individuals with the 17q12 deletion from 26 studies for which this information is available, the deletion was
• In reported families with parent-to-child transmission of the 17q12 recurrent deletion, significant intrafamilial variability has been observed in clinical manifestations [
• Genomic testing that will detect the 17q12 recurrent deletion present in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and assess their risk of kidney structural or functional defects, maturity-onset diabetes of the young, and other features associated with the 17q12 recurrent deletion. Because features range in severity, it is possible for parents who are mildly affected to be unaware of any clinical manifestations (diabetes and kidney problems may not be evident until adulthood).
• If the 17q12 recurrent deletion identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a deletion from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a deletion from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a deletion from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only.
• If one of the parents has the 17q12 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the full phenotypic expression in a sib who inherits the deletion because significant intrafamilial variability may be observed.
• If the 17q12 recurrent deletion identified in the proband is not identified in a parent, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental gonadal mosaicism.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having a child with 17q12 recurrent deletion syndrome.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having a child with 17q12 recurrent deletion syndrome.
## Prenatal Testing and Preimplantation Genetic Testing
Note: Regardless of whether the pregnancy is known or not known to be at increased risk for 17q12 recurrent deletion syndrome, prenatal test results cannot reliably predict the phenotype.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
17q12 Recurrent Deletion Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for 17q12 Recurrent Deletion Syndrome (
The 17q12 deletion is recurrent, meaning that it involves the same unique genomic sequence. The 17q12 region is considered a hot spot for copy number variants, as it has specific molecular features (known as segmental duplications) that predispose to these events [
Three genes are of particular interest with respect to phenotypes associated with 17q12 recurrent deletion syndrome:
## Molecular Pathogenesis
The 17q12 deletion is recurrent, meaning that it involves the same unique genomic sequence. The 17q12 region is considered a hot spot for copy number variants, as it has specific molecular features (known as segmental duplications) that predispose to these events [
Three genes are of particular interest with respect to phenotypes associated with 17q12 recurrent deletion syndrome:
## Chapter Notes
Dr Moreno De Luca (
This work was funded in part by the National Institute for Mental Health of the National Institutes of Health under awards RO1MH074090 (to DHL and CLM), RO1MH107431 (to CLM), K23MH120376 (to DMD), and grants from the Simons Foundation (SFARI# 215355 to CLM and SFARI# 240413 to DHL). The authors would also like to thank all of the individuals and families with 17q12 deletions for their participation in these research studies.
Brenda Finucane, MS, LGC; Geisinger Health System (2016-2020)David H Ledbetter, PhD, FACMG (2016-present)Rebecca V Levy, BM BCh, MSc (2020-present)Christa L Martin, PhD, FACMG (2016-present)Marissa W Mitchel, MS, CCC-SLP (2016-present)Daniel Moreno-De-Luca, MD, MSc (2016-present)Scott M Myers, MD (2016-present)Stefanie Turner, MS, CGC (2020-present)
14 August 2025 (aa) Revision:
6 February 2025 (sw) Comprehensive update posted live
15 October 2020 (sw) Comprehensive update posted live
8 December 2016 (bp) Review posted live
10 August 2015 (mm) Original submission
• 14 August 2025 (aa) Revision:
• 6 February 2025 (sw) Comprehensive update posted live
• 15 October 2020 (sw) Comprehensive update posted live
• 8 December 2016 (bp) Review posted live
• 10 August 2015 (mm) Original submission
## Author Notes
Dr Moreno De Luca (
## Acknowledgments
This work was funded in part by the National Institute for Mental Health of the National Institutes of Health under awards RO1MH074090 (to DHL and CLM), RO1MH107431 (to CLM), K23MH120376 (to DMD), and grants from the Simons Foundation (SFARI# 215355 to CLM and SFARI# 240413 to DHL). The authors would also like to thank all of the individuals and families with 17q12 deletions for their participation in these research studies.
## Author History
Brenda Finucane, MS, LGC; Geisinger Health System (2016-2020)David H Ledbetter, PhD, FACMG (2016-present)Rebecca V Levy, BM BCh, MSc (2020-present)Christa L Martin, PhD, FACMG (2016-present)Marissa W Mitchel, MS, CCC-SLP (2016-present)Daniel Moreno-De-Luca, MD, MSc (2016-present)Scott M Myers, MD (2016-present)Stefanie Turner, MS, CGC (2020-present)
## Revision History
14 August 2025 (aa) Revision:
6 February 2025 (sw) Comprehensive update posted live
15 October 2020 (sw) Comprehensive update posted live
8 December 2016 (bp) Review posted live
10 August 2015 (mm) Original submission
• 14 August 2025 (aa) Revision:
• 6 February 2025 (sw) Comprehensive update posted live
• 15 October 2020 (sw) Comprehensive update posted live
• 8 December 2016 (bp) Review posted live
• 10 August 2015 (mm) Original submission
## References
## Literature Cited
|
[] |
8/12/2016
|
6/2/2025
|
14/8/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mdel17q21_31
|
mdel17q21_31
|
[
"KdVS",
"KdVS",
"KAT8 regulatory NSL complex subunit 1",
"Not applicable",
"KANSL1",
"Not applicable",
"Koolen-de Vries Syndrome"
] |
Koolen-de Vries Syndrome
|
David A Koolen, Angela Morgan, Bert BA de Vries
|
Summary Koolen-de Vries syndrome (KdVS) is characterized by congenital malformations, developmental delay / intellectual disability, neonatal/childhood hypotonia, epilepsy, dysmorphisms, and behavioral features. Psychomotor developmental delay is noted in all individuals from an early age. The majority of individuals with KdVS function in the mild-to-moderate range of intellectual disability. Other findings include speech and language delay (100%), epilepsy (~33%), congenital heart defects (25%-50%), renal and urologic anomalies (25%-50%), and cryptorchidism. Behavior in most is described as friendly, amiable, and cooperative. The diagnosis of KdVS is established in a proband who has either a heterozygous 500- to 650-kb deletion at chromosome 17q21.31 that includes KdVS, caused by a heterozygous deletion at chromosome 17q21.31 or a heterozygous intragenic
|
## Diagnosis
No consensus clinical diagnostic criteria for Koolen-de Vries syndrome (KdVS) have been published.
KdVS
Mild-to-moderate developmental delay or intellectual disability in which speech and language development is particularly affected
AND
Neonatal/childhood hypotonia and feeding difficulties
Epilepsy
Dysmorphic facial features (See
Hypermetropia
Congenital heart anomalies
Congenital renal/urologic anomalies
Hypermobility of the joints and/or joint dislocation/dysplasia
Deformities of the spine and/or feet
The diagnosis of KdVS
A heterozygous deletion at chromosome 17q21.31 that includes
A heterozygous intragenic pathogenic (or likely pathogenic) variant in
Haploinsufficiency of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of KdVS, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of KdVS is not considered because an individual has atypical phenotypic features,
Note: Some exome sequencing platforms also provide information on DNA copy number variants (CNVs); genome sequencing frequently includes information on DNA CNVs. As such, exome sequencing with CNV analysis or genome sequencing could be considered as a first-line test for KdVS.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Koolen-de Vries Syndrome
See
See
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Many affected individuals are identified by a genome-wide CMA screen for deletions/duplications that includes probe coverage of
To date, testing in all unaffected parents from whom the deleted chromosome 17 originated has shown a 900-kb inversion involving chromosome 17q21.31. The frequency of this inversion (also referred to as the H2 lineage) in these parents is significantly greater than the ~20% frequency of the inversion found in the European population as a whole [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
• Mild-to-moderate developmental delay or intellectual disability in which speech and language development is particularly affected
• Neonatal/childhood hypotonia and feeding difficulties
• Epilepsy
• Dysmorphic facial features (See
• Hypermetropia
• Congenital heart anomalies
• Congenital renal/urologic anomalies
• Hypermobility of the joints and/or joint dislocation/dysplasia
• Deformities of the spine and/or feet
• A heterozygous deletion at chromosome 17q21.31 that includes
• A heterozygous intragenic pathogenic (or likely pathogenic) variant in
• Haploinsufficiency of
• For an introduction to multigene panels click
## Suggestive Findings
KdVS
Mild-to-moderate developmental delay or intellectual disability in which speech and language development is particularly affected
AND
Neonatal/childhood hypotonia and feeding difficulties
Epilepsy
Dysmorphic facial features (See
Hypermetropia
Congenital heart anomalies
Congenital renal/urologic anomalies
Hypermobility of the joints and/or joint dislocation/dysplasia
Deformities of the spine and/or feet
• Mild-to-moderate developmental delay or intellectual disability in which speech and language development is particularly affected
• Neonatal/childhood hypotonia and feeding difficulties
• Epilepsy
• Dysmorphic facial features (See
• Hypermetropia
• Congenital heart anomalies
• Congenital renal/urologic anomalies
• Hypermobility of the joints and/or joint dislocation/dysplasia
• Deformities of the spine and/or feet
## Establishing the Diagnosis
The diagnosis of KdVS
A heterozygous deletion at chromosome 17q21.31 that includes
A heterozygous intragenic pathogenic (or likely pathogenic) variant in
Haploinsufficiency of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of KdVS, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of KdVS is not considered because an individual has atypical phenotypic features,
Note: Some exome sequencing platforms also provide information on DNA copy number variants (CNVs); genome sequencing frequently includes information on DNA CNVs. As such, exome sequencing with CNV analysis or genome sequencing could be considered as a first-line test for KdVS.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Koolen-de Vries Syndrome
See
See
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Many affected individuals are identified by a genome-wide CMA screen for deletions/duplications that includes probe coverage of
To date, testing in all unaffected parents from whom the deleted chromosome 17 originated has shown a 900-kb inversion involving chromosome 17q21.31. The frequency of this inversion (also referred to as the H2 lineage) in these parents is significantly greater than the ~20% frequency of the inversion found in the European population as a whole [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
• A heterozygous deletion at chromosome 17q21.31 that includes
• A heterozygous intragenic pathogenic (or likely pathogenic) variant in
• Haploinsufficiency of
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of KdVS, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of KdVS is not considered because an individual has atypical phenotypic features,
Note: Some exome sequencing platforms also provide information on DNA copy number variants (CNVs); genome sequencing frequently includes information on DNA CNVs. As such, exome sequencing with CNV analysis or genome sequencing could be considered as a first-line test for KdVS.
For an introduction to comprehensive genomic testing click
## Further Testing to Consider
Molecular Genetic Testing Used in Koolen-de Vries Syndrome
See
See
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Many affected individuals are identified by a genome-wide CMA screen for deletions/duplications that includes probe coverage of
To date, testing in all unaffected parents from whom the deleted chromosome 17 originated has shown a 900-kb inversion involving chromosome 17q21.31. The frequency of this inversion (also referred to as the H2 lineage) in these parents is significantly greater than the ~20% frequency of the inversion found in the European population as a whole [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
## Clinical Characteristics
Koolen-de Vries syndrome (KdVS) has a clinically recognizable phenotype that includes neonatal/childhood hypotonia, developmental delay / intellectual givdisability, dysmorphisms (see
Koolen-de Vries Syndrome: Frequency of Select Features
Based on data from the
ADHD = attention-deficit/hyperactivity disorder; ASD = atrial septal defect; VSD = ventriculoseptal defect; VUR = vesicoureteral reflux
Present in more than 75% of affected individuals
Present in 50%-75% of affected individuals
Present in 25%-49% of affected individuals
Present in 10-24% of affected individuals
Upslanted palpebral fissures
Blepharophimosis
Epicanthus
Ptosis
Pear-shaped nose
Bulbous nose
Large/protruding ears
The nose can have a high nasal bridge, a broad nasal root, long columella, and underdeveloped and/or thick alae nasi. The facial characteristics change with age. In infancy the facial gestalt is mostly characterized by hypotonia with an "open mouth" appearance. With increasing age there is usually elongation of the face and broadening of the chin, and the "tubular'' or "pear'' shape of the nose may become more apparent.
First words occur on average between ages 2.5 and 3.5 years.
Augmentative (e.g., sign language) or alternative (e.g., communication devices) communication may alleviate frustration for the child and promote communication development.
Overall, however, speech prognosis is positive, with CAS improving markedly around age eight to 12 years. At this time, the dysarthric element of speech is more apparent with a slow rate and monotone presentation.
The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features.
Multifocal epileptiform discharges are the typical EEG pattern.
Ventriculomegaly
Aplasia/hypoplasia of the corpus callosum
Hydrocephalus
Arnold-Chiari malformation
Intraventricular hemorrhage
Infrequent findings (present in fewer than 10% of reported individuals) may include the following:
Sacral dimple
Dural ectasia
Spina bifida
Pineal cyst
Cervical spinal canal stenosis
Long, slender fingers
Persistence of the fetal fingertip pads
Hypoplasia of the hand muscles
Pes planus
Pes cavus
Calcaneovalgus deformity
Congenital hip dislocation
Scoliosis/kyphosis
Pectus anomalies, including pectus excavatum or pectus carinatum
Slender build
Spondylolisthesis (infrequently)
Craniosynostosis (infrequently), most commonly sagittal, but metopic has also been observed
Multiple nevi
Other pigmentary skin abnormalities, such as vitiligo and café au lait macules
Hemangioma
Eczema
Ichthyosis/hyperkeratosis
Hair abnormalities, such as fair hair and/or alopecia
Genotype-phenotype correlations in KdVS have not been demonstrated. Notably, the clinical features of affected individuals with atypical deletions and those with pathogenic variants in
Penetrance is 100%. Clinical features of KdVS are apparent in all individuals with a deletion of or a pathogenic variant in
The disorder was first recognized following chromosomal microarray analysis among large cohorts of unselected individuals with intellectual disability [
The prevalence of KdVS is unknown. The authors estimate the prevalence of the 17q21.31 deletion to be 1:55,000 individuals [
• Upslanted palpebral fissures
• Blepharophimosis
• Epicanthus
• Ptosis
• Pear-shaped nose
• Bulbous nose
• Large/protruding ears
• First words occur on average between ages 2.5 and 3.5 years.
• Augmentative (e.g., sign language) or alternative (e.g., communication devices) communication may alleviate frustration for the child and promote communication development.
• Overall, however, speech prognosis is positive, with CAS improving markedly around age eight to 12 years. At this time, the dysarthric element of speech is more apparent with a slow rate and monotone presentation.
• First words occur on average between ages 2.5 and 3.5 years.
• Augmentative (e.g., sign language) or alternative (e.g., communication devices) communication may alleviate frustration for the child and promote communication development.
• Overall, however, speech prognosis is positive, with CAS improving markedly around age eight to 12 years. At this time, the dysarthric element of speech is more apparent with a slow rate and monotone presentation.
• First words occur on average between ages 2.5 and 3.5 years.
• Augmentative (e.g., sign language) or alternative (e.g., communication devices) communication may alleviate frustration for the child and promote communication development.
• Overall, however, speech prognosis is positive, with CAS improving markedly around age eight to 12 years. At this time, the dysarthric element of speech is more apparent with a slow rate and monotone presentation.
• The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features.
• Multifocal epileptiform discharges are the typical EEG pattern.
• Ventriculomegaly
• Aplasia/hypoplasia of the corpus callosum
• Hydrocephalus
• Arnold-Chiari malformation
• Intraventricular hemorrhage
• Ventriculomegaly
• Aplasia/hypoplasia of the corpus callosum
• Hydrocephalus
• Arnold-Chiari malformation
• Intraventricular hemorrhage
• Infrequent findings (present in fewer than 10% of reported individuals) may include the following:
• Sacral dimple
• Dural ectasia
• Spina bifida
• Pineal cyst
• Cervical spinal canal stenosis
• Sacral dimple
• Dural ectasia
• Spina bifida
• Pineal cyst
• Cervical spinal canal stenosis
• Ventriculomegaly
• Aplasia/hypoplasia of the corpus callosum
• Hydrocephalus
• Arnold-Chiari malformation
• Intraventricular hemorrhage
• Sacral dimple
• Dural ectasia
• Spina bifida
• Pineal cyst
• Cervical spinal canal stenosis
• Long, slender fingers
• Persistence of the fetal fingertip pads
• Hypoplasia of the hand muscles
• Pes planus
• Pes cavus
• Calcaneovalgus deformity
• Congenital hip dislocation
• Scoliosis/kyphosis
• Pectus anomalies, including pectus excavatum or pectus carinatum
• Slender build
• Spondylolisthesis (infrequently)
• Craniosynostosis (infrequently), most commonly sagittal, but metopic has also been observed
• Multiple nevi
• Other pigmentary skin abnormalities, such as vitiligo and café au lait macules
• Hemangioma
• Eczema
• Ichthyosis/hyperkeratosis
• Hair abnormalities, such as fair hair and/or alopecia
• Multiple nevi
• Other pigmentary skin abnormalities, such as vitiligo and café au lait macules
• Hemangioma
• Eczema
• Ichthyosis/hyperkeratosis
• Hair abnormalities, such as fair hair and/or alopecia
• Multiple nevi
• Other pigmentary skin abnormalities, such as vitiligo and café au lait macules
• Hemangioma
• Eczema
• Ichthyosis/hyperkeratosis
• Hair abnormalities, such as fair hair and/or alopecia
## Clinical Description
Koolen-de Vries syndrome (KdVS) has a clinically recognizable phenotype that includes neonatal/childhood hypotonia, developmental delay / intellectual givdisability, dysmorphisms (see
Koolen-de Vries Syndrome: Frequency of Select Features
Based on data from the
ADHD = attention-deficit/hyperactivity disorder; ASD = atrial septal defect; VSD = ventriculoseptal defect; VUR = vesicoureteral reflux
Present in more than 75% of affected individuals
Present in 50%-75% of affected individuals
Present in 25%-49% of affected individuals
Present in 10-24% of affected individuals
Upslanted palpebral fissures
Blepharophimosis
Epicanthus
Ptosis
Pear-shaped nose
Bulbous nose
Large/protruding ears
The nose can have a high nasal bridge, a broad nasal root, long columella, and underdeveloped and/or thick alae nasi. The facial characteristics change with age. In infancy the facial gestalt is mostly characterized by hypotonia with an "open mouth" appearance. With increasing age there is usually elongation of the face and broadening of the chin, and the "tubular'' or "pear'' shape of the nose may become more apparent.
First words occur on average between ages 2.5 and 3.5 years.
Augmentative (e.g., sign language) or alternative (e.g., communication devices) communication may alleviate frustration for the child and promote communication development.
Overall, however, speech prognosis is positive, with CAS improving markedly around age eight to 12 years. At this time, the dysarthric element of speech is more apparent with a slow rate and monotone presentation.
The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features.
Multifocal epileptiform discharges are the typical EEG pattern.
Ventriculomegaly
Aplasia/hypoplasia of the corpus callosum
Hydrocephalus
Arnold-Chiari malformation
Intraventricular hemorrhage
Infrequent findings (present in fewer than 10% of reported individuals) may include the following:
Sacral dimple
Dural ectasia
Spina bifida
Pineal cyst
Cervical spinal canal stenosis
Long, slender fingers
Persistence of the fetal fingertip pads
Hypoplasia of the hand muscles
Pes planus
Pes cavus
Calcaneovalgus deformity
Congenital hip dislocation
Scoliosis/kyphosis
Pectus anomalies, including pectus excavatum or pectus carinatum
Slender build
Spondylolisthesis (infrequently)
Craniosynostosis (infrequently), most commonly sagittal, but metopic has also been observed
Multiple nevi
Other pigmentary skin abnormalities, such as vitiligo and café au lait macules
Hemangioma
Eczema
Ichthyosis/hyperkeratosis
Hair abnormalities, such as fair hair and/or alopecia
• Upslanted palpebral fissures
• Blepharophimosis
• Epicanthus
• Ptosis
• Pear-shaped nose
• Bulbous nose
• Large/protruding ears
• First words occur on average between ages 2.5 and 3.5 years.
• Augmentative (e.g., sign language) or alternative (e.g., communication devices) communication may alleviate frustration for the child and promote communication development.
• Overall, however, speech prognosis is positive, with CAS improving markedly around age eight to 12 years. At this time, the dysarthric element of speech is more apparent with a slow rate and monotone presentation.
• First words occur on average between ages 2.5 and 3.5 years.
• Augmentative (e.g., sign language) or alternative (e.g., communication devices) communication may alleviate frustration for the child and promote communication development.
• Overall, however, speech prognosis is positive, with CAS improving markedly around age eight to 12 years. At this time, the dysarthric element of speech is more apparent with a slow rate and monotone presentation.
• First words occur on average between ages 2.5 and 3.5 years.
• Augmentative (e.g., sign language) or alternative (e.g., communication devices) communication may alleviate frustration for the child and promote communication development.
• Overall, however, speech prognosis is positive, with CAS improving markedly around age eight to 12 years. At this time, the dysarthric element of speech is more apparent with a slow rate and monotone presentation.
• The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features.
• Multifocal epileptiform discharges are the typical EEG pattern.
• Ventriculomegaly
• Aplasia/hypoplasia of the corpus callosum
• Hydrocephalus
• Arnold-Chiari malformation
• Intraventricular hemorrhage
• Ventriculomegaly
• Aplasia/hypoplasia of the corpus callosum
• Hydrocephalus
• Arnold-Chiari malformation
• Intraventricular hemorrhage
• Infrequent findings (present in fewer than 10% of reported individuals) may include the following:
• Sacral dimple
• Dural ectasia
• Spina bifida
• Pineal cyst
• Cervical spinal canal stenosis
• Sacral dimple
• Dural ectasia
• Spina bifida
• Pineal cyst
• Cervical spinal canal stenosis
• Ventriculomegaly
• Aplasia/hypoplasia of the corpus callosum
• Hydrocephalus
• Arnold-Chiari malformation
• Intraventricular hemorrhage
• Sacral dimple
• Dural ectasia
• Spina bifida
• Pineal cyst
• Cervical spinal canal stenosis
• Long, slender fingers
• Persistence of the fetal fingertip pads
• Hypoplasia of the hand muscles
• Pes planus
• Pes cavus
• Calcaneovalgus deformity
• Congenital hip dislocation
• Scoliosis/kyphosis
• Pectus anomalies, including pectus excavatum or pectus carinatum
• Slender build
• Spondylolisthesis (infrequently)
• Craniosynostosis (infrequently), most commonly sagittal, but metopic has also been observed
• Multiple nevi
• Other pigmentary skin abnormalities, such as vitiligo and café au lait macules
• Hemangioma
• Eczema
• Ichthyosis/hyperkeratosis
• Hair abnormalities, such as fair hair and/or alopecia
• Multiple nevi
• Other pigmentary skin abnormalities, such as vitiligo and café au lait macules
• Hemangioma
• Eczema
• Ichthyosis/hyperkeratosis
• Hair abnormalities, such as fair hair and/or alopecia
• Multiple nevi
• Other pigmentary skin abnormalities, such as vitiligo and café au lait macules
• Hemangioma
• Eczema
• Ichthyosis/hyperkeratosis
• Hair abnormalities, such as fair hair and/or alopecia
## Genotype-Phenotype Correlations
Genotype-phenotype correlations in KdVS have not been demonstrated. Notably, the clinical features of affected individuals with atypical deletions and those with pathogenic variants in
## Penetrance
Penetrance is 100%. Clinical features of KdVS are apparent in all individuals with a deletion of or a pathogenic variant in
## Nomenclature
The disorder was first recognized following chromosomal microarray analysis among large cohorts of unselected individuals with intellectual disability [
## Prevalence
The prevalence of KdVS is unknown. The authors estimate the prevalence of the 17q21.31 deletion to be 1:55,000 individuals [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The most common findings in Koolen-de Vries syndrome (KdVS) – developmental delay and childhood hypotonia – are common and relatively nonspecific indications for molecular cytogenetic analysis. However, the concurrent finding of characteristic facial dysmorphic features, epilepsy, hypermetropia, congenital heart defects, renal or urologic anomalies, cryptorchidism, and/or distinctive friendly/amiable behavior may prompt specific consideration of the diagnosis of KdVS. See
Selected Disorders with Developmental Delay, Childhood Hypotonia, and Concurrent Findings Similar to Koolen-de Vries Syndrome
AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CHD = congenital heart defect; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PWCR = Prader-Willi critical region; UPD = uniparental disomy; XL = X-linked
PWS is caused by an absence of expression of imprinted genes in the paternally derived PWS/Angelman syndrome (AS) region (i.e., 15q11.2-q13) of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and rarely an imprinting defect). The risk to the sibs of a proband with PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.
The risk to sibs of a proband with Angelman syndrome depends on the genetic mechanism leading to the loss of
## Management
To establish the clinical consequences in an individual diagnosed with Koolen-de Vries syndrome (KdVS), the evaluations in
Recommended Evaluations Following Initial Diagnosis of Koolen-de Vries Syndrome
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Joint hypermobility, pes planus, calcenovalgus deformity, scoliosis/kyphosis, pectus anomalies
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Physical exam for hypospadias & cryptorchidism in males
Renal ultrasound exam
Voiding cystourethrogram, if indicated
Community or
Social work involvement for parental support;
Home nursing referral;
Information & resources for sibs of persons w/KdVS.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for Koolen-de Vries syndrome.
Treatment of Manifestations in Individuals with Koolen-de Vries Syndrome
Many ASMs may be effective
Education of parents/caregivers
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy
One affected infant with seizures had a partial response to levetiracetam, but complete control was achieved when topiramate was added to the anti-seizure regimen [
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Children with KdVS require early, intensive speech motor and language therapy, with targeted literacy and social language interventions as developmentally appropriate.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.
In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment as needed (e.g., walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Recommended Surveillance for Individuals with Koolen-de Vries Syndrome
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
See
Search
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Joint hypermobility, pes planus, calcenovalgus deformity, scoliosis/kyphosis, pectus anomalies
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Physical exam for hypospadias & cryptorchidism in males
• Renal ultrasound exam
• Voiding cystourethrogram, if indicated
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Information & resources for sibs of persons w/KdVS.
• Many ASMs may be effective
• Education of parents/caregivers
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., walkers, bath chairs, orthotics, adaptive strollers).
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone.
## Evaluations Following Initial Diagnosis
To establish the clinical consequences in an individual diagnosed with Koolen-de Vries syndrome (KdVS), the evaluations in
Recommended Evaluations Following Initial Diagnosis of Koolen-de Vries Syndrome
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Joint hypermobility, pes planus, calcenovalgus deformity, scoliosis/kyphosis, pectus anomalies
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Physical exam for hypospadias & cryptorchidism in males
Renal ultrasound exam
Voiding cystourethrogram, if indicated
Community or
Social work involvement for parental support;
Home nursing referral;
Information & resources for sibs of persons w/KdVS.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Joint hypermobility, pes planus, calcenovalgus deformity, scoliosis/kyphosis, pectus anomalies
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Physical exam for hypospadias & cryptorchidism in males
• Renal ultrasound exam
• Voiding cystourethrogram, if indicated
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Information & resources for sibs of persons w/KdVS.
## Treatment of Manifestations
There is no cure for Koolen-de Vries syndrome.
Treatment of Manifestations in Individuals with Koolen-de Vries Syndrome
Many ASMs may be effective
Education of parents/caregivers
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy
One affected infant with seizures had a partial response to levetiracetam, but complete control was achieved when topiramate was added to the anti-seizure regimen [
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Children with KdVS require early, intensive speech motor and language therapy, with targeted literacy and social language interventions as developmentally appropriate.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.
In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment as needed (e.g., walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.
• Many ASMs may be effective
• Education of parents/caregivers
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
Children with KdVS require early, intensive speech motor and language therapy, with targeted literacy and social language interventions as developmentally appropriate.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.
In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment as needed (e.g., walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Recommended Surveillance for Individuals with Koolen-de Vries Syndrome
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Koolen-de Vries syndrome (KdVS), caused by a heterozygous deletion at chromosome 17q21.31 or a heterozygous intragenic
To date, all reported intragenic
Evaluation of the parents by testing that will detect the 17q21.31 deletion or intragenic
All unaffected parents tested to date from whom a deleted chromosome 17 originated have shown a 900-kb inversion involving chromosome 17q21.31. This inversion (also referred to as the H2 lineage) is enriched in Europeans, and carriers are predisposed to the 17q21.31 deletion (see
Note: Testing for the 17q21.31 inversion polymorphism in parents is not recommended for recurrence risk assessment because it does not provide additional information that is of clinical use. The inversion is common in northern European populations, and although it seems to be a necessary factor for the deletion to occur, many other factors are important given the fact that the 17q21.31 deletion is relatively rare.
If the 17q21.31 deletion or intragenic
The proband has a
The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Somatic and (presumed) germline mosaicism for a 17q21.31 deletion has been identified in at least two parents [
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ cells only.
Theoretically, a parent could have a balanced chromosome rearrangement involving 17q21.31 resulting in a 17q21.31 deletion in an affected child; balanced chromosome rearrangements in parents involving 17q21.31 have not been reported to date.
If the parents are clinically unaffected and the 17q21.31 deletion or intragenic
Parental germline mosaicism [
A balanced chromosome rearrangement involving 17q21.31 (not reported, but theoretically possible).
Individuals who have the 17q21.31 deletion or an intragenic
To date, one individual diagnosed with KdVS has been known to reproduce [Author, personal observation].
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of a child with KdVS.
Once the KdVS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• To date, all reported intragenic
• Evaluation of the parents by testing that will detect the 17q21.31 deletion or intragenic
• All unaffected parents tested to date from whom a deleted chromosome 17 originated have shown a 900-kb inversion involving chromosome 17q21.31. This inversion (also referred to as the H2 lineage) is enriched in Europeans, and carriers are predisposed to the 17q21.31 deletion (see
• Note: Testing for the 17q21.31 inversion polymorphism in parents is not recommended for recurrence risk assessment because it does not provide additional information that is of clinical use. The inversion is common in northern European populations, and although it seems to be a necessary factor for the deletion to occur, many other factors are important given the fact that the 17q21.31 deletion is relatively rare.
• If the 17q21.31 deletion or intragenic
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Somatic and (presumed) germline mosaicism for a 17q21.31 deletion has been identified in at least two parents [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ cells only.
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Somatic and (presumed) germline mosaicism for a 17q21.31 deletion has been identified in at least two parents [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ cells only.
• Theoretically, a parent could have a balanced chromosome rearrangement involving 17q21.31 resulting in a 17q21.31 deletion in an affected child; balanced chromosome rearrangements in parents involving 17q21.31 have not been reported to date.
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Somatic and (presumed) germline mosaicism for a 17q21.31 deletion has been identified in at least two parents [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ cells only.
• If the parents are clinically unaffected and the 17q21.31 deletion or intragenic
• Parental germline mosaicism [
• A balanced chromosome rearrangement involving 17q21.31 (not reported, but theoretically possible).
• Parental germline mosaicism [
• A balanced chromosome rearrangement involving 17q21.31 (not reported, but theoretically possible).
• Parental germline mosaicism [
• A balanced chromosome rearrangement involving 17q21.31 (not reported, but theoretically possible).
• Individuals who have the 17q21.31 deletion or an intragenic
• To date, one individual diagnosed with KdVS has been known to reproduce [Author, personal observation].
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of a child with KdVS.
## Mode of Inheritance
Koolen-de Vries syndrome (KdVS), caused by a heterozygous deletion at chromosome 17q21.31 or a heterozygous intragenic
## Risk to Family Members
To date, all reported intragenic
Evaluation of the parents by testing that will detect the 17q21.31 deletion or intragenic
All unaffected parents tested to date from whom a deleted chromosome 17 originated have shown a 900-kb inversion involving chromosome 17q21.31. This inversion (also referred to as the H2 lineage) is enriched in Europeans, and carriers are predisposed to the 17q21.31 deletion (see
Note: Testing for the 17q21.31 inversion polymorphism in parents is not recommended for recurrence risk assessment because it does not provide additional information that is of clinical use. The inversion is common in northern European populations, and although it seems to be a necessary factor for the deletion to occur, many other factors are important given the fact that the 17q21.31 deletion is relatively rare.
If the 17q21.31 deletion or intragenic
The proband has a
The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Somatic and (presumed) germline mosaicism for a 17q21.31 deletion has been identified in at least two parents [
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ cells only.
Theoretically, a parent could have a balanced chromosome rearrangement involving 17q21.31 resulting in a 17q21.31 deletion in an affected child; balanced chromosome rearrangements in parents involving 17q21.31 have not been reported to date.
If the parents are clinically unaffected and the 17q21.31 deletion or intragenic
Parental germline mosaicism [
A balanced chromosome rearrangement involving 17q21.31 (not reported, but theoretically possible).
Individuals who have the 17q21.31 deletion or an intragenic
To date, one individual diagnosed with KdVS has been known to reproduce [Author, personal observation].
• To date, all reported intragenic
• Evaluation of the parents by testing that will detect the 17q21.31 deletion or intragenic
• All unaffected parents tested to date from whom a deleted chromosome 17 originated have shown a 900-kb inversion involving chromosome 17q21.31. This inversion (also referred to as the H2 lineage) is enriched in Europeans, and carriers are predisposed to the 17q21.31 deletion (see
• Note: Testing for the 17q21.31 inversion polymorphism in parents is not recommended for recurrence risk assessment because it does not provide additional information that is of clinical use. The inversion is common in northern European populations, and although it seems to be a necessary factor for the deletion to occur, many other factors are important given the fact that the 17q21.31 deletion is relatively rare.
• If the 17q21.31 deletion or intragenic
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Somatic and (presumed) germline mosaicism for a 17q21.31 deletion has been identified in at least two parents [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ cells only.
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Somatic and (presumed) germline mosaicism for a 17q21.31 deletion has been identified in at least two parents [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ cells only.
• Theoretically, a parent could have a balanced chromosome rearrangement involving 17q21.31 resulting in a 17q21.31 deletion in an affected child; balanced chromosome rearrangements in parents involving 17q21.31 have not been reported to date.
• The proband has a
• The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Somatic and (presumed) germline mosaicism for a 17q21.31 deletion has been identified in at least two parents [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ cells only.
• If the parents are clinically unaffected and the 17q21.31 deletion or intragenic
• Parental germline mosaicism [
• A balanced chromosome rearrangement involving 17q21.31 (not reported, but theoretically possible).
• Parental germline mosaicism [
• A balanced chromosome rearrangement involving 17q21.31 (not reported, but theoretically possible).
• Parental germline mosaicism [
• A balanced chromosome rearrangement involving 17q21.31 (not reported, but theoretically possible).
• Individuals who have the 17q21.31 deletion or an intragenic
• To date, one individual diagnosed with KdVS has been known to reproduce [Author, personal observation].
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of a child with KdVS.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of a child with KdVS.
## Prenatal Testing and Preimplantation Genetic Testing
Once the KdVS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
France
•
•
•
•
•
•
•
•
•
•
• United Kingdom
•
•
•
• France
•
•
•
## Molecular Genetics
Koolen-de Vries Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Koolen-de Vries Syndrome (
H4K16ac activates the expression of a broad set of genes including several autophagy-related genes [
Studies in mice have shown that heterozygous loss of
The 17q21.31 inversion polymorphism (H2 haplotype) and the copy number polymorphism clusters encompassing exons 1-3 of
## Molecular Pathogenesis
H4K16ac activates the expression of a broad set of genes including several autophagy-related genes [
Studies in mice have shown that heterozygous loss of
The 17q21.31 inversion polymorphism (H2 haplotype) and the copy number polymorphism clusters encompassing exons 1-3 of
## Chapter Notes
Radboudumc Center of Expertise:
The authors gratefully acknowledge the
2 February 2023 (ma) Comprehensive update posted live
13 June 2019 (ma) Comprehensive update posted live
20 November 2012 (me) Comprehensive update posted live
26 January 2010 (me) Review posted live
28 August 2009 (dak) Original submission
• 2 February 2023 (ma) Comprehensive update posted live
• 13 June 2019 (ma) Comprehensive update posted live
• 20 November 2012 (me) Comprehensive update posted live
• 26 January 2010 (me) Review posted live
• 28 August 2009 (dak) Original submission
## Author Notes
Radboudumc Center of Expertise:
## Acknowledgments
The authors gratefully acknowledge the
## Revision History
2 February 2023 (ma) Comprehensive update posted live
13 June 2019 (ma) Comprehensive update posted live
20 November 2012 (me) Comprehensive update posted live
26 January 2010 (me) Review posted live
28 August 2009 (dak) Original submission
• 2 February 2023 (ma) Comprehensive update posted live
• 13 June 2019 (ma) Comprehensive update posted live
• 20 November 2012 (me) Comprehensive update posted live
• 26 January 2010 (me) Review posted live
• 28 August 2009 (dak) Original submission
## References
## Literature Cited
Photographs of eight individuals with a 17q21.31 deletion
|
[] |
26/1/2010
|
2/2/2023
|
10/1/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mdel1q21_1
|
mdel1q21_1
|
[
"Gap junction alpha-5 protein",
"Gap junction alpha-8 protein",
"Not applicable",
"GJA5",
"GJA8",
"Not applicable",
"1q21.1 Recurrent Microdeletion"
] |
1q21.1 Recurrent Deletion
|
Rose Guo, Chad R Haldeman-Englert
|
Summary The 1q21.1 recurrent deletion itself does not lead to a clinically recognizable syndrome, as some persons with the deletion have no obvious clinical findings. Others have variable findings that most commonly include mildly dysmorphic but nonspecific facial features (>75%), mild intellectual disability or learning disabilities (25%), microcephaly (43%), and eye abnormalities (26%). Other findings can include cardiac defects, genitourinary anomalies, skeletal malformations, joint laxity, and seizures (~23%). Psychiatric and behavioral abnormalities can include autism spectrum disorder, attention-deficit/hyperactivity disorder, and sleep disturbances. Sensorineural hearing loss and recurrent infections /otitis media are rare. The diagnosis of the 1q21.1 recurrent deletion is established by the detection of the recurrent distal heterozygous deletion between BP3 and BP4 at the approximate position of chr1:147105904-147917509 in the reference genome (NCBI Build 38). The 1q21.1 recurrent deletion is inherited in an autosomal dominant manner. Between 18% and 35% of deletions occur
|
## Diagnosis
The breakpoints of the distal 1q21.1 recurrent deletion described in this
The 1q21.1 recurrent deletion
Hypotonia
Developmental delays
Intellectual disability (ID), typically in the mild-to-moderate range, although not all individuals with this deletion have ID
Microcephaly
Poor growth
Neurobehavioral/psychiatric manifestations, such as behavioral outbursts, attention-deficit/hyperactivity disorder, aggression, sleep disturbances, or autism spectrum disorder
Seizures
Ophthalmologic involvement, such as strabismus or nystagmus
Hearing impairment
Joint laxity
Mild but nonspecific dysmorphic facial features (See
The diagnosis of the 1q21.1 recurrent deletion is established by detection of the recurrent distal 0.8-Mb heterozygous deletion at the approximate position of chr1:147105904-147917509 in the reference genome (NCBI Build 38).
Note: (1) The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 1q21.1 recurrent deletion (see
Although several genes of interest (
Note: (1) The 1q21.1 recurrent deletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques. (2) Most individuals with the 1q21.1 recurrent deletion are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (3) Prior to 2008 many CMA platforms did not include coverage of the 1q21.1 region and thus may not have detected this deletion.
Molecular Genetic Testing Used to Detect the 1q21.1 Recurrent Deletion
See
Genomic coordinates represent the minimum deletion size associated with the 1q21.1 recurrent deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the deletion as calculated from these genomic positions may differ from the expected deletion size due to the presence of segmental duplications near breakpoints. Previous reports have used various size ranges for this recurrent deletion, with the most common sizes used being 1.2 Mb and 1.35 Mb. However, these estimates likely include some of the flanking segmental duplication regions and are not specific to the unique DNA sequence [
See
Chromosome microarray analysis (CMA) using oligonucleotide arrays or SNP genotyping arrays. CMA designs in current clinical use target the 1q21.1 region. Note: The 1q21.1 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms.
Targeted deletion analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Targeted deletion analysis is not appropriate for an individual in whom the 1q21.1 recurrent deletion was not detected by CMA designed to target this region.
• Hypotonia
• Developmental delays
• Intellectual disability (ID), typically in the mild-to-moderate range, although not all individuals with this deletion have ID
• Microcephaly
• Poor growth
• Neurobehavioral/psychiatric manifestations, such as behavioral outbursts, attention-deficit/hyperactivity disorder, aggression, sleep disturbances, or autism spectrum disorder
• Seizures
• Ophthalmologic involvement, such as strabismus or nystagmus
• Hearing impairment
• Joint laxity
• Mild but nonspecific dysmorphic facial features (See
## Suggestive Findings
The 1q21.1 recurrent deletion
Hypotonia
Developmental delays
Intellectual disability (ID), typically in the mild-to-moderate range, although not all individuals with this deletion have ID
Microcephaly
Poor growth
Neurobehavioral/psychiatric manifestations, such as behavioral outbursts, attention-deficit/hyperactivity disorder, aggression, sleep disturbances, or autism spectrum disorder
Seizures
Ophthalmologic involvement, such as strabismus or nystagmus
Hearing impairment
Joint laxity
Mild but nonspecific dysmorphic facial features (See
• Hypotonia
• Developmental delays
• Intellectual disability (ID), typically in the mild-to-moderate range, although not all individuals with this deletion have ID
• Microcephaly
• Poor growth
• Neurobehavioral/psychiatric manifestations, such as behavioral outbursts, attention-deficit/hyperactivity disorder, aggression, sleep disturbances, or autism spectrum disorder
• Seizures
• Ophthalmologic involvement, such as strabismus or nystagmus
• Hearing impairment
• Joint laxity
• Mild but nonspecific dysmorphic facial features (See
## Establishing the Diagnosis
The diagnosis of the 1q21.1 recurrent deletion is established by detection of the recurrent distal 0.8-Mb heterozygous deletion at the approximate position of chr1:147105904-147917509 in the reference genome (NCBI Build 38).
Note: (1) The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 1q21.1 recurrent deletion (see
Although several genes of interest (
Note: (1) The 1q21.1 recurrent deletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques. (2) Most individuals with the 1q21.1 recurrent deletion are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (3) Prior to 2008 many CMA platforms did not include coverage of the 1q21.1 region and thus may not have detected this deletion.
Molecular Genetic Testing Used to Detect the 1q21.1 Recurrent Deletion
See
Genomic coordinates represent the minimum deletion size associated with the 1q21.1 recurrent deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the deletion as calculated from these genomic positions may differ from the expected deletion size due to the presence of segmental duplications near breakpoints. Previous reports have used various size ranges for this recurrent deletion, with the most common sizes used being 1.2 Mb and 1.35 Mb. However, these estimates likely include some of the flanking segmental duplication regions and are not specific to the unique DNA sequence [
See
Chromosome microarray analysis (CMA) using oligonucleotide arrays or SNP genotyping arrays. CMA designs in current clinical use target the 1q21.1 region. Note: The 1q21.1 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms.
Targeted deletion analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Targeted deletion analysis is not appropriate for an individual in whom the 1q21.1 recurrent deletion was not detected by CMA designed to target this region.
## Clinical Characteristics
Individuals with the 1q21.1 recurrent deletion (BP3-BP4) have a wide range of clinical manifestations, ranging from unaffected to severely affected. The most common findings include developmental delay and mild but nonspecific dysmorphic facies. There is not a clinically recognizable syndrome, as a subset of persons with the deletion do not have obvious clinical findings.
Clinical information from reports involving 102 probands with the 1q21.1 recurrent deletion is summarized in
Select Features Present in Individuals with the 1q21.1 Recurrent Deletion
Mild-to-moderate developmental delay (includes speech & motor delays)
Gastrointestinal abnormalities
Eye abnormalities
Intellectual disability
Microcephaly
Short stature
Musculoskeletal abnormalities
Attention-deficit/hyperactivity disorder
Cardiac abnormalities
Genitourinary abnormalities
Poor growth
Hypotonia
Seizures
Autism spectrum disorder / autistic features
Brain malformations
Sensorineural deafness
Frequent/recurrent infections
Clinical data shown is summarized from 102 probands with the 1q21.1 recurrent deletion [
Most delays are mild and may involve specific areas, particularly gross motor delay, or be global, involving all areas of development.
Some may also have generalized learning disabilities throughout life.
Mild intellectual disability and learning disabilities are seen in approximately 25% of affected individuals.
Patent ductus arteriosus
Truncus arteriosus
Ventricular and atrial septal defects
Tetralogy of Fallot
Bicuspid aortic valve
Dilatation of ascending aorta, with no further information on whether this is progressive or static
Aortic insufficiency
Coarctation of the aorta
Interrupted aortic arch
Supravalvular aortic stenosis
Anomalous origin of the right coronary artery
Pulmonary valve stenosis
Transposition of the great vessels
Rhythm abnormalities (sinus bradycardia, prolonged QT interval). Of note, one individual with long QT syndrome was also found to have a pathogenic
Females are more likely to have a cardiac anomaly.
Craniosynostosis (one report of metopic synostosis specifically)
Scoliosis, ranging from mild to severe (requiring spinal hardware)
Joint laxity
Brachydactyly with or without short distal phalanges
Broad thumbs
Clinodactyly of the fifth finger
Clubfoot
Small feet
Pes planus
Broad or duplicated/bifid great toes
Overlapping or syndactyly of the toes
Polydactyly of the hands or feet
No genotype-phenotype correlations are observed in those with the 1q21.1 recurrent deletion.
Little information is available regarding penetrance of the 1q21.1 recurrent deletion. Similar to several other recurrent deletions (e.g., 16p11.2, 15q13.3), the 1q21.1 recurrent deletion can be inherited from a parent with minimally abnormal or completely normal clinical findings. In addition, several relatives of probands (e.g., sibs, cousins) with the same 1q21.1 deletion have a normal phenotype or only mild manifestations [
The frequency of the 1q21.1 recurrent deletion is approximately 0.2% (46/22,563) of individuals with developmental delays, intellectual disabilities, and/or congenital anomalies evaluated by chromosomal microarray [
• Mild-to-moderate developmental delay (includes speech & motor delays)
• Gastrointestinal abnormalities
• Eye abnormalities
• Intellectual disability
• Microcephaly
• Short stature
• Musculoskeletal abnormalities
• Attention-deficit/hyperactivity disorder
• Cardiac abnormalities
• Genitourinary abnormalities
• Poor growth
• Hypotonia
• Seizures
• Autism spectrum disorder / autistic features
• Brain malformations
• Sensorineural deafness
• Frequent/recurrent infections
• Most delays are mild and may involve specific areas, particularly gross motor delay, or be global, involving all areas of development.
• Some may also have generalized learning disabilities throughout life.
• Mild intellectual disability and learning disabilities are seen in approximately 25% of affected individuals.
• Patent ductus arteriosus
• Truncus arteriosus
• Ventricular and atrial septal defects
• Tetralogy of Fallot
• Bicuspid aortic valve
• Dilatation of ascending aorta, with no further information on whether this is progressive or static
• Aortic insufficiency
• Coarctation of the aorta
• Interrupted aortic arch
• Supravalvular aortic stenosis
• Anomalous origin of the right coronary artery
• Pulmonary valve stenosis
• Transposition of the great vessels
• Rhythm abnormalities (sinus bradycardia, prolonged QT interval). Of note, one individual with long QT syndrome was also found to have a pathogenic
• Craniosynostosis (one report of metopic synostosis specifically)
• Scoliosis, ranging from mild to severe (requiring spinal hardware)
• Joint laxity
• Brachydactyly with or without short distal phalanges
• Broad thumbs
• Clinodactyly of the fifth finger
• Clubfoot
• Small feet
• Pes planus
• Broad or duplicated/bifid great toes
• Overlapping or syndactyly of the toes
• Polydactyly of the hands or feet
## Clinical Description
Individuals with the 1q21.1 recurrent deletion (BP3-BP4) have a wide range of clinical manifestations, ranging from unaffected to severely affected. The most common findings include developmental delay and mild but nonspecific dysmorphic facies. There is not a clinically recognizable syndrome, as a subset of persons with the deletion do not have obvious clinical findings.
Clinical information from reports involving 102 probands with the 1q21.1 recurrent deletion is summarized in
Select Features Present in Individuals with the 1q21.1 Recurrent Deletion
Mild-to-moderate developmental delay (includes speech & motor delays)
Gastrointestinal abnormalities
Eye abnormalities
Intellectual disability
Microcephaly
Short stature
Musculoskeletal abnormalities
Attention-deficit/hyperactivity disorder
Cardiac abnormalities
Genitourinary abnormalities
Poor growth
Hypotonia
Seizures
Autism spectrum disorder / autistic features
Brain malformations
Sensorineural deafness
Frequent/recurrent infections
Clinical data shown is summarized from 102 probands with the 1q21.1 recurrent deletion [
Most delays are mild and may involve specific areas, particularly gross motor delay, or be global, involving all areas of development.
Some may also have generalized learning disabilities throughout life.
Mild intellectual disability and learning disabilities are seen in approximately 25% of affected individuals.
Patent ductus arteriosus
Truncus arteriosus
Ventricular and atrial septal defects
Tetralogy of Fallot
Bicuspid aortic valve
Dilatation of ascending aorta, with no further information on whether this is progressive or static
Aortic insufficiency
Coarctation of the aorta
Interrupted aortic arch
Supravalvular aortic stenosis
Anomalous origin of the right coronary artery
Pulmonary valve stenosis
Transposition of the great vessels
Rhythm abnormalities (sinus bradycardia, prolonged QT interval). Of note, one individual with long QT syndrome was also found to have a pathogenic
Females are more likely to have a cardiac anomaly.
Craniosynostosis (one report of metopic synostosis specifically)
Scoliosis, ranging from mild to severe (requiring spinal hardware)
Joint laxity
Brachydactyly with or without short distal phalanges
Broad thumbs
Clinodactyly of the fifth finger
Clubfoot
Small feet
Pes planus
Broad or duplicated/bifid great toes
Overlapping or syndactyly of the toes
Polydactyly of the hands or feet
• Mild-to-moderate developmental delay (includes speech & motor delays)
• Gastrointestinal abnormalities
• Eye abnormalities
• Intellectual disability
• Microcephaly
• Short stature
• Musculoskeletal abnormalities
• Attention-deficit/hyperactivity disorder
• Cardiac abnormalities
• Genitourinary abnormalities
• Poor growth
• Hypotonia
• Seizures
• Autism spectrum disorder / autistic features
• Brain malformations
• Sensorineural deafness
• Frequent/recurrent infections
• Most delays are mild and may involve specific areas, particularly gross motor delay, or be global, involving all areas of development.
• Some may also have generalized learning disabilities throughout life.
• Mild intellectual disability and learning disabilities are seen in approximately 25% of affected individuals.
• Patent ductus arteriosus
• Truncus arteriosus
• Ventricular and atrial septal defects
• Tetralogy of Fallot
• Bicuspid aortic valve
• Dilatation of ascending aorta, with no further information on whether this is progressive or static
• Aortic insufficiency
• Coarctation of the aorta
• Interrupted aortic arch
• Supravalvular aortic stenosis
• Anomalous origin of the right coronary artery
• Pulmonary valve stenosis
• Transposition of the great vessels
• Rhythm abnormalities (sinus bradycardia, prolonged QT interval). Of note, one individual with long QT syndrome was also found to have a pathogenic
• Craniosynostosis (one report of metopic synostosis specifically)
• Scoliosis, ranging from mild to severe (requiring spinal hardware)
• Joint laxity
• Brachydactyly with or without short distal phalanges
• Broad thumbs
• Clinodactyly of the fifth finger
• Clubfoot
• Small feet
• Pes planus
• Broad or duplicated/bifid great toes
• Overlapping or syndactyly of the toes
• Polydactyly of the hands or feet
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are observed in those with the 1q21.1 recurrent deletion.
## Penetrance
Little information is available regarding penetrance of the 1q21.1 recurrent deletion. Similar to several other recurrent deletions (e.g., 16p11.2, 15q13.3), the 1q21.1 recurrent deletion can be inherited from a parent with minimally abnormal or completely normal clinical findings. In addition, several relatives of probands (e.g., sibs, cousins) with the same 1q21.1 deletion have a normal phenotype or only mild manifestations [
## Prevalence
The frequency of the 1q21.1 recurrent deletion is approximately 0.2% (46/22,563) of individuals with developmental delays, intellectual disabilities, and/or congenital anomalies evaluated by chromosomal microarray [
## Genetically Related (Allelic) Disorders
Features seen in individuals with this duplication may include hypotonia, macrocephaly, prominent forehead, widely spaced eyes, tremor, learning or developmental delay, intellectual disability, attention-deficit/hyperactivity disorder (ADHD), and autistic features or autism spectrum disorder.
The duplications can be inherited from a parent or occur
## Differential Diagnosis
The differential diagnosis of the 1q21.1 recurrent deletion is broad due to the nonspecific, variable spectrum and the presence of relatively common abnormal phenotypes that occur in affected individuals, including developmental delay, learning problems, and neuropsychiatric disorders. All manifestations of the 1q21.1 recurrent deletion can also be seen in individuals with other genomic disorders.
## Management
No clinical practice guidelines for the 1q21.1 recurrent deletion have been published.
To establish the extent of disease and needs in an individual diagnosed with the 1q21.1 recurrent deletion, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of the 1q21.1 Recurrent Deletion
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI for those w/microcephaly, macrocephaly, or seizures.
Consider EEG if seizures are a concern.
Consider referral to neurologist for those w/hypotonia, seizures, tics, or tremors.
Gross motor & fine motor skills
Clubfoot & scoliosis
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for the 1q21.1 recurrent deletion. Supportive care to improve quality of life, maximize function, and reduce complications is recommended (see
Treatment of Manifestations in Individuals with the 1q21.1 Recurrent Deletion
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance in Individuals with the 1q21 Recurrent Deletion
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, tremors, & tics.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Using genomic testing that will detect the 1q21.1 recurrent deletion found in the proband, it is appropriate to evaluate the sibs of a proband in order to identify as early as possible those who would benefit from close assessment/monitoring of developmental milestones in childhood.
Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 1q21.1 recurrent deletion was not detected by chromosomal microarray designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider brain MRI for those w/microcephaly, macrocephaly, or seizures.
• Consider EEG if seizures are a concern.
• Consider referral to neurologist for those w/hypotonia, seizures, tics, or tremors.
• Gross motor & fine motor skills
• Clubfoot & scoliosis
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, tremors, & tics.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with the 1q21.1 recurrent deletion, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of the 1q21.1 Recurrent Deletion
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI for those w/microcephaly, macrocephaly, or seizures.
Consider EEG if seizures are a concern.
Consider referral to neurologist for those w/hypotonia, seizures, tics, or tremors.
Gross motor & fine motor skills
Clubfoot & scoliosis
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider brain MRI for those w/microcephaly, macrocephaly, or seizures.
• Consider EEG if seizures are a concern.
• Consider referral to neurologist for those w/hypotonia, seizures, tics, or tremors.
• Gross motor & fine motor skills
• Clubfoot & scoliosis
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support
## Treatment of Manifestations
There is no cure for the 1q21.1 recurrent deletion. Supportive care to improve quality of life, maximize function, and reduce complications is recommended (see
Treatment of Manifestations in Individuals with the 1q21.1 Recurrent Deletion
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
## Neurobehavioral/Psychiatric Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance in Individuals with the 1q21 Recurrent Deletion
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, tremors, & tics.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, tremors, & tics.
## Evaluation of Relatives at Risk
Using genomic testing that will detect the 1q21.1 recurrent deletion found in the proband, it is appropriate to evaluate the sibs of a proband in order to identify as early as possible those who would benefit from close assessment/monitoring of developmental milestones in childhood.
Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 1q21.1 recurrent deletion was not detected by chromosomal microarray designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.
See
## Therapies Under Investigation
Search
## Genetic Counseling
The 1q21.1 recurrent deletion is inherited in an autosomal dominant manner.
The recurrent deletion can be inherited from either parent, and it does not appear that the phenotypic severity varies with the parent of origin.
Many individuals with the 1q21.1 recurrent deletion inherited the deletion from a parent. A parent with the recurrent deletion may show an abnormal phenotype similar to their child but in general is less severely affected. In approximately 25% of instances in which the recurrent deletion is inherited, the parent has a normal phenotype.
In another study [
Genomic testing that will detect the 1q21.1 recurrent deletion present in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the 1q21.1 recurrent deletion identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered:
The proband has a
The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
The family history of some individuals diagnosed with the 1q21.1 recurrent deletion may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the 1q21.1 recurrent deletion.
If one of the parents has the 1q21.1 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. Because studies suggest that the 1q21.1 recurrent deletion is associated with variable expressivity and reduced
If the 1q21.1 recurrent deletion identified in the proband cannot be detected in either of the parents, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having a child with the 1q21.1 recurrent deletion.
Note: Regardless of whether a pregnancy is known or not known to be at increased risk for the 1q21.1 recurrent deletion, the prenatal finding of a 1q21.1 recurrent deletion cannot be used to predict the phenotype (see
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Many individuals with the 1q21.1 recurrent deletion inherited the deletion from a parent. A parent with the recurrent deletion may show an abnormal phenotype similar to their child but in general is less severely affected. In approximately 25% of instances in which the recurrent deletion is inherited, the parent has a normal phenotype.
• In another study [
• In another study [
• Genomic testing that will detect the 1q21.1 recurrent deletion present in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the 1q21.1 recurrent deletion identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• The family history of some individuals diagnosed with the 1q21.1 recurrent deletion may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the 1q21.1 recurrent deletion.
• In another study [
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• If one of the parents has the 1q21.1 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. Because studies suggest that the 1q21.1 recurrent deletion is associated with variable expressivity and reduced
• If the 1q21.1 recurrent deletion identified in the proband cannot be detected in either of the parents, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having a child with the 1q21.1 recurrent deletion.
## Mode of Inheritance
The 1q21.1 recurrent deletion is inherited in an autosomal dominant manner.
The recurrent deletion can be inherited from either parent, and it does not appear that the phenotypic severity varies with the parent of origin.
## Risk to Family Members
Many individuals with the 1q21.1 recurrent deletion inherited the deletion from a parent. A parent with the recurrent deletion may show an abnormal phenotype similar to their child but in general is less severely affected. In approximately 25% of instances in which the recurrent deletion is inherited, the parent has a normal phenotype.
In another study [
Genomic testing that will detect the 1q21.1 recurrent deletion present in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the 1q21.1 recurrent deletion identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered:
The proband has a
The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
The family history of some individuals diagnosed with the 1q21.1 recurrent deletion may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the 1q21.1 recurrent deletion.
If one of the parents has the 1q21.1 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. Because studies suggest that the 1q21.1 recurrent deletion is associated with variable expressivity and reduced
If the 1q21.1 recurrent deletion identified in the proband cannot be detected in either of the parents, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
• Many individuals with the 1q21.1 recurrent deletion inherited the deletion from a parent. A parent with the recurrent deletion may show an abnormal phenotype similar to their child but in general is less severely affected. In approximately 25% of instances in which the recurrent deletion is inherited, the parent has a normal phenotype.
• In another study [
• In another study [
• Genomic testing that will detect the 1q21.1 recurrent deletion present in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the 1q21.1 recurrent deletion identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• The family history of some individuals diagnosed with the 1q21.1 recurrent deletion may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the 1q21.1 recurrent deletion.
• In another study [
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• If one of the parents has the 1q21.1 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. Because studies suggest that the 1q21.1 recurrent deletion is associated with variable expressivity and reduced
• If the 1q21.1 recurrent deletion identified in the proband cannot be detected in either of the parents, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having a child with the 1q21.1 recurrent deletion.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having a child with the 1q21.1 recurrent deletion.
## Prenatal Testing and Preimplantation Genetic Testing
Note: Regardless of whether a pregnancy is known or not known to be at increased risk for the 1q21.1 recurrent deletion, the prenatal finding of a 1q21.1 recurrent deletion cannot be used to predict the phenotype (see
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
•
•
• United Kingdom
•
•
•
•
## Molecular Genetics
1q21.1 Recurrent Microdeletion: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for 1q21.1 Recurrent Microdeletion (
Similar to other genomic disorders (e.g., deletions and reciprocal duplications of
In the 1q21.1 region, there are four copies of segmental duplications in direct orientation, each with high sequence identity. These noncontiguous segmental duplication elements are termed BP1, BP2, BP3, and BP4, so named because they are recombination breakpoint (BP) hotspots for deletion and duplication of sequences between the BP elements [
The breakpoints of the distal 1q21.1 recurrent deletion described in this
A smaller, more proximal deletion occurring between BP2 and BP3 has been associated with
A third type of deletion, sometimes called a class II deletion, occurs between BP2 and BP4. This approximately 2-Mb deletion involves the chromosomal regions of both the TAR syndrome-associated deletion and the 0.8-Mb distal 1q21.1 deletion (the subject of this
Although several genes of interest (
A mouse model for the 1q21.1 deletion has been established, showing shortened head-to-tail length, altered dopamine transmission, and increased response to stimulant medication [
## Molecular Pathogenesis
Similar to other genomic disorders (e.g., deletions and reciprocal duplications of
In the 1q21.1 region, there are four copies of segmental duplications in direct orientation, each with high sequence identity. These noncontiguous segmental duplication elements are termed BP1, BP2, BP3, and BP4, so named because they are recombination breakpoint (BP) hotspots for deletion and duplication of sequences between the BP elements [
The breakpoints of the distal 1q21.1 recurrent deletion described in this
A smaller, more proximal deletion occurring between BP2 and BP3 has been associated with
A third type of deletion, sometimes called a class II deletion, occurs between BP2 and BP4. This approximately 2-Mb deletion involves the chromosomal regions of both the TAR syndrome-associated deletion and the 0.8-Mb distal 1q21.1 deletion (the subject of this
Although several genes of interest (
A mouse model for the 1q21.1 deletion has been established, showing shortened head-to-tail length, altered dopamine transmission, and increased response to stimulant medication [
## Deletion Mechanism
Similar to other genomic disorders (e.g., deletions and reciprocal duplications of
In the 1q21.1 region, there are four copies of segmental duplications in direct orientation, each with high sequence identity. These noncontiguous segmental duplication elements are termed BP1, BP2, BP3, and BP4, so named because they are recombination breakpoint (BP) hotspots for deletion and duplication of sequences between the BP elements [
The breakpoints of the distal 1q21.1 recurrent deletion described in this
A smaller, more proximal deletion occurring between BP2 and BP3 has been associated with
A third type of deletion, sometimes called a class II deletion, occurs between BP2 and BP4. This approximately 2-Mb deletion involves the chromosomal regions of both the TAR syndrome-associated deletion and the 0.8-Mb distal 1q21.1 deletion (the subject of this
## Genes of Interest in this Region
Although several genes of interest (
## Pathophysiology
A mouse model for the 1q21.1 deletion has been established, showing shortened head-to-tail length, altered dopamine transmission, and increased response to stimulant medication [
## Chapter Notes
Baylor Genetics is conducting data collection on individuals with 1q21.1 distal deletions. Interested parties should contact
Rose Guo, DO (2024-present)Chad R Haldeman-Englert, MD (2011-present)Tamison Jewett, MD; Wake Forest University School of Medicine (2011-2024)
1 February 2024 (ma) Comprehensive update posted live
12 November 2015 (me) Comprehensive update posted live
24 February 2011 (me) Review posted live
30 November 2010 (che) Original submission
• 1 February 2024 (ma) Comprehensive update posted live
• 12 November 2015 (me) Comprehensive update posted live
• 24 February 2011 (me) Review posted live
• 30 November 2010 (che) Original submission
## Author Notes
Baylor Genetics is conducting data collection on individuals with 1q21.1 distal deletions. Interested parties should contact
## Author History
Rose Guo, DO (2024-present)Chad R Haldeman-Englert, MD (2011-present)Tamison Jewett, MD; Wake Forest University School of Medicine (2011-2024)
## Revision History
1 February 2024 (ma) Comprehensive update posted live
12 November 2015 (me) Comprehensive update posted live
24 February 2011 (me) Review posted live
30 November 2010 (che) Original submission
• 1 February 2024 (ma) Comprehensive update posted live
• 12 November 2015 (me) Comprehensive update posted live
• 24 February 2011 (me) Review posted live
• 30 November 2010 (che) Original submission
## References
## Literature Cited
|
[] |
24/2/2011
|
1/2/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mdel3q29
|
mdel3q29
|
[
"3q29 Deletion Syndrome",
"3q29 Microdeletion Syndrome",
"3q29 Deletion Syndrome",
"3q29 Microdeletion Syndrome",
"Not applicable",
"3q29 Recurrent Deletion"
] |
3q29 Recurrent Deletion
|
Jennifer Gladys Mulle, Michael J Gambello, Rossana Sanchez Russo, Melissa M Murphy, T Lindsey Burrell, Cheryl Klaiman, Stormi White, Celine A Saulnier, Elaine F Walker, Joseph F Cubells, Sarah Shultz, Longchuan Li
|
Summary 3q29 recurrent deletion is characterized by neurodevelopmental and/or psychiatric manifestations including mild-to-moderate intellectual disability (ID), autism spectrum disorder (ASD), anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), executive function deficits, graphomotor weakness, and psychosis/schizophrenia. Age at onset for psychosis or prodrome can be younger than the typical age at onset in the general population. Neurodevelopmental and psychiatric conditions are responsible for the majority of the disability associated with the 3q29 deletion. Other common findings are failure to thrive and feeding problems in infancy that persist into childhood, gastrointestinal disorders (including constipation and gastroesophageal reflux disease [GERD]), ocular issues, dental anomalies, and congenital heart defects (especially patent ductus arteriosus). Structural anomalies of the posterior fossa may be seen on neuroimaging. To date more than 200 affected individuals have been identified. The diagnosis of the 3q29 recurrent deletion is established by identification of a heterozygous 1.6-Mb deletion at the approximate position of chr3:195998129-197623129 in the reference genome (NCBI Build 38). 3q29 recurrent deletion is an autosomal dominant disorder typically caused by a
|
## Diagnosis
The 3q29 recurrent deletion
Developmental delay typically including speech and motor delays
Intellectual disability; mild to moderate (34%), severe (<5%)
Neuropsychiatric disorders including attention-deficit/hyperactivity disorder, anxiety disorders, and/or autism spectrum disorder (ASD)
Failure to thrive and/or feeding problems in infancy that persist into childhood
Gastrointestinal disorders including gastroesophageal reflux disease
Ocular issues
Dental anomalies
Congenital heart defects, especially patent ductus arteriosus
Subtle facial dysmorphology including a prominent forehead, prominent nasal tip, and thin vermilion of the upper lip [
Of note, most individuals with the 3q29 recurrent deletion are identified by chromosomal microarray (CMA) analysis performed in the context of evaluation for developmental delay (DD), intellectual disability (ID), and/or ASD.
The diagnosis of the 3q29 recurrent deletion
For this
Note: (1) Since these deletions are recurrent and mediated by segmental duplications, the unique genetic sequence that is deleted is the same in all individuals with the deletion; however, the reported size of the deletion: (a) may be larger if adjacent segmental duplications are included in the size; and (b) may vary based on the design of the microarray used to detect it (see
Note: (1) Most individuals with a 3q29 recurrent deletion are identified by CMA performed in the context of evaluation for DD, ID, or ASD. (2) Prior to 2005 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. This recurrent deletion was detected by early BAC arrays; at least 14 individuals with 3q29 deletion were identified with this technology [
Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 3q29 recurrent deletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.
Genomic Testing Used in the 3q29 Recurrent Deletion
ISCN: seq[GRCh37] del(3)(q29) chr3:195,756,054-197,344,665
See
Standardized ISCN annotation and interpretation for genomic variants from the
Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays. CMA designs in current clinical use target the 3q29 region.
Targeted deletion analysis methods can include FISH, quantitative PCR, and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods.
Not applicable. Targeted deletion analysis is not appropriate for an individual in whom the 3q29 recurrent deletion was not detected by CMA designed to target this region.
Targeted deletion analysis may be used to test at-risk relatives of a proband known to have the 3q29 recurrent deletion.
• Developmental delay typically including speech and motor delays
• Intellectual disability; mild to moderate (34%), severe (<5%)
• Neuropsychiatric disorders including attention-deficit/hyperactivity disorder, anxiety disorders, and/or autism spectrum disorder (ASD)
• Failure to thrive and/or feeding problems in infancy that persist into childhood
• Gastrointestinal disorders including gastroesophageal reflux disease
• Ocular issues
• Dental anomalies
• Congenital heart defects, especially patent ductus arteriosus
• Subtle facial dysmorphology including a prominent forehead, prominent nasal tip, and thin vermilion of the upper lip [
• Note: (1) Most individuals with a 3q29 recurrent deletion are identified by CMA performed in the context of evaluation for DD, ID, or ASD. (2) Prior to 2005 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. This recurrent deletion was detected by early BAC arrays; at least 14 individuals with 3q29 deletion were identified with this technology [
• Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 3q29 recurrent deletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.
• ISCN: seq[GRCh37] del(3)(q29) chr3:195,756,054-197,344,665
## Suggestive Findings
The 3q29 recurrent deletion
Developmental delay typically including speech and motor delays
Intellectual disability; mild to moderate (34%), severe (<5%)
Neuropsychiatric disorders including attention-deficit/hyperactivity disorder, anxiety disorders, and/or autism spectrum disorder (ASD)
Failure to thrive and/or feeding problems in infancy that persist into childhood
Gastrointestinal disorders including gastroesophageal reflux disease
Ocular issues
Dental anomalies
Congenital heart defects, especially patent ductus arteriosus
Subtle facial dysmorphology including a prominent forehead, prominent nasal tip, and thin vermilion of the upper lip [
Of note, most individuals with the 3q29 recurrent deletion are identified by chromosomal microarray (CMA) analysis performed in the context of evaluation for developmental delay (DD), intellectual disability (ID), and/or ASD.
• Developmental delay typically including speech and motor delays
• Intellectual disability; mild to moderate (34%), severe (<5%)
• Neuropsychiatric disorders including attention-deficit/hyperactivity disorder, anxiety disorders, and/or autism spectrum disorder (ASD)
• Failure to thrive and/or feeding problems in infancy that persist into childhood
• Gastrointestinal disorders including gastroesophageal reflux disease
• Ocular issues
• Dental anomalies
• Congenital heart defects, especially patent ductus arteriosus
• Subtle facial dysmorphology including a prominent forehead, prominent nasal tip, and thin vermilion of the upper lip [
## Establishing the Diagnosis
The diagnosis of the 3q29 recurrent deletion
For this
Note: (1) Since these deletions are recurrent and mediated by segmental duplications, the unique genetic sequence that is deleted is the same in all individuals with the deletion; however, the reported size of the deletion: (a) may be larger if adjacent segmental duplications are included in the size; and (b) may vary based on the design of the microarray used to detect it (see
Note: (1) Most individuals with a 3q29 recurrent deletion are identified by CMA performed in the context of evaluation for DD, ID, or ASD. (2) Prior to 2005 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. This recurrent deletion was detected by early BAC arrays; at least 14 individuals with 3q29 deletion were identified with this technology [
Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 3q29 recurrent deletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.
Genomic Testing Used in the 3q29 Recurrent Deletion
ISCN: seq[GRCh37] del(3)(q29) chr3:195,756,054-197,344,665
See
Standardized ISCN annotation and interpretation for genomic variants from the
Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays. CMA designs in current clinical use target the 3q29 region.
Targeted deletion analysis methods can include FISH, quantitative PCR, and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods.
Not applicable. Targeted deletion analysis is not appropriate for an individual in whom the 3q29 recurrent deletion was not detected by CMA designed to target this region.
Targeted deletion analysis may be used to test at-risk relatives of a proband known to have the 3q29 recurrent deletion.
• Note: (1) Most individuals with a 3q29 recurrent deletion are identified by CMA performed in the context of evaluation for DD, ID, or ASD. (2) Prior to 2005 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. This recurrent deletion was detected by early BAC arrays; at least 14 individuals with 3q29 deletion were identified with this technology [
• Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 3q29 recurrent deletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.
• ISCN: seq[GRCh37] del(3)(q29) chr3:195,756,054-197,344,665
## Clinical Characteristics
3q29 recurrent deletion is characterized by neurodevelopmental and/or psychiatric manifestations. Other common findings are failure to thrive, feeding problems, gastrointestinal disorders, ocular issues, dental anomalies, and congenital heart defects. To date more than 200 affected individuals have been identified. The summary below is based on the comprehensive review of all reported individuals in
3q29 Recurrent Deletion: Frequency of Select Features
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; GI = gastrointestinal; ID = intellectual disability
ASD (38%). Individuals with the 3q29 recurrent deletion without a diagnosis of autism may exhibit social disability [
Anxiety disorder (40%)
Schizophrenia (at least 20%) [
ADHD (63%)
Bipolar disorder (5%)
Individuals with the 3q29 recurrent deletion may exhibit more than one neuropsychiatric disorder. For example, roughly 50% of individuals with the 3q29 deletion and ASD also report an anxiety disorder.
The age at onset for psychosis or prodrome can be younger than the typical age at onset in the general population. Early-onset psychosis was reported in one boy age five years [
No genotype-phenotype correlations for the 3q29 recurrent deletion are known.
Penetrance for the 3q29 recurrent deletion is not known. Reports of the deletion having been inherited from an unaffected parent suggest that while penetrance is high, it is likely not 100%. However, in reports of inherited 3q29 deletion, transmitting parents are rarely assessed for neurodevelopmental and psychiatric phenotypes. One transmitting parent who was assessed with a comprehensive phenotyping protocol was found to have schizoaffective disorder, ADHD, panic disorder, social anxiety disorder, clinically significant deficits in executive function, and significant delays in adaptive behavior – all previously undiagnosed. This individual had an average IQ score of 94 [
The approximate prevalence is 1:30,000-1:40,000, based on (1) a large population-based study in Iceland in which three of 101,655 individuals tested had the 3q29 recurrent deletion [
• ASD (38%). Individuals with the 3q29 recurrent deletion without a diagnosis of autism may exhibit social disability [
• Anxiety disorder (40%)
• Schizophrenia (at least 20%) [
• ADHD (63%)
• Bipolar disorder (5%)
## Clinical Description
3q29 recurrent deletion is characterized by neurodevelopmental and/or psychiatric manifestations. Other common findings are failure to thrive, feeding problems, gastrointestinal disorders, ocular issues, dental anomalies, and congenital heart defects. To date more than 200 affected individuals have been identified. The summary below is based on the comprehensive review of all reported individuals in
3q29 Recurrent Deletion: Frequency of Select Features
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; GI = gastrointestinal; ID = intellectual disability
ASD (38%). Individuals with the 3q29 recurrent deletion without a diagnosis of autism may exhibit social disability [
Anxiety disorder (40%)
Schizophrenia (at least 20%) [
ADHD (63%)
Bipolar disorder (5%)
Individuals with the 3q29 recurrent deletion may exhibit more than one neuropsychiatric disorder. For example, roughly 50% of individuals with the 3q29 deletion and ASD also report an anxiety disorder.
The age at onset for psychosis or prodrome can be younger than the typical age at onset in the general population. Early-onset psychosis was reported in one boy age five years [
• ASD (38%). Individuals with the 3q29 recurrent deletion without a diagnosis of autism may exhibit social disability [
• Anxiety disorder (40%)
• Schizophrenia (at least 20%) [
• ADHD (63%)
• Bipolar disorder (5%)
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for the 3q29 recurrent deletion are known.
## Penetrance
Penetrance for the 3q29 recurrent deletion is not known. Reports of the deletion having been inherited from an unaffected parent suggest that while penetrance is high, it is likely not 100%. However, in reports of inherited 3q29 deletion, transmitting parents are rarely assessed for neurodevelopmental and psychiatric phenotypes. One transmitting parent who was assessed with a comprehensive phenotyping protocol was found to have schizoaffective disorder, ADHD, panic disorder, social anxiety disorder, clinically significant deficits in executive function, and significant delays in adaptive behavior – all previously undiagnosed. This individual had an average IQ score of 94 [
## Prevalence
The approximate prevalence is 1:30,000-1:40,000, based on (1) a large population-based study in Iceland in which three of 101,655 individuals tested had the 3q29 recurrent deletion [
## Genetically Related Disorders
At least 50 individuals with
## Differential Diagnosis
The differential diagnosis of the 3q29 recurrent deletion is broad due to the variable spectrum and presence of relatively common abnormal phenotypes that occur in affected individuals including developmental delay, learning problems, and neuropsychiatric disorders. All manifestations of the 3q29 recurrent deletion can also be seen in individuals with other genomic disorders.
## Management
To establish the extent of disease and needs in an individual diagnosed with the 3q29 recurrent deletion, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with 3q29 Recurrent Deletion
Eval for developmental needs & early intervention (e.g., PT, speech-language therapy, cognitive behavioral therapy for social skills training)
Eval of fine motor function (e.g., OT)
Eval for ASD, cognitive ability, & for executive function deficits
Eval for seizures if indicated
Eval of muscle tone
Brain MRI to identify posterior fossa anomalies
Assess growth & feeding
Assess for signs/symptoms of GER, constipation, &/or chronic diarrhea
Otolaryngology eval
Audiology eval
Assess for sleep issues.
Polysomnography as needed
Allergy testing as needed
Assess for food allergies.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GER = gastroesophageal reflux; GI = gastrointestinal; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with 3q29 Recurrent Deletion
Early speech & language therapy to address speech delays
PT/OT as necessary to address fine & gross motor delays
IEP for school-age children
Care by a child psychiatrist for anxiety disorder &/or other neuropsychiatric manifestations w/transfer of care to adult psychiatrist when appropriate
Cognitive behavioral therapy for social disability &/or anxiety
Adaptive behavior (e.g., social skills training)
Applied behavioral analysis or other treatment for manifestations of ASD
Medication as necessary for anxiety disorder, ADHD, or psychosis
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Behavioral &/or medical treatment of constipation (stool softeners, prokinetics, osmotic agents, or laxatives) if persistent
Consider referral to gastroenterologist.
More frequent dental exams & cleanings
Assistance w/daily brushing & flossing
Consider eval for enuresis if persistent.
Consider behavioral interventions incl alarm techniques if indicated.
Assess for medications that could contribute to enuresis.
Recommendations for implementing healthy sleep hygiene habits
Referral to pulmonologist/sleep clinic as needed
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; FTT = failure to thrive; GER = gastroesophageal reflux; IEP = individualized education program; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Recommended Surveillance for Individuals with 3q29 Recurrent Deletion
Monitor those w/seizures as clinically indicated.
Assess for new seizures.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
If genomic testing detects the 3q29 recurrent deletion in one of the proband's parents, it is appropriate to clarify the genetic status of older and younger sibs of the proband in order to identify those who would benefit from close assessment/monitoring of developmental milestones (in children) and monitoring for neuropsychiatric manifestations (in children and adults).
See
Search
• Eval for developmental needs & early intervention (e.g., PT, speech-language therapy, cognitive behavioral therapy for social skills training)
• Eval of fine motor function (e.g., OT)
• Eval for ASD, cognitive ability, & for executive function deficits
• Eval for seizures if indicated
• Eval of muscle tone
• Brain MRI to identify posterior fossa anomalies
• Assess growth & feeding
• Assess for signs/symptoms of GER, constipation, &/or chronic diarrhea
• Otolaryngology eval
• Audiology eval
• Assess for sleep issues.
• Polysomnography as needed
• Allergy testing as needed
• Assess for food allergies.
• Early speech & language therapy to address speech delays
• PT/OT as necessary to address fine & gross motor delays
• IEP for school-age children
• Care by a child psychiatrist for anxiety disorder &/or other neuropsychiatric manifestations w/transfer of care to adult psychiatrist when appropriate
• Cognitive behavioral therapy for social disability &/or anxiety
• Adaptive behavior (e.g., social skills training)
• Applied behavioral analysis or other treatment for manifestations of ASD
• Medication as necessary for anxiety disorder, ADHD, or psychosis
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Behavioral &/or medical treatment of constipation (stool softeners, prokinetics, osmotic agents, or laxatives) if persistent
• Consider referral to gastroenterologist.
• More frequent dental exams & cleanings
• Assistance w/daily brushing & flossing
• Consider eval for enuresis if persistent.
• Consider behavioral interventions incl alarm techniques if indicated.
• Assess for medications that could contribute to enuresis.
• Recommendations for implementing healthy sleep hygiene habits
• Referral to pulmonologist/sleep clinic as needed
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Monitor those w/seizures as clinically indicated.
• Assess for new seizures.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with the 3q29 recurrent deletion, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with 3q29 Recurrent Deletion
Eval for developmental needs & early intervention (e.g., PT, speech-language therapy, cognitive behavioral therapy for social skills training)
Eval of fine motor function (e.g., OT)
Eval for ASD, cognitive ability, & for executive function deficits
Eval for seizures if indicated
Eval of muscle tone
Brain MRI to identify posterior fossa anomalies
Assess growth & feeding
Assess for signs/symptoms of GER, constipation, &/or chronic diarrhea
Otolaryngology eval
Audiology eval
Assess for sleep issues.
Polysomnography as needed
Allergy testing as needed
Assess for food allergies.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GER = gastroesophageal reflux; GI = gastrointestinal; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Eval for developmental needs & early intervention (e.g., PT, speech-language therapy, cognitive behavioral therapy for social skills training)
• Eval of fine motor function (e.g., OT)
• Eval for ASD, cognitive ability, & for executive function deficits
• Eval for seizures if indicated
• Eval of muscle tone
• Brain MRI to identify posterior fossa anomalies
• Assess growth & feeding
• Assess for signs/symptoms of GER, constipation, &/or chronic diarrhea
• Otolaryngology eval
• Audiology eval
• Assess for sleep issues.
• Polysomnography as needed
• Allergy testing as needed
• Assess for food allergies.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with 3q29 Recurrent Deletion
Early speech & language therapy to address speech delays
PT/OT as necessary to address fine & gross motor delays
IEP for school-age children
Care by a child psychiatrist for anxiety disorder &/or other neuropsychiatric manifestations w/transfer of care to adult psychiatrist when appropriate
Cognitive behavioral therapy for social disability &/or anxiety
Adaptive behavior (e.g., social skills training)
Applied behavioral analysis or other treatment for manifestations of ASD
Medication as necessary for anxiety disorder, ADHD, or psychosis
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Behavioral &/or medical treatment of constipation (stool softeners, prokinetics, osmotic agents, or laxatives) if persistent
Consider referral to gastroenterologist.
More frequent dental exams & cleanings
Assistance w/daily brushing & flossing
Consider eval for enuresis if persistent.
Consider behavioral interventions incl alarm techniques if indicated.
Assess for medications that could contribute to enuresis.
Recommendations for implementing healthy sleep hygiene habits
Referral to pulmonologist/sleep clinic as needed
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; FTT = failure to thrive; GER = gastroesophageal reflux; IEP = individualized education program; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
• Early speech & language therapy to address speech delays
• PT/OT as necessary to address fine & gross motor delays
• IEP for school-age children
• Care by a child psychiatrist for anxiety disorder &/or other neuropsychiatric manifestations w/transfer of care to adult psychiatrist when appropriate
• Cognitive behavioral therapy for social disability &/or anxiety
• Adaptive behavior (e.g., social skills training)
• Applied behavioral analysis or other treatment for manifestations of ASD
• Medication as necessary for anxiety disorder, ADHD, or psychosis
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Behavioral &/or medical treatment of constipation (stool softeners, prokinetics, osmotic agents, or laxatives) if persistent
• Consider referral to gastroenterologist.
• More frequent dental exams & cleanings
• Assistance w/daily brushing & flossing
• Consider eval for enuresis if persistent.
• Consider behavioral interventions incl alarm techniques if indicated.
• Assess for medications that could contribute to enuresis.
• Recommendations for implementing healthy sleep hygiene habits
• Referral to pulmonologist/sleep clinic as needed
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
## Surveillance
Recommended Surveillance for Individuals with 3q29 Recurrent Deletion
Monitor those w/seizures as clinically indicated.
Assess for new seizures.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new seizures.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluation of Relatives at Risk
If genomic testing detects the 3q29 recurrent deletion in one of the proband's parents, it is appropriate to clarify the genetic status of older and younger sibs of the proband in order to identify those who would benefit from close assessment/monitoring of developmental milestones (in children) and monitoring for neuropsychiatric manifestations (in children and adults).
See
## Therapies Under Investigation
Search
## Genetic Counseling
The 3q29 recurrent deletion is an autosomal dominant disorder typically caused by a
Although most deletions are
Evaluation of the parents by genomic testing that will detect the 3q29 recurrent deletion present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. (Note: A parent who has a 3q29 recurrent deletion may have only mild manifestations of the disorder or have phenotypes that go undetected because appropriate evaluations have not been conducted.) Testing for a balanced chromosome rearrangement in the parents is also recommended.
If neither parent has the 3q29 recurrent deletion identified in the proband or a balanced chromosome rearrangement, the following possibilities should be considered:
The proband has a
The proband inherited the deletion from a parent with germline (or somatic and germline) mosaicism. Somatic/germline mosaicism was reported in one father of a proband with the 3q29 recurrent deletion [
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
If the proband represents a simplex case (i.e., a single affected family member) and neither parent has the 3q29 recurrent deletion or a balanced chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental germline mosaicism for the deletion.
If one of the parents has the 3q29 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the phenotype in a sib who inherits the deletion, as the phenotypic spectrum associated with the 3q29 recurrent deletion can vary widely among family members [
If one of the parents has a balanced chromosome rearrangement, the risk to sibs of having the 3q29 recurrent deletion is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 3q29 recurrent deletion. Note: If a parent is known to have a balanced chromosome rearrangement, genetic counseling should also address reproductive risks associated with balanced chromosome rearrangements.
Prenatal testing or preimplantation genetic testing using genomic testing that will detect the 3q29 recurrent deletion found in the proband may be offered when:
A parent has the 3q29 recurrent deletion;
The parents do not have the recurrent deletion but have had a child with the 3q29 recurrent deletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is probably slightly greater than that of the general population (though still presumed to be <1%).
Note: Regardless of whether a pregnancy is known or not known to be at increased risk for the 3q29 recurrent deletion, prenatal test results cannot reliably predict the phenotype.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Although most deletions are
• Evaluation of the parents by genomic testing that will detect the 3q29 recurrent deletion present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. (Note: A parent who has a 3q29 recurrent deletion may have only mild manifestations of the disorder or have phenotypes that go undetected because appropriate evaluations have not been conducted.) Testing for a balanced chromosome rearrangement in the parents is also recommended.
• If neither parent has the 3q29 recurrent deletion identified in the proband or a balanced chromosome rearrangement, the following possibilities should be considered:
• The proband has a
• The proband inherited the deletion from a parent with germline (or somatic and germline) mosaicism. Somatic/germline mosaicism was reported in one father of a proband with the 3q29 recurrent deletion [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• The proband has a
• The proband inherited the deletion from a parent with germline (or somatic and germline) mosaicism. Somatic/germline mosaicism was reported in one father of a proband with the 3q29 recurrent deletion [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• The proband has a
• The proband inherited the deletion from a parent with germline (or somatic and germline) mosaicism. Somatic/germline mosaicism was reported in one father of a proband with the 3q29 recurrent deletion [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• If the proband represents a simplex case (i.e., a single affected family member) and neither parent has the 3q29 recurrent deletion or a balanced chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental germline mosaicism for the deletion.
• If one of the parents has the 3q29 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the phenotype in a sib who inherits the deletion, as the phenotypic spectrum associated with the 3q29 recurrent deletion can vary widely among family members [
• If one of the parents has a balanced chromosome rearrangement, the risk to sibs of having the 3q29 recurrent deletion is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 3q29 recurrent deletion. Note: If a parent is known to have a balanced chromosome rearrangement, genetic counseling should also address reproductive risks associated with balanced chromosome rearrangements.
• A parent has the 3q29 recurrent deletion;
• The parents do not have the recurrent deletion but have had a child with the 3q29 recurrent deletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is probably slightly greater than that of the general population (though still presumed to be <1%).
## Mode of Inheritance
The 3q29 recurrent deletion is an autosomal dominant disorder typically caused by a
## Risk to Family Members
Although most deletions are
Evaluation of the parents by genomic testing that will detect the 3q29 recurrent deletion present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. (Note: A parent who has a 3q29 recurrent deletion may have only mild manifestations of the disorder or have phenotypes that go undetected because appropriate evaluations have not been conducted.) Testing for a balanced chromosome rearrangement in the parents is also recommended.
If neither parent has the 3q29 recurrent deletion identified in the proband or a balanced chromosome rearrangement, the following possibilities should be considered:
The proband has a
The proband inherited the deletion from a parent with germline (or somatic and germline) mosaicism. Somatic/germline mosaicism was reported in one father of a proband with the 3q29 recurrent deletion [
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
If the proband represents a simplex case (i.e., a single affected family member) and neither parent has the 3q29 recurrent deletion or a balanced chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental germline mosaicism for the deletion.
If one of the parents has the 3q29 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the phenotype in a sib who inherits the deletion, as the phenotypic spectrum associated with the 3q29 recurrent deletion can vary widely among family members [
If one of the parents has a balanced chromosome rearrangement, the risk to sibs of having the 3q29 recurrent deletion is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• Although most deletions are
• Evaluation of the parents by genomic testing that will detect the 3q29 recurrent deletion present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. (Note: A parent who has a 3q29 recurrent deletion may have only mild manifestations of the disorder or have phenotypes that go undetected because appropriate evaluations have not been conducted.) Testing for a balanced chromosome rearrangement in the parents is also recommended.
• If neither parent has the 3q29 recurrent deletion identified in the proband or a balanced chromosome rearrangement, the following possibilities should be considered:
• The proband has a
• The proband inherited the deletion from a parent with germline (or somatic and germline) mosaicism. Somatic/germline mosaicism was reported in one father of a proband with the 3q29 recurrent deletion [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• The proband has a
• The proband inherited the deletion from a parent with germline (or somatic and germline) mosaicism. Somatic/germline mosaicism was reported in one father of a proband with the 3q29 recurrent deletion [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• The proband has a
• The proband inherited the deletion from a parent with germline (or somatic and germline) mosaicism. Somatic/germline mosaicism was reported in one father of a proband with the 3q29 recurrent deletion [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.
• If the proband represents a simplex case (i.e., a single affected family member) and neither parent has the 3q29 recurrent deletion or a balanced chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental germline mosaicism for the deletion.
• If one of the parents has the 3q29 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the phenotype in a sib who inherits the deletion, as the phenotypic spectrum associated with the 3q29 recurrent deletion can vary widely among family members [
• If one of the parents has a balanced chromosome rearrangement, the risk to sibs of having the 3q29 recurrent deletion is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 3q29 recurrent deletion. Note: If a parent is known to have a balanced chromosome rearrangement, genetic counseling should also address reproductive risks associated with balanced chromosome rearrangements.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 3q29 recurrent deletion. Note: If a parent is known to have a balanced chromosome rearrangement, genetic counseling should also address reproductive risks associated with balanced chromosome rearrangements.
## Prenatal Testing and Preimplantation Genetic Testing
Prenatal testing or preimplantation genetic testing using genomic testing that will detect the 3q29 recurrent deletion found in the proband may be offered when:
A parent has the 3q29 recurrent deletion;
The parents do not have the recurrent deletion but have had a child with the 3q29 recurrent deletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is probably slightly greater than that of the general population (though still presumed to be <1%).
Note: Regardless of whether a pregnancy is known or not known to be at increased risk for the 3q29 recurrent deletion, prenatal test results cannot reliably predict the phenotype.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• A parent has the 3q29 recurrent deletion;
• The parents do not have the recurrent deletion but have had a child with the 3q29 recurrent deletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is probably slightly greater than that of the general population (though still presumed to be <1%).
## Resources
United Kingdom
Rutgers University
Robert Wood Johnson School of Medicine
679 Hoes Lane West
Piscataway NJ 08854
•
•
•
• United Kingdom
•
•
• Rutgers University
• Robert Wood Johnson School of Medicine
• 679 Hoes Lane West
• Piscataway NJ 08854
•
## Molecular Genetics
3q29 Recurrent Deletion: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for 3q29 Recurrent Deletion (
## Molecular Pathogenesis
## Chapter Notes
The 3q29 Project (
Research into 3q29 deletion syndrome has been generously supported by the NIH (NIMH: R01 MH110701, R01 MH118534-01; NIGMS: R01 GM097331) and PCORI (EAIN-00097). We also wish to acknowledge the probands affected by the 3q29 deletion and their families; their participation and engagement in research has been critical for advancing our understanding of the syndrome.
T Lindsey Burrell, PhD (2021-present)Edwin H Cook, MD; University of Illinois at Chicago (2016-2021)Joseph F Cubells, MD, PhD (2021-present)Michael J Gambello, MD, PhD (2016-present)Megan Glassford, MMSc; Emory University School of Medicine (2016-2021)Cheryl Klaiman, PhD (2021-present)Longchuan Li, PhD (2021-present)Jennifer Gladys Mulle, MHS, PhD (2016-present)Melissa M Murphy, PhD (2021-present)Timothy P Rutkowski, PhD; Emory University School of Medicine (2016-2021)Rossana Sanchez Russo, MD (2021-present)Celine A Saulnier, PhD (2021-present)Sarah Shultz, PhD (2021-present)Elaine F Walker, PhD (2021-present)Stormi White, PsyD (2021-present)
1 July 2021 (sw) Comprehensive update posted live
22 September 2016 (bp) Review posted live
30 November 2015 (jgm) Original submission
• 1 July 2021 (sw) Comprehensive update posted live
• 22 September 2016 (bp) Review posted live
• 30 November 2015 (jgm) Original submission
## Author Notes
The 3q29 Project (
## Acknowledgments
Research into 3q29 deletion syndrome has been generously supported by the NIH (NIMH: R01 MH110701, R01 MH118534-01; NIGMS: R01 GM097331) and PCORI (EAIN-00097). We also wish to acknowledge the probands affected by the 3q29 deletion and their families; their participation and engagement in research has been critical for advancing our understanding of the syndrome.
## Author History
T Lindsey Burrell, PhD (2021-present)Edwin H Cook, MD; University of Illinois at Chicago (2016-2021)Joseph F Cubells, MD, PhD (2021-present)Michael J Gambello, MD, PhD (2016-present)Megan Glassford, MMSc; Emory University School of Medicine (2016-2021)Cheryl Klaiman, PhD (2021-present)Longchuan Li, PhD (2021-present)Jennifer Gladys Mulle, MHS, PhD (2016-present)Melissa M Murphy, PhD (2021-present)Timothy P Rutkowski, PhD; Emory University School of Medicine (2016-2021)Rossana Sanchez Russo, MD (2021-present)Celine A Saulnier, PhD (2021-present)Sarah Shultz, PhD (2021-present)Elaine F Walker, PhD (2021-present)Stormi White, PsyD (2021-present)
## Revision History
1 July 2021 (sw) Comprehensive update posted live
22 September 2016 (bp) Review posted live
30 November 2015 (jgm) Original submission
• 1 July 2021 (sw) Comprehensive update posted live
• 22 September 2016 (bp) Review posted live
• 30 November 2015 (jgm) Original submission
## References
## Literature Cited
|
[] |
22/9/2016
|
1/7/2021
|
19/10/2017
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mdel9q22_3
|
mdel9q22_3
|
[
"Fanconi anemia group C protein",
"Not applicable",
"Protein patched homolog 1",
"FANCC",
"Not applicable",
"PTCH1",
"9q22.3 Microdeletion"
] |
9q22.3 Microdeletion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Eric Muller, Louanne Hudgins
|
Summary 9q22.3 microdeletion, which includes deletion of The diagnosis of the 9q22.3 microdeletion is confirmed by demonstration of a heterozygous microdeletion at chromosome 9q22.3. The minimal critical region that is deleted recurrently in affected individuals (but not in controls) is 352 kb, and includes The 9q22.3 microdeletion is inherited in an autosomal dominant manner. In the majority of individuals, the microdeletion appears to result from either a
|
## Diagnosis
The clinical spectrum of the 9q22.3 microdeletion is variable and the clinical findings depend somewhat on the size of the microdeletion.
All reported 9q22.3 microdeletions include
Lamellar calcification of the falx cerebri prior to age 20 years
Five or more basal cell carcinomas in a lifetime or one prior to age 30 years
Jaw keratocysts
Palmar/plantar pits
First-degree relative with Gorlin syndrome
Cleft lip and/or cleft palate
Pre- or postaxial polydactyly
Macrocephaly (occipital-frontal circumference of >97th centile)
Ocular anomalies (including microphthalmia, cataracts, retinal anomalies, developmental defects)
Rib and/or vertebral anomalies
Cardiac and ovarian fibromas
Childhood medulloblastoma (also called primitive neuroectodermal tumor [PNET])
Lymphomesenteric or pleural cysts
Developmental delay and/or intellectual disability
Short nose and long and tented philtrum
Metopic craniosynostosis
Obstructive hydrocephalus
Pre- and postnatal height and weight of >95th centile
Seizures
Note: The genes that are deleted vary with the size and breakpoints of the microdeletion.
Molecular Genetic Testing Used in 9q22.3 Microdeletion
See
The ability of the test method used to detect the indicated deletion
Chromosomal microarray (CMA) using arrays of BACs, oligonucleotides, SNPs or combinations thereof can detect the 352-kb minimal critical deletion along with larger deletions. The ability to determine that the deletion involves the 352-kb critical region depends on both the type of microarray used and the density of probes in the 9q22.3 region. Note: Depending on the resolution, some chromosomal microarrays used before 2008 may not have been effective in detecting this deletion.
Testing that identifies deletions/duplications; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted genome chromosomal microarray analysis (gene/segment-specific) may be used.
If the deletion is suspected clinically fluorescence in situ hybridization (FISH) may be considered. However, the size of a deletion cannot be determined by a single FISH probe.
If the 9q22.3 microdeletion is suspected based on the clinical features, a targeted technique (e.g., FISH, MLPA) can be employed.
Deletions may also be detected by genomic chromosomal microarray (CMA) analysis performed as part of the evaluation of developmental delay or intellectual disability, and/or after detection of a whole
Note: The deletion cannot be identified by routine chromosome analysis.
• Lamellar calcification of the falx cerebri prior to age 20 years
• Five or more basal cell carcinomas in a lifetime or one prior to age 30 years
• Jaw keratocysts
• Palmar/plantar pits
• First-degree relative with Gorlin syndrome
• Cleft lip and/or cleft palate
• Pre- or postaxial polydactyly
• Macrocephaly (occipital-frontal circumference of >97th centile)
• Ocular anomalies (including microphthalmia, cataracts, retinal anomalies, developmental defects)
• Rib and/or vertebral anomalies
• Cardiac and ovarian fibromas
• Childhood medulloblastoma (also called primitive neuroectodermal tumor [PNET])
• Lymphomesenteric or pleural cysts
• Developmental delay and/or intellectual disability
• Short nose and long and tented philtrum
• Metopic craniosynostosis
• Obstructive hydrocephalus
• Pre- and postnatal height and weight of >95th centile
• Seizures
• If the 9q22.3 microdeletion is suspected based on the clinical features, a targeted technique (e.g., FISH, MLPA) can be employed.
• Deletions may also be detected by genomic chromosomal microarray (CMA) analysis performed as part of the evaluation of developmental delay or intellectual disability, and/or after detection of a whole
## Clinical Diagnosis
The clinical spectrum of the 9q22.3 microdeletion is variable and the clinical findings depend somewhat on the size of the microdeletion.
All reported 9q22.3 microdeletions include
Lamellar calcification of the falx cerebri prior to age 20 years
Five or more basal cell carcinomas in a lifetime or one prior to age 30 years
Jaw keratocysts
Palmar/plantar pits
First-degree relative with Gorlin syndrome
Cleft lip and/or cleft palate
Pre- or postaxial polydactyly
Macrocephaly (occipital-frontal circumference of >97th centile)
Ocular anomalies (including microphthalmia, cataracts, retinal anomalies, developmental defects)
Rib and/or vertebral anomalies
Cardiac and ovarian fibromas
Childhood medulloblastoma (also called primitive neuroectodermal tumor [PNET])
Lymphomesenteric or pleural cysts
Developmental delay and/or intellectual disability
Short nose and long and tented philtrum
Metopic craniosynostosis
Obstructive hydrocephalus
Pre- and postnatal height and weight of >95th centile
Seizures
• Lamellar calcification of the falx cerebri prior to age 20 years
• Five or more basal cell carcinomas in a lifetime or one prior to age 30 years
• Jaw keratocysts
• Palmar/plantar pits
• First-degree relative with Gorlin syndrome
• Cleft lip and/or cleft palate
• Pre- or postaxial polydactyly
• Macrocephaly (occipital-frontal circumference of >97th centile)
• Ocular anomalies (including microphthalmia, cataracts, retinal anomalies, developmental defects)
• Rib and/or vertebral anomalies
• Cardiac and ovarian fibromas
• Childhood medulloblastoma (also called primitive neuroectodermal tumor [PNET])
• Lymphomesenteric or pleural cysts
• Developmental delay and/or intellectual disability
• Short nose and long and tented philtrum
• Metopic craniosynostosis
• Obstructive hydrocephalus
• Pre- and postnatal height and weight of >95th centile
• Seizures
## Testing
Note: The genes that are deleted vary with the size and breakpoints of the microdeletion.
Molecular Genetic Testing Used in 9q22.3 Microdeletion
See
The ability of the test method used to detect the indicated deletion
Chromosomal microarray (CMA) using arrays of BACs, oligonucleotides, SNPs or combinations thereof can detect the 352-kb minimal critical deletion along with larger deletions. The ability to determine that the deletion involves the 352-kb critical region depends on both the type of microarray used and the density of probes in the 9q22.3 region. Note: Depending on the resolution, some chromosomal microarrays used before 2008 may not have been effective in detecting this deletion.
Testing that identifies deletions/duplications; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted genome chromosomal microarray analysis (gene/segment-specific) may be used.
If the deletion is suspected clinically fluorescence in situ hybridization (FISH) may be considered. However, the size of a deletion cannot be determined by a single FISH probe.
## Molecular Genetic Testing
Note: The genes that are deleted vary with the size and breakpoints of the microdeletion.
Molecular Genetic Testing Used in 9q22.3 Microdeletion
See
The ability of the test method used to detect the indicated deletion
Chromosomal microarray (CMA) using arrays of BACs, oligonucleotides, SNPs or combinations thereof can detect the 352-kb minimal critical deletion along with larger deletions. The ability to determine that the deletion involves the 352-kb critical region depends on both the type of microarray used and the density of probes in the 9q22.3 region. Note: Depending on the resolution, some chromosomal microarrays used before 2008 may not have been effective in detecting this deletion.
Testing that identifies deletions/duplications; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted genome chromosomal microarray analysis (gene/segment-specific) may be used.
If the deletion is suspected clinically fluorescence in situ hybridization (FISH) may be considered. However, the size of a deletion cannot be determined by a single FISH probe.
## Interpretation of Test Results
## Testing Strategy
If the 9q22.3 microdeletion is suspected based on the clinical features, a targeted technique (e.g., FISH, MLPA) can be employed.
Deletions may also be detected by genomic chromosomal microarray (CMA) analysis performed as part of the evaluation of developmental delay or intellectual disability, and/or after detection of a whole
Note: The deletion cannot be identified by routine chromosome analysis.
• If the 9q22.3 microdeletion is suspected based on the clinical features, a targeted technique (e.g., FISH, MLPA) can be employed.
• Deletions may also be detected by genomic chromosomal microarray (CMA) analysis performed as part of the evaluation of developmental delay or intellectual disability, and/or after detection of a whole
## Clinical Characteristics
Many individuals with 9q22.3 microdeletion exhibit hypotonia in infancy and all exhibit gross motor delay. Hypotonia may persist even into late childhood and adolescence in individuals with larger deletions [
Individuals with deletions of approximately 2 Mb or larger exhibit persistent delays in attaining motor, speech, and behavioral/social milestones [
A fraction of all individuals with 9q22.3 microdeletion develop seizures [
Many (16/37) individuals reported with 9q22.3 microdeletion have cerebral ventricular dilation that ranges from severe to mild and asymmetric, and can be associated with cerebral atrophy or a space-occupying lesion (e.g., medulloblastoma) [
Approximately 20% of individuals with 9q22.3 microdeletion have prenatal onset of macrosomia characterized by birth length and weight above the 95
A few case reports describe either macrosomia or hemihyperplasia in individuals with 9q22.3 microdeletion [
Eight of the 37 affected individuals reported and reviewed by
Affected individuals may have a facial gestalt that includes a broad forehead with bossing, vertical forehead creases, angulated palpebral fissures that may be either up- or downslanted, and a short nose with a long and tented philtrum [
Many of the features seen in individuals with 9q22.3 microdeletion result from haploinsufficiency of
Metopic craniosynostosis: a 929-kb region containing 16 genes
Severe obstructive hydrocephalus: a 1.08-Mb region containing 18 genes
Macrosomia: a 1.8-Mb region containing 31 genes
Note: Some genes within these intervals have not been fully characterized, and no specific candidate genes were identified.
Multiple authors have proposed that the macrosomia present in a subset of individuals with 9q22.3 microdeletion is specifically the result of loss of the paternal allele [
It is expected that 9q22.3 microdeletion is fully penetrant for phenotype, but with variable expressivity. No unaffected individuals with this microdeletion have been reported to date.
The 9q22.3 microdeletion is presumed to be rare. To date, 42 affected individuals have been reported in the medical literature, including one with somatic mosaicism [
• Metopic craniosynostosis: a 929-kb region containing 16 genes
• Severe obstructive hydrocephalus: a 1.08-Mb region containing 18 genes
• Macrosomia: a 1.8-Mb region containing 31 genes
## Clinical Description
Many individuals with 9q22.3 microdeletion exhibit hypotonia in infancy and all exhibit gross motor delay. Hypotonia may persist even into late childhood and adolescence in individuals with larger deletions [
Individuals with deletions of approximately 2 Mb or larger exhibit persistent delays in attaining motor, speech, and behavioral/social milestones [
A fraction of all individuals with 9q22.3 microdeletion develop seizures [
Many (16/37) individuals reported with 9q22.3 microdeletion have cerebral ventricular dilation that ranges from severe to mild and asymmetric, and can be associated with cerebral atrophy or a space-occupying lesion (e.g., medulloblastoma) [
Approximately 20% of individuals with 9q22.3 microdeletion have prenatal onset of macrosomia characterized by birth length and weight above the 95
A few case reports describe either macrosomia or hemihyperplasia in individuals with 9q22.3 microdeletion [
Eight of the 37 affected individuals reported and reviewed by
Affected individuals may have a facial gestalt that includes a broad forehead with bossing, vertical forehead creases, angulated palpebral fissures that may be either up- or downslanted, and a short nose with a long and tented philtrum [
## Genotype-Phenotype Correlations
Many of the features seen in individuals with 9q22.3 microdeletion result from haploinsufficiency of
Metopic craniosynostosis: a 929-kb region containing 16 genes
Severe obstructive hydrocephalus: a 1.08-Mb region containing 18 genes
Macrosomia: a 1.8-Mb region containing 31 genes
Note: Some genes within these intervals have not been fully characterized, and no specific candidate genes were identified.
Multiple authors have proposed that the macrosomia present in a subset of individuals with 9q22.3 microdeletion is specifically the result of loss of the paternal allele [
• Metopic craniosynostosis: a 929-kb region containing 16 genes
• Severe obstructive hydrocephalus: a 1.08-Mb region containing 18 genes
• Macrosomia: a 1.8-Mb region containing 31 genes
## Penetrance
It is expected that 9q22.3 microdeletion is fully penetrant for phenotype, but with variable expressivity. No unaffected individuals with this microdeletion have been reported to date.
## Prevalence
The 9q22.3 microdeletion is presumed to be rare. To date, 42 affected individuals have been reported in the medical literature, including one with somatic mosaicism [
## Genetically Related (Allelic) Disorders
Duplication of the 9q22.3 region, consisting of a 360-kb region containing
Germline dominant pathogenic loss-of-function variants in
Germline dominant pathogenic gain-of-function variants in
Sporadic tumors (including medulloblastomas, odontogenic keratocysts, cardiac fibromas, ovarian fibromas, and basal cell carcinomas) occurring as single tumors in the absence of any other findings of this syndrome can harbor somatic variants in
## Differential Diagnosis
A 9q22.2-q22.3 deletion of 5.3 Mb that did not include
Among syndromes that share multiple features of 9q22.3 microdeletion,
Numerous other genomic microdeletions or microdeletion syndromes result in developmental delay or intellectual impairment and/or some of the individual nonspecific phenotypic features of 9q22.3 microdeletion.
## Management
To establish the extent of disease and needs of an individual diagnosed with the 9q22.3 microdeletion, the following evaluations are recommended:
Brain imaging (not using CT) and neurologic evaluation
Complete physical examination, including dermatologic assessment for the manifestations of Gorlin syndrome
Comprehensive developmental assessment
Renal and pelvic ultrasound examination for evaluation of possible renal anomalies and ovarian fibromas
Echocardiogram
Ophthalmologic evaluation
Careful consideration of skeletal and/or dental imaging for associated anomalies
Familial genetic counseling
Routine treatment and management by appropriate specialists for cardiac, neurologic, dermatologic findings
Comprehensive physical, occupational, and speech therapy services as needed
Surgical intervention as needed for excision or treatment of mandibular keratocysts, basal cell carcinomas, or other tumors that develop, or for management or correction of physical anomalies
The following are appropriate:
Routine treatment and management by appropriate specialists for cardiac, neurologic, dermatologic findings
Comprehensive physical, occupational, and speech therapy services as needed
Surgical intervention as needed for excision or treatment of mandibular keratocysts, basal cell carcinomas, or other tumors that develop, or for management or correction of physical anomalies
Avoidance of excessive sunlight or other ultraviolet radiation, and limiting exposure to ionizing radiation (e.g., by computed tomography and x-ray) is recommended because of the increased predisposition for the development of basal cell carcinomas.
The following recommended surveillance is the same as that for Gorlin syndrome (see
Head circumference should be followed throughout childhood and plotted on appropriate growth charts. Rapid enlargement should prompt evaluation for possible hydrocephalus.
Awareness of the risk of medulloblastoma in the first years of life is important and may justify developmental assessment and physical examination every six months. No evidence for the efficacy of regular neuroimaging exists; frequent computer tomography (CT) should be avoided because of risks associated with radiation sensitivity.
Orthopantogram is indicated every 12-18 months in individuals older than age eight years to identify jaw keratocysts.
Skin should be examined at least annually; some physicians recommend skin examination by a professional every three to four months.
While there are currently no published guidelines regarding monitoring for intraabdominal embryonal tumors in individuals with 9q22.3 microdeletion, 12% of the published cases have been diagnosed with Wilms tumor. Thus regular abdominal ultrasound for Wilms tumor, similar to surveillance for
As all individuals to date have had involvement of
Liberal use of topical sunblock and avoidance of excessive exposure to sunlight are warranted.
See
Macrosomia and/or macrocephaly of prenatal onset is present in many individuals with 9q22.3 microdeletion. This may necessitate delivery by Cesarean section, including emergently, as has been reported for some individuals [
Search
• Brain imaging (not using CT) and neurologic evaluation
• Complete physical examination, including dermatologic assessment for the manifestations of Gorlin syndrome
• Comprehensive developmental assessment
• Renal and pelvic ultrasound examination for evaluation of possible renal anomalies and ovarian fibromas
• Echocardiogram
• Ophthalmologic evaluation
• Careful consideration of skeletal and/or dental imaging for associated anomalies
• Familial genetic counseling
• Routine treatment and management by appropriate specialists for cardiac, neurologic, dermatologic findings
• Comprehensive physical, occupational, and speech therapy services as needed
• Surgical intervention as needed for excision or treatment of mandibular keratocysts, basal cell carcinomas, or other tumors that develop, or for management or correction of physical anomalies
• Routine treatment and management by appropriate specialists for cardiac, neurologic, dermatologic findings
• Comprehensive physical, occupational, and speech therapy services as needed
• Surgical intervention as needed for excision or treatment of mandibular keratocysts, basal cell carcinomas, or other tumors that develop, or for management or correction of physical anomalies
• Head circumference should be followed throughout childhood and plotted on appropriate growth charts. Rapid enlargement should prompt evaluation for possible hydrocephalus.
• Awareness of the risk of medulloblastoma in the first years of life is important and may justify developmental assessment and physical examination every six months. No evidence for the efficacy of regular neuroimaging exists; frequent computer tomography (CT) should be avoided because of risks associated with radiation sensitivity.
• Orthopantogram is indicated every 12-18 months in individuals older than age eight years to identify jaw keratocysts.
• Skin should be examined at least annually; some physicians recommend skin examination by a professional every three to four months.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with the 9q22.3 microdeletion, the following evaluations are recommended:
Brain imaging (not using CT) and neurologic evaluation
Complete physical examination, including dermatologic assessment for the manifestations of Gorlin syndrome
Comprehensive developmental assessment
Renal and pelvic ultrasound examination for evaluation of possible renal anomalies and ovarian fibromas
Echocardiogram
Ophthalmologic evaluation
Careful consideration of skeletal and/or dental imaging for associated anomalies
Familial genetic counseling
Routine treatment and management by appropriate specialists for cardiac, neurologic, dermatologic findings
Comprehensive physical, occupational, and speech therapy services as needed
Surgical intervention as needed for excision or treatment of mandibular keratocysts, basal cell carcinomas, or other tumors that develop, or for management or correction of physical anomalies
• Brain imaging (not using CT) and neurologic evaluation
• Complete physical examination, including dermatologic assessment for the manifestations of Gorlin syndrome
• Comprehensive developmental assessment
• Renal and pelvic ultrasound examination for evaluation of possible renal anomalies and ovarian fibromas
• Echocardiogram
• Ophthalmologic evaluation
• Careful consideration of skeletal and/or dental imaging for associated anomalies
• Familial genetic counseling
• Routine treatment and management by appropriate specialists for cardiac, neurologic, dermatologic findings
• Comprehensive physical, occupational, and speech therapy services as needed
• Surgical intervention as needed for excision or treatment of mandibular keratocysts, basal cell carcinomas, or other tumors that develop, or for management or correction of physical anomalies
## Treatment of Manifestations
The following are appropriate:
Routine treatment and management by appropriate specialists for cardiac, neurologic, dermatologic findings
Comprehensive physical, occupational, and speech therapy services as needed
Surgical intervention as needed for excision or treatment of mandibular keratocysts, basal cell carcinomas, or other tumors that develop, or for management or correction of physical anomalies
• Routine treatment and management by appropriate specialists for cardiac, neurologic, dermatologic findings
• Comprehensive physical, occupational, and speech therapy services as needed
• Surgical intervention as needed for excision or treatment of mandibular keratocysts, basal cell carcinomas, or other tumors that develop, or for management or correction of physical anomalies
## Prevention of Primary Manifestations
Avoidance of excessive sunlight or other ultraviolet radiation, and limiting exposure to ionizing radiation (e.g., by computed tomography and x-ray) is recommended because of the increased predisposition for the development of basal cell carcinomas.
## Surveillance
The following recommended surveillance is the same as that for Gorlin syndrome (see
Head circumference should be followed throughout childhood and plotted on appropriate growth charts. Rapid enlargement should prompt evaluation for possible hydrocephalus.
Awareness of the risk of medulloblastoma in the first years of life is important and may justify developmental assessment and physical examination every six months. No evidence for the efficacy of regular neuroimaging exists; frequent computer tomography (CT) should be avoided because of risks associated with radiation sensitivity.
Orthopantogram is indicated every 12-18 months in individuals older than age eight years to identify jaw keratocysts.
Skin should be examined at least annually; some physicians recommend skin examination by a professional every three to four months.
While there are currently no published guidelines regarding monitoring for intraabdominal embryonal tumors in individuals with 9q22.3 microdeletion, 12% of the published cases have been diagnosed with Wilms tumor. Thus regular abdominal ultrasound for Wilms tumor, similar to surveillance for
• Head circumference should be followed throughout childhood and plotted on appropriate growth charts. Rapid enlargement should prompt evaluation for possible hydrocephalus.
• Awareness of the risk of medulloblastoma in the first years of life is important and may justify developmental assessment and physical examination every six months. No evidence for the efficacy of regular neuroimaging exists; frequent computer tomography (CT) should be avoided because of risks associated with radiation sensitivity.
• Orthopantogram is indicated every 12-18 months in individuals older than age eight years to identify jaw keratocysts.
• Skin should be examined at least annually; some physicians recommend skin examination by a professional every three to four months.
## Agents/Circumstances to Avoid
As all individuals to date have had involvement of
Liberal use of topical sunblock and avoidance of excessive exposure to sunlight are warranted.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Macrosomia and/or macrocephaly of prenatal onset is present in many individuals with 9q22.3 microdeletion. This may necessitate delivery by Cesarean section, including emergently, as has been reported for some individuals [
## Therapies Under Investigation
Search
## Genetic Counseling
The 9q22.3 microdeletion is inherited in an autosomal dominant manner.
The parents of a proband with 9q22.3 microdeletion are generally unaffected.
The majority of cases have resulted from either an apparent
Somatic/germline mosaicism for the 9q22.3 microdeletion has not been reported in an asymptomatic parent of an affected individual.
Recurrence in one family has been described: a woman with features of the deletion condition and mosaicism for a 1.7-Mb 9q22.3 deletion (including
Recurrence in two families in which a parent had a balanced translocation involving the 9q22.3 region has been reported [
Recommendations for the evaluation of asymptomatic parents of a proband include high resolution chromosome analysis to determine if a balanced chromosome rearrangement involving 9q22.3 is present.
The risk to the sibs of the proband depends on the genetic status of the parents.
Recurrence risk to the sibs of a proband is low (probably <5%) but greater than that of the general population because a parent may have (a) germline mosaicism for the 9q22.3 microdeletion, or (b) low-level somatic mosaicism for the 9q22.3 microdeletion that also includes the germline.
If a parent has a balanced structural chromosome rearrangement involving the 9q22.3 critical region, the risk to sibs is increased and depends on the specific chromosome rearrangement.
If a parent has a constitutional 9q22.3 microdeletion (i.e., the microdeletion is present in all of the parent's cells), the risk to sibs of the proband is 50% for also inheriting the microdeletion; however, this has not been reported.
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 9q22.3 microdeletion.
Prenatal testing is technically feasible. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using specific FISH probe analysis or chromosomal microarray (CMA), in the manner described in
Prenatal testing may be offered to parents who have had a child with the 9q22.3 microdeletion because of the recurrence risk (probably <5%) associated with the possibility of germline mosaicism. Prenatal testing is also offered to parents who carry a balanced chromosome rearrangement or who have the microdeletion.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
• The parents of a proband with 9q22.3 microdeletion are generally unaffected.
• The majority of cases have resulted from either an apparent
• Somatic/germline mosaicism for the 9q22.3 microdeletion has not been reported in an asymptomatic parent of an affected individual.
• Recurrence in one family has been described: a woman with features of the deletion condition and mosaicism for a 1.7-Mb 9q22.3 deletion (including
• Recurrence in two families in which a parent had a balanced translocation involving the 9q22.3 region has been reported [
• Recommendations for the evaluation of asymptomatic parents of a proband include high resolution chromosome analysis to determine if a balanced chromosome rearrangement involving 9q22.3 is present.
• The risk to the sibs of the proband depends on the genetic status of the parents.
• Recurrence risk to the sibs of a proband is low (probably <5%) but greater than that of the general population because a parent may have (a) germline mosaicism for the 9q22.3 microdeletion, or (b) low-level somatic mosaicism for the 9q22.3 microdeletion that also includes the germline.
• If a parent has a balanced structural chromosome rearrangement involving the 9q22.3 critical region, the risk to sibs is increased and depends on the specific chromosome rearrangement.
• If a parent has a constitutional 9q22.3 microdeletion (i.e., the microdeletion is present in all of the parent's cells), the risk to sibs of the proband is 50% for also inheriting the microdeletion; however, this has not been reported.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 9q22.3 microdeletion.
## Mode of Inheritance
The 9q22.3 microdeletion is inherited in an autosomal dominant manner.
## Risk to Family Members
The parents of a proband with 9q22.3 microdeletion are generally unaffected.
The majority of cases have resulted from either an apparent
Somatic/germline mosaicism for the 9q22.3 microdeletion has not been reported in an asymptomatic parent of an affected individual.
Recurrence in one family has been described: a woman with features of the deletion condition and mosaicism for a 1.7-Mb 9q22.3 deletion (including
Recurrence in two families in which a parent had a balanced translocation involving the 9q22.3 region has been reported [
Recommendations for the evaluation of asymptomatic parents of a proband include high resolution chromosome analysis to determine if a balanced chromosome rearrangement involving 9q22.3 is present.
The risk to the sibs of the proband depends on the genetic status of the parents.
Recurrence risk to the sibs of a proband is low (probably <5%) but greater than that of the general population because a parent may have (a) germline mosaicism for the 9q22.3 microdeletion, or (b) low-level somatic mosaicism for the 9q22.3 microdeletion that also includes the germline.
If a parent has a balanced structural chromosome rearrangement involving the 9q22.3 critical region, the risk to sibs is increased and depends on the specific chromosome rearrangement.
If a parent has a constitutional 9q22.3 microdeletion (i.e., the microdeletion is present in all of the parent's cells), the risk to sibs of the proband is 50% for also inheriting the microdeletion; however, this has not been reported.
• The parents of a proband with 9q22.3 microdeletion are generally unaffected.
• The majority of cases have resulted from either an apparent
• Somatic/germline mosaicism for the 9q22.3 microdeletion has not been reported in an asymptomatic parent of an affected individual.
• Recurrence in one family has been described: a woman with features of the deletion condition and mosaicism for a 1.7-Mb 9q22.3 deletion (including
• Recurrence in two families in which a parent had a balanced translocation involving the 9q22.3 region has been reported [
• Recommendations for the evaluation of asymptomatic parents of a proband include high resolution chromosome analysis to determine if a balanced chromosome rearrangement involving 9q22.3 is present.
• The risk to the sibs of the proband depends on the genetic status of the parents.
• Recurrence risk to the sibs of a proband is low (probably <5%) but greater than that of the general population because a parent may have (a) germline mosaicism for the 9q22.3 microdeletion, or (b) low-level somatic mosaicism for the 9q22.3 microdeletion that also includes the germline.
• If a parent has a balanced structural chromosome rearrangement involving the 9q22.3 critical region, the risk to sibs is increased and depends on the specific chromosome rearrangement.
• If a parent has a constitutional 9q22.3 microdeletion (i.e., the microdeletion is present in all of the parent's cells), the risk to sibs of the proband is 50% for also inheriting the microdeletion; however, this has not been reported.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 9q22.3 microdeletion.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 9q22.3 microdeletion.
## Prenatal Testing
Prenatal testing is technically feasible. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using specific FISH probe analysis or chromosomal microarray (CMA), in the manner described in
Prenatal testing may be offered to parents who have had a child with the 9q22.3 microdeletion because of the recurrence risk (probably <5%) associated with the possibility of germline mosaicism. Prenatal testing is also offered to parents who carry a balanced chromosome rearrangement or who have the microdeletion.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
## Resources
PO Box 724
Boca Raton FL 33429-0724
G1 The Stables
Station Road West
Oxted Surrey RH8 9EE
United Kingdom
•
• PO Box 724
• Boca Raton FL 33429-0724
•
•
• G1 The Stables
• Station Road West
• Oxted Surrey RH8 9EE
• United Kingdom
•
## Molecular Genetics
9q22.3 Microdeletion: Genes and Databases
Data are compiled from the following standard references: gene from
The mechanism that predisposes the 9q22.3 region to deletion is unclear. The numerous SINEs, large LINEs, and LTRs that flank
The microdeletion size among the reported affected individuals does not appear to be recurrent. The earliest reports of 9q22.3 deletions preceded CMA technology; at that time only large deletions visible by routine cytogenetic banding techniques were described, making specific breakpoint comparison with reports from the last several years difficult. Following the availability of CMA technology, the minimal interstitial 9q22.3 microdeletion reported contains only two genes,
In ten individuals with 9q22.3 microdeletion,
Somatic dominant pathogenic loss-of-function variants in
A somatic nonsense variant in
## Molecular Genetic Pathogenesis
The mechanism that predisposes the 9q22.3 region to deletion is unclear. The numerous SINEs, large LINEs, and LTRs that flank
The microdeletion size among the reported affected individuals does not appear to be recurrent. The earliest reports of 9q22.3 deletions preceded CMA technology; at that time only large deletions visible by routine cytogenetic banding techniques were described, making specific breakpoint comparison with reports from the last several years difficult. Following the availability of CMA technology, the minimal interstitial 9q22.3 microdeletion reported contains only two genes,
In ten individuals with 9q22.3 microdeletion,
Somatic dominant pathogenic loss-of-function variants in
A somatic nonsense variant in
## Cancer and Benign Tumors
Somatic dominant pathogenic loss-of-function variants in
A somatic nonsense variant in
## References
## Literature Cited
## Chapter Notes
2 August 2018 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population
20 February 2014 (me) Comprehensive update posted live
18 August 2011 (me) Review posted live
25 April 2011 (em) Original submission
• 2 August 2018 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population
• 20 February 2014 (me) Comprehensive update posted live
• 18 August 2011 (me) Review posted live
• 25 April 2011 (em) Original submission
## Revision History
2 August 2018 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population
20 February 2014 (me) Comprehensive update posted live
18 August 2011 (me) Review posted live
25 April 2011 (em) Original submission
• 2 August 2018 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population
• 20 February 2014 (me) Comprehensive update posted live
• 18 August 2011 (me) Review posted live
• 25 April 2011 (em) Original submission
Schematic of genes involved in ten individuals with 9q22.3 microdeletion and shared phenotypes
Adapted from
|
[
"MM Cajaiba, AE Bale, M Alvarez-Franco, J McNamara, M Reyes-Mugica. Rhabdomyosarcoma, Wilms tumor, and deletion of the patched gene in Gorlin syndrome.. Nat Clin Pract Oncol 2006;3:575-80",
"CP Chen, SP Lin, TH Wang, YJ Chen, M Chen, W Wang. Perinatal findings and molecular cytogenetic analyses of de novo interstitial deletion of 9q (9q22.3-->q31.3) associated with Gorlin syndrome.. Prenat Diagn 2006;26:725-9",
"K Derwińska, M Smyk, ML Cooper, P Bader, SW Cheung, P Stankiewicz. PTCH1 duplication in a family with microcephaly and mild developmental delay.. Eur J Hum Genet 2009;17:267-71",
"SA Farrell, J Siegel-Bartelt, I Teshima. Patients with deletions of 9q22q34 do not define a syndrome: three case reports and a literature review.. Clin Genet 1991;40:207-14",
"K Fujii, S Ishikawa, H Uchikawa, D Komura, MH Shapero, F Shen, J Hung, H Arai, Y Tanaka, K Sasaki, Y Kohno, M Yamada, KW Jones, H Aburatani, T Miyashita. High-density oligonucleotide array with sub-kilobase resolution reveals breakpoint information of submicroscopic deletions in nevoid basal cell carcinoma syndrome.. Hum Genet 2007;122:459-66",
"L Garavelli, MR Piemontese, A Cavazza, S Rosato, A Wischmeijer, C Gelmini, E Albertini, G Albertini, F Forzano, F Franchi, M Carella, L Zelante, A Superti-Furga. Multiple tumor types including leiomyoma and Wilms tumor in a patient with Gorlin syndrome due to 9q22.3 microdeletion encompassing the PTCH1 and FANC-C loci.. Am J Med Genet A 2013;161A:2894-901",
"H Hahn, C Wicking, PG Zaphiropoulous, MR Gailani, S Shanley, A Chidambaram, I Vorechovsky, E Holmberg, AB Unden, S Gillies, K Negus, I Smyth, C Pressman, DJ Leffell, B Gerrard, AM Goldstein, M Dean, R Toftgard, G Chenevix-Trench, B Wainwright, AE Bale. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.. Cell 1996;85:841-51",
"B Isidor, F Bourdeaut, D Lafon, G Plessis, E Lacaze, C Kannengiesser, S Rossignol, O Pichon, A Briand, D Martin-Coignard, M Piccione, A David, O Delattre, C Jeanpierre, N Sévenet, C Le Caignec. Wilms' tumor in patients with 9q22.3 microdeletion syndrome suggests a role for. Eur J Hum Genet 2013;21:784-7",
"VE Kimonis, SG Mehta, JJ Digiovanna, SJ Bale, B Pastakia. Radiological features in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome.. Genet Med 2004;6:495-502",
"HY Kroes, JH Tuerlings, R Hordijk, NR Folkers, LP ten Kate. Another patient with an interstitial deletion of chromosome 9: case report and a review of six cases with del(9)(q22q32).. J Med Genet 1994;31:156-8",
"AT Midro, B Panasiuk, Z Tumer, P Stankiewicz, A Silahtaroglu, JR Lupski, Z Zemanova, B Stasiewicz-Jarocka, E Hubert, E Tarasow, W Famulski, B Zadrozna-Tolwinska, E Wasilewska, M Kirchhoff, V Kalscheuer, K Michalova, N Tommerup. Interstitial deletion 9q22.32-q33.2 associated with additional familial translocation t(9;17)(q34.11;p11.2) in a patient with Gorlin-Goltz syndrome and features of Nail-Patella syndrome.. Am J Med Genet A 2004;124A:179-91",
"JE Ming, ME Kaupas, E Roessler, HG Brunner, M Golabi, M Tekin, RF Stratton, E Sujansky, SJ Bale, M Muenke. Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly.. Hum Genet 2002;110:297-301",
"EA Muller, S Aradhya, JF Atkin, EP Carmany, AM Elliott, AE Chudley, RD Clark, DB Everman, S Garner, BD Hall, GE Herman, E Kivuva, S Ramanathan, DA Stevenson, DW Stockton, L Hudgins. Microdeletion 9q22.3 syndrome includes metopic craniosynostosis, hydrocephalus, macrosomia and developmental delay.. Am J Med Genet A 2012;158A:391-9",
"B Nowakowska, A Kutkowska-Kazmierczak, P Stankiewicz, E Bocian, E Obersztyn, Z Ou, SW Cheung, WW Cai. A girl with deletion 9q22.1-q22.32 including the PTCH and ROR2 genes identified by genome-wide array-CGH.. Am J Med Genet A 2007;143A:1885-9",
"C Olivieri, P Maraschio, D Caselli, C Martini, G Beluffi, E Maserati, C Danesino. Interstitial deletion of chromosome 9, int del(9)(9q22.31-q31.2), including the genes causing multiple basal cell nevus syndrome and Robinow/brachydactyly 1 syndrome.. Eur J Pediatr 2003;162:100-3",
"R Redon, G Baujat, D Sanlaville, M Le Merrer, M Vekemans, A Munnich, NP Carter, V Cormier-Daire, L Colleaux. Interstitial 9q22.3 microdeletion: clinical and molecular characterisation of a newly recognised overgrowth syndrome.. Eur J Hum Genet 2006;14:759-67",
"LA Ribeiro, JC Murray, A Richieri-Costa. PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI.. Am J Med Genet A 2006;140:2584-6",
"R Shimkets, MR Gailani, VM Siu, T Yang-Feng, CL Pressman, S Levanat, A Goldstein, M Dean, AE Bale. Molecular analysis of chromosome 9q deletions in two Gorlin syndrome patients.. Am J Hum Genet 1996;59:417-22",
"K Shimojima, M Adachi, M Tanaka, Y Tanaka, K Kurosawa, T Yamamoto. Clinical features of microdeletion 9q22.3 (pat).. Clin Genet 2009;75:384-93",
"L Siggberg, M Peippo, M Sipponen, T Miikkulainen, K Shimojima, T Yamamoto, J Ignatius, S Knuutila. 9q22 deletion - first familial case.. Orphanet J Rare Dis. 2011;6:45",
"K Yamamoto, H Yoshihashi, N Furuya, M Adachi, S Ito, Y Tanaka, M Masuno, H Chiyo, K Kurosawa. Further delineation of 9q22 deletion syndrome associated with basal cell nevus (Gorlin) syndrome: report of two cases and review of the literature.. Congenit Anom (Kyoto) 2009;49:8-14",
"KL Ying, CJ Curry, KB Rajani, SH Kassel, RS Sparkes. De novo interstitial deletion in the long arm of chromosome 9: a new chromosome syndrome.. J Med Genet 1982;19:68-70"
] |
18/8/2011
|
20/2/2014
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
me-ataxia
|
me-ataxia
|
[
"PRICKLE1-Related Progressive Myoclonic Epilepsy (PME) with Ataxia (Epilepsy, Progressive Myoclonic 1B [EPM1B])",
"PRICKLE1-Related Non-PME Seizures",
"PRICKLE1-Related Myoclonic Seizures, Developmental Delay, Mild Intellectual Disability, and Autism Spectrum Disorder",
"PRICKLE1-Related Distal Symmetric Polyneuropathy",
"PRICKLE1-Related Central Nervous System Malformations",
"Prickle-like protein 1",
"PRICKLE1",
"PRICKLE1-Related Disorders"
] |
Mario Mastrangelo, Caterina Caputi, Dario Esposito, Vincenzo Leuzzi
|
Summary Individuals with biallelic Individuals with heterozygous The diagnosis of a Once the
|
Non-PME seizures
Myoclonic seizures, developmental delay, mild intellectual disability, & autism spectrum disorder
Distal symmetric polyneuropathy
Central nervous system malformations
For other genetic causes of these phenotypes, see
• Non-PME seizures
• Myoclonic seizures, developmental delay, mild intellectual disability, & autism spectrum disorder
• Distal symmetric polyneuropathy
• Central nervous system malformations
## Diagnosis
Myoclonic seizures (lightning-like jerks)
Generalized convulsive seizures
Varying degrees of cognitive decline and motor impairment especially presenting with ataxia
Family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Autosomal dominant transmission or absence of a known family history does not preclude the diagnosis.
Seizures
Developmental delay / intellectual disability
Autism spectrum disorder
Central nervous system malformations
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
The
For an introduction to multigene panels click
An
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice-site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Myoclonic seizures (lightning-like jerks)
• Generalized convulsive seizures
• Varying degrees of cognitive decline and motor impairment especially presenting with ataxia
• Family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Autosomal dominant transmission or absence of a known family history does not preclude the diagnosis.
• Seizures
• Developmental delay / intellectual disability
• Autism spectrum disorder
• Central nervous system malformations
## Suggestive Findings
Myoclonic seizures (lightning-like jerks)
Generalized convulsive seizures
Varying degrees of cognitive decline and motor impairment especially presenting with ataxia
Family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Autosomal dominant transmission or absence of a known family history does not preclude the diagnosis.
Seizures
Developmental delay / intellectual disability
Autism spectrum disorder
Central nervous system malformations
• Myoclonic seizures (lightning-like jerks)
• Generalized convulsive seizures
• Varying degrees of cognitive decline and motor impairment especially presenting with ataxia
• Family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Autosomal dominant transmission or absence of a known family history does not preclude the diagnosis.
• Seizures
• Developmental delay / intellectual disability
• Autism spectrum disorder
• Central nervous system malformations
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
The
For an introduction to multigene panels click
An
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice-site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Individuals with biallelic
Individuals with heterozygous
Non-PME seizures including isolated myoclonic seizures and juvenile myoclonic epilepsy [
Myoclonic seizures, developmental delay, mild intellectual disability, and autism spectrum disorder [
Distal symmetric polyneuropathy consistent with Charcot-Marie-Tooth disease [
Central nervous system malformations: myelomeningocele, tethered cord, hydrocephalus, diastematomyelia, caudal agenesis, Chiari type II malformation, agenesis of the corpus callosum, ventriculomegaly, and polymicrogyria [
No longitudinal data on the natural history of
No genotype-phenotype correlations have been identified.
Prevalence for
Fewer than 50 individuals have been described with heterozygous
• Non-PME seizures including isolated myoclonic seizures and juvenile myoclonic epilepsy [
• Myoclonic seizures, developmental delay, mild intellectual disability, and autism spectrum disorder [
• Distal symmetric polyneuropathy consistent with Charcot-Marie-Tooth disease [
• Central nervous system malformations: myelomeningocele, tethered cord, hydrocephalus, diastematomyelia, caudal agenesis, Chiari type II malformation, agenesis of the corpus callosum, ventriculomegaly, and polymicrogyria [
## Clinical Description
Individuals with biallelic
Individuals with heterozygous
Non-PME seizures including isolated myoclonic seizures and juvenile myoclonic epilepsy [
Myoclonic seizures, developmental delay, mild intellectual disability, and autism spectrum disorder [
Distal symmetric polyneuropathy consistent with Charcot-Marie-Tooth disease [
Central nervous system malformations: myelomeningocele, tethered cord, hydrocephalus, diastematomyelia, caudal agenesis, Chiari type II malformation, agenesis of the corpus callosum, ventriculomegaly, and polymicrogyria [
No longitudinal data on the natural history of
• Non-PME seizures including isolated myoclonic seizures and juvenile myoclonic epilepsy [
• Myoclonic seizures, developmental delay, mild intellectual disability, and autism spectrum disorder [
• Distal symmetric polyneuropathy consistent with Charcot-Marie-Tooth disease [
• Central nervous system malformations: myelomeningocele, tethered cord, hydrocephalus, diastematomyelia, caudal agenesis, Chiari type II malformation, agenesis of the corpus callosum, ventriculomegaly, and polymicrogyria [
Individuals with biallelic
## Heterozygous
Individuals with heterozygous
Non-PME seizures including isolated myoclonic seizures and juvenile myoclonic epilepsy [
Myoclonic seizures, developmental delay, mild intellectual disability, and autism spectrum disorder [
Distal symmetric polyneuropathy consistent with Charcot-Marie-Tooth disease [
Central nervous system malformations: myelomeningocele, tethered cord, hydrocephalus, diastematomyelia, caudal agenesis, Chiari type II malformation, agenesis of the corpus callosum, ventriculomegaly, and polymicrogyria [
• Non-PME seizures including isolated myoclonic seizures and juvenile myoclonic epilepsy [
• Myoclonic seizures, developmental delay, mild intellectual disability, and autism spectrum disorder [
• Distal symmetric polyneuropathy consistent with Charcot-Marie-Tooth disease [
• Central nervous system malformations: myelomeningocele, tethered cord, hydrocephalus, diastematomyelia, caudal agenesis, Chiari type II malformation, agenesis of the corpus callosum, ventriculomegaly, and polymicrogyria [
## Prognosis
No longitudinal data on the natural history of
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Prevalence
Prevalence for
Fewer than 50 individuals have been described with heterozygous
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders of Interest in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; ASM = anti-seizure medication; EPM = epilepsy, progressive myoclonic; Mat = maternal; MERRF = myoclonus epilepsy with ragged-red fibers; MOI = mode of inheritance; PME = progressive myoclonic epilepsy
Except for
EPM1 is caused by either biallelic abnormal CCC-CGC-CCC-GCG dodecamer repeat expansions in
See also
•
•
•
•
•
•
•
•
•
•
•
•
•
•
## Management
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with
Neurologic eval
EEG
To evaluate progression of motor & cognitive impairment
To monitor efficacy of ASM
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
To inform affected persons & their families re nature, MOI, & implications of
To facilitate medical and personal decision making
Community or
Social work involvement for parental support;
Home nursing referral.
To improve quality of live, social integration, & family networking
ADL = activities of daily living; ASM = anti-seizure medication; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with
OT, psychomotricity/PT, & speech therapy
Consider adaptive devices to maintain/improve independence in mobility & feeding.
ASM incl valproic acid, clonazepam, zonisamide, & levetiracetam; valproate was particularly helpful in one family.
Education of parents/caregivers
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Recommended Surveillance for Individuals with
Developmental assessment incl speech, walking (mobility), coordination, & handwriting
Eval of school performance & emotional status
Avoid the following drugs, which could worsen myoclonic seizures:
Phenytoin [
Carbamezapine and oxycarbazepine [
Gabapentin, pregabalin, tiagabine, and vigabatrin [
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual to identify as early as possible those who would benefit from institution of treatment and preventive measures.
See
Search
• Neurologic eval
• EEG
• To evaluate progression of motor & cognitive impairment
• To monitor efficacy of ASM
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• To inform affected persons & their families re nature, MOI, & implications of
• To facilitate medical and personal decision making
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• OT, psychomotricity/PT, & speech therapy
• Consider adaptive devices to maintain/improve independence in mobility & feeding.
• ASM incl valproic acid, clonazepam, zonisamide, & levetiracetam; valproate was particularly helpful in one family.
• Education of parents/caregivers
• Developmental assessment incl speech, walking (mobility), coordination, & handwriting
• Eval of school performance & emotional status
• Phenytoin [
• Carbamezapine and oxycarbazepine [
• Gabapentin, pregabalin, tiagabine, and vigabatrin [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with
Neurologic eval
EEG
To evaluate progression of motor & cognitive impairment
To monitor efficacy of ASM
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
To inform affected persons & their families re nature, MOI, & implications of
To facilitate medical and personal decision making
Community or
Social work involvement for parental support;
Home nursing referral.
To improve quality of live, social integration, & family networking
ADL = activities of daily living; ASM = anti-seizure medication; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Neurologic eval
• EEG
• To evaluate progression of motor & cognitive impairment
• To monitor efficacy of ASM
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• To inform affected persons & their families re nature, MOI, & implications of
• To facilitate medical and personal decision making
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
OT, psychomotricity/PT, & speech therapy
Consider adaptive devices to maintain/improve independence in mobility & feeding.
ASM incl valproic acid, clonazepam, zonisamide, & levetiracetam; valproate was particularly helpful in one family.
Education of parents/caregivers
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
• OT, psychomotricity/PT, & speech therapy
• Consider adaptive devices to maintain/improve independence in mobility & feeding.
• ASM incl valproic acid, clonazepam, zonisamide, & levetiracetam; valproate was particularly helpful in one family.
• Education of parents/caregivers
## Surveillance
Recommended Surveillance for Individuals with
Developmental assessment incl speech, walking (mobility), coordination, & handwriting
Eval of school performance & emotional status
• Developmental assessment incl speech, walking (mobility), coordination, & handwriting
• Eval of school performance & emotional status
## Agents/Circumstances to Avoid
Avoid the following drugs, which could worsen myoclonic seizures:
Phenytoin [
Carbamezapine and oxycarbazepine [
Gabapentin, pregabalin, tiagabine, and vigabatrin [
• Phenytoin [
• Carbamezapine and oxycarbazepine [
• Gabapentin, pregabalin, tiagabine, and vigabatrin [
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual to identify as early as possible those who would benefit from institution of treatment and preventive measures.
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an individual with
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
If both parents of a proband with
To date, the heterozygous sibs of individuals with
An individual with an autosomal dominant
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with an autosomal dominant
Because reduced penetrance has been suggested in autosomal dominant
If the
If the parents have not been tested for the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an individual with
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents of a proband with
• To date, the heterozygous sibs of individuals with
• An individual with an autosomal dominant
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with an autosomal dominant
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Mode of Inheritance
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an individual with
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
If both parents of a proband with
To date, the heterozygous sibs of individuals with
• The parents of an individual with
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents of a proband with
• To date, the heterozygous sibs of individuals with
## Autosomal Dominant Inheritance – Risk to Family Members
An individual with an autosomal dominant
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with an autosomal dominant
Because reduced penetrance has been suggested in autosomal dominant
If the
If the parents have not been tested for the
• An individual with an autosomal dominant
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with an autosomal dominant
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
United Kingdom
•
•
•
• United Kingdom
•
•
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
PRICKLE1-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for PRICKLE1-Related Disorders (
The alterations of neuronal signaling and networking cascades in which
## Molecular Pathogenesis
The alterations of neuronal signaling and networking cascades in which
## Chapter Notes
Mario Mastrangelo, MD, PhDCaterina Caputi, MDDario Esposito, MDVincenzo Leuzzi, MD
Unit of Child Neurology and PsychiatryDepartment of Human NeuroscienceSapienza Università di RomaReferring Center for Rare and Complex Neurologic and Neurometabolic Pediatric Diseases
Department of Human Neuroscience
Unit of Child Neurology and Psychiatry
We acknowledge the patient association
Alexander G Bassuk, MD, PhD; University of Iowa (2009-2022)Caterina Caputi, MD (2022-present)Dario Esposito, MD (2022-present)Mark H Fox, MD; University of Iowa (2009-2022)Vincenzo Leuzzi, MD (2022-present)Mario Mastrangelo, MD, PhD (2022-present)
21 April 2022 (sw) Comprehensive update posted live
10 April 2014 (me) Comprehensive update posted live
10 January 2013 (cd) Revision: prenatal diagnosis available
8 December 2011 (me) Comprehensive update posted live
8 September 2009 (et) Review posted live
25 March 2009 (ab) Original submission
• 21 April 2022 (sw) Comprehensive update posted live
• 10 April 2014 (me) Comprehensive update posted live
• 10 January 2013 (cd) Revision: prenatal diagnosis available
• 8 December 2011 (me) Comprehensive update posted live
• 8 September 2009 (et) Review posted live
• 25 March 2009 (ab) Original submission
## Author Notes
Mario Mastrangelo, MD, PhDCaterina Caputi, MDDario Esposito, MDVincenzo Leuzzi, MD
Unit of Child Neurology and PsychiatryDepartment of Human NeuroscienceSapienza Università di RomaReferring Center for Rare and Complex Neurologic and Neurometabolic Pediatric Diseases
Department of Human Neuroscience
Unit of Child Neurology and Psychiatry
## Acknowledgments
We acknowledge the patient association
## Author History
Alexander G Bassuk, MD, PhD; University of Iowa (2009-2022)Caterina Caputi, MD (2022-present)Dario Esposito, MD (2022-present)Mark H Fox, MD; University of Iowa (2009-2022)Vincenzo Leuzzi, MD (2022-present)Mario Mastrangelo, MD, PhD (2022-present)
## Revision History
21 April 2022 (sw) Comprehensive update posted live
10 April 2014 (me) Comprehensive update posted live
10 January 2013 (cd) Revision: prenatal diagnosis available
8 December 2011 (me) Comprehensive update posted live
8 September 2009 (et) Review posted live
25 March 2009 (ab) Original submission
• 21 April 2022 (sw) Comprehensive update posted live
• 10 April 2014 (me) Comprehensive update posted live
• 10 January 2013 (cd) Revision: prenatal diagnosis available
• 8 December 2011 (me) Comprehensive update posted live
• 8 September 2009 (et) Review posted live
• 25 March 2009 (ab) Original submission
## References
## Literature Cited
|
[
"H Algahtani, F Al-Hakami, M Al-Shehri, B Shirah, MH Al-Qahtani, AA Abdulkareem, MI Naseer. A very rare form of autosomal dominant progressive myoclonus epilepsy caused by a novel variant in the PRICKLE1 gene.. Seizure. 2019;69:133-9",
"AG Bassuk, EH Sherr. A de novo mutation in PRICKLE1 in fetal agenesis of the corpus callosum and polymicrogyria.. J Neurogenet. 2015;29:174-7",
"CM Bosoi, V Capra, R Allache, VQ Trinh, P De Marco, E Merello, Z Kibar. Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects.. Hum Mutat. 2011;32:1371-5",
"R Eldridge, M Iivanainen, R Stern, T Koerber, BJ Wilder. \"Baltic\" myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin.. Lancet. 1983;2:838-42",
"H El-Shanti, A Daoud, AA Sadoon, SM Leal, S Chen, K Lee, R Spiegel. A distinct autosomal recessive ataxia maps to chromosome 12 in an inbred family from Jordan.. Brain Dev. 2006;28:353-7",
"Y Hata, K Yoshida, N Nishida. Sudden unexpected death with rare compound heterozygous variants in PRICKLE1.. Neurogenetics. 2019;20:39-43",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"C Liu, C Lin, DT Whitaker, H Bakeri, OV Bulgakov, P Liu, J Lei, L Dong, T Li, A Swaroop. Prickle1 is expressed in distinct cell populations of the central nervous system and contributes to neuronal morphogenesis.. Hum Mol Genet. 2013;22:2234-46",
"M Mastrangelo, M Tolve, M Martinelli, SP Di Noia, E Parrini, V Leuzzi. PRICKLE1-related early onset epileptic encephalopathy.. Am J Med Genet A. 2018;176:2841-5",
"D Pehlivan, CR Beck, Y Okamoto, T Harel, ZHC Akdemir, SN Jhangiani, JR Lupski. The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy.. Genet Med. 2016;18:443-51",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"R Straussberg, L Basel-Vanagaite, S Kivity, R Dabby, S Cirak, P Nurnberg, T Voit, M Mahajnah, D Inbar, GM Saifi, JR Lupski, V Delague, A Megarbane, A Richter, E Leshinsky, SF Berkovic. An autosomal recessive cerebellar ataxia syndrome with upward gaze palsy, neuropathy, and seizures.. Neurology. 2005;64:142-4",
"H Tao, JR Manak, L Sowers, X Mei, H Kiyonari, T Abe, NS Dahdaleh, T Yang, S Wu, S Chen, MH Fox, C Gurnett, T Montine, T Bird, LG Shaffer, JA Rosenfeld, J McConnell, S Madan-Khetarpal, E Berry-Kravis, H Griesbach, RP Saneto, MP Scott, D Antic, J Reed, R Boland, SN Ehaideb, H El-Shanti, VB Mahajan, PJ Ferguson, JD Axelrod, AE Lehesjoki, B Fritzsch, DC Slusarski, J Wemmie, N Ueno, AG Bassuk. Mutations in prickle orthologs cause seizures in flies, mice, and humans.. Am J Hum Genet. 2011;88:138-49",
"BP Todd, AG Bassuk. A de novo mutation in PRICKLE1 associated with myoclonic epilepsy and autism spectrum disorder.. J Neurogenet. 2018;32:313-15"
] |
8/9/2009
|
21/4/2022
|
10/1/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mecp2-dup
|
mecp2-dup
|
[
"Methyl-CpG-binding protein 2",
"MECP2",
"MECP2 Duplication Syndrome"
] |
Hilde Van Esch
|
Summary The diagnosis of
|
## Diagnosis
Severe-to-profound intellectual disability with limited or absent speech
Early-onset hypotonia with very slow motor development
Progressive spasticity predominantly of the lower limbs
Predisposition to infections manifest as recurrent respiratory infections (in 75% of affected males)
Epileptic seizures (in 50%)
Other variably present features including autistic features, gastrointestinal dysfunction, and mild facial dysmorphism
Note:
The diagnosis of
Note: Routine G-banded cytogenetic analysis only detects duplications of Xq28 (the chromosomal locus of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Duplications ranging from 0.3 to 4 Mb are found in 100% of affected males [
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Severe-to-profound intellectual disability with limited or absent speech
• Early-onset hypotonia with very slow motor development
• Progressive spasticity predominantly of the lower limbs
• Predisposition to infections manifest as recurrent respiratory infections (in 75% of affected males)
• Epileptic seizures (in 50%)
• Other variably present features including autistic features, gastrointestinal dysfunction, and mild facial dysmorphism
## Suggestive Findings
Severe-to-profound intellectual disability with limited or absent speech
Early-onset hypotonia with very slow motor development
Progressive spasticity predominantly of the lower limbs
Predisposition to infections manifest as recurrent respiratory infections (in 75% of affected males)
Epileptic seizures (in 50%)
Other variably present features including autistic features, gastrointestinal dysfunction, and mild facial dysmorphism
Note:
• Severe-to-profound intellectual disability with limited or absent speech
• Early-onset hypotonia with very slow motor development
• Progressive spasticity predominantly of the lower limbs
• Predisposition to infections manifest as recurrent respiratory infections (in 75% of affected males)
• Epileptic seizures (in 50%)
• Other variably present features including autistic features, gastrointestinal dysfunction, and mild facial dysmorphism
## Establishing the Diagnosis
The diagnosis of
Note: Routine G-banded cytogenetic analysis only detects duplications of Xq28 (the chromosomal locus of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Duplications ranging from 0.3 to 4 Mb are found in 100% of affected males [
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
## Clinical Characteristics
More than 300 affected males have been reported to date and the clinical findings are consistent in all reports [
Select Features of
In 65% of affected males, hypotonia gives way to spasticity in childhood. The spasticity is more pronounced in the legs; mild contractures may develop over time. Often the use of a wheelchair is necessary in adulthood.
Nonspecific neuroradiologic findings on brain MRI including hypoplasia of the corpus callosum, enlarged ventricles, nonspecific changes in the white matter, and cerebellar hypoplasia [
Autistic features including anxiety, stereotypic hand movements, and decreased sensitivity to pain/temperature [
Mottled appearance of the skin
Urogenital anomalies including bladder dysfunction, cryptorchidism, and small penis [
Most females heterozygous for
More recently, several symptomatic females with an Xq28 duplication without skewing of X-chromosome inactivation have been reported. In the majority of these females, the duplication arises from an unbalanced X-autosomal translocation or a genomic insertion elsewhere in the genome, explaining the absence of skewing of the aberrant X chromosome and leading to a complex and severe phenotype. To date, about 20 females have been described with an interstitial Xq28 duplication including
No clear genotype-phenotype correlation has been identified to date. However, the following have been noted:
Individuals with a large, cytogenetically visible Xq28 duplication have growth deficiency, microcephaly, and urogenital anomalies in addition to those findings described in
A more important correlation with clinical severity is
To date, more than 300 affected individuals have been reported [
• Nonspecific neuroradiologic findings on brain MRI including hypoplasia of the corpus callosum, enlarged ventricles, nonspecific changes in the white matter, and cerebellar hypoplasia [
• Autistic features including anxiety, stereotypic hand movements, and decreased sensitivity to pain/temperature [
• Mottled appearance of the skin
• Urogenital anomalies including bladder dysfunction, cryptorchidism, and small penis [
• Individuals with a large, cytogenetically visible Xq28 duplication have growth deficiency, microcephaly, and urogenital anomalies in addition to those findings described in
• A more important correlation with clinical severity is
## Clinical Description
More than 300 affected males have been reported to date and the clinical findings are consistent in all reports [
Select Features of
In 65% of affected males, hypotonia gives way to spasticity in childhood. The spasticity is more pronounced in the legs; mild contractures may develop over time. Often the use of a wheelchair is necessary in adulthood.
Nonspecific neuroradiologic findings on brain MRI including hypoplasia of the corpus callosum, enlarged ventricles, nonspecific changes in the white matter, and cerebellar hypoplasia [
Autistic features including anxiety, stereotypic hand movements, and decreased sensitivity to pain/temperature [
Mottled appearance of the skin
Urogenital anomalies including bladder dysfunction, cryptorchidism, and small penis [
Most females heterozygous for
More recently, several symptomatic females with an Xq28 duplication without skewing of X-chromosome inactivation have been reported. In the majority of these females, the duplication arises from an unbalanced X-autosomal translocation or a genomic insertion elsewhere in the genome, explaining the absence of skewing of the aberrant X chromosome and leading to a complex and severe phenotype. To date, about 20 females have been described with an interstitial Xq28 duplication including
• Nonspecific neuroradiologic findings on brain MRI including hypoplasia of the corpus callosum, enlarged ventricles, nonspecific changes in the white matter, and cerebellar hypoplasia [
• Autistic features including anxiety, stereotypic hand movements, and decreased sensitivity to pain/temperature [
• Mottled appearance of the skin
• Urogenital anomalies including bladder dysfunction, cryptorchidism, and small penis [
## Heterozygous Females
Most females heterozygous for
More recently, several symptomatic females with an Xq28 duplication without skewing of X-chromosome inactivation have been reported. In the majority of these females, the duplication arises from an unbalanced X-autosomal translocation or a genomic insertion elsewhere in the genome, explaining the absence of skewing of the aberrant X chromosome and leading to a complex and severe phenotype. To date, about 20 females have been described with an interstitial Xq28 duplication including
## Genotype-Phenotype Correlations
No clear genotype-phenotype correlation has been identified to date. However, the following have been noted:
Individuals with a large, cytogenetically visible Xq28 duplication have growth deficiency, microcephaly, and urogenital anomalies in addition to those findings described in
A more important correlation with clinical severity is
• Individuals with a large, cytogenetically visible Xq28 duplication have growth deficiency, microcephaly, and urogenital anomalies in addition to those findings described in
• A more important correlation with clinical severity is
## Penetrance
## Prevalence
To date, more than 300 affected individuals have been reported [
## Genetically Related (Allelic) Disorders
Other kinds of pathogenic variants and intragenic rearrangements of
## Differential Diagnosis
Because the phenotypic features associated with
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures, spasticity
Mobility, activities of daily living, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Consider need for positioning & mobility devices, disability parking placard.
PT w/attention to stretching exercises can help maintain joint range of motion & prevent secondary contractures, thus prolonging ability to walk.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Seizure treatment may require multidrug therapy.
Education of parents/caregivers
Treat infections (esp respiratory tract) immediately w/appropriate antibiotics.
All vaccines should be given.
If aspiration occurs, consider placement of a permanent gastrostomy.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, spasticity.
OT = occupational therapy; PT = physical therapy
See
Search
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures, spasticity
• Mobility, activities of daily living, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Consider need for positioning & mobility devices, disability parking placard.
• PT w/attention to stretching exercises can help maintain joint range of motion & prevent secondary contractures, thus prolonging ability to walk.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Seizure treatment may require multidrug therapy.
• Education of parents/caregivers
• Treat infections (esp respiratory tract) immediately w/appropriate antibiotics.
• All vaccines should be given.
• If aspiration occurs, consider placement of a permanent gastrostomy.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, spasticity.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures, spasticity
Mobility, activities of daily living, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures, spasticity
• Mobility, activities of daily living, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Consider need for positioning & mobility devices, disability parking placard.
PT w/attention to stretching exercises can help maintain joint range of motion & prevent secondary contractures, thus prolonging ability to walk.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Seizure treatment may require multidrug therapy.
Education of parents/caregivers
Treat infections (esp respiratory tract) immediately w/appropriate antibiotics.
All vaccines should be given.
If aspiration occurs, consider placement of a permanent gastrostomy.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Consider need for positioning & mobility devices, disability parking placard.
• PT w/attention to stretching exercises can help maintain joint range of motion & prevent secondary contractures, thus prolonging ability to walk.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Seizure treatment may require multidrug therapy.
• Education of parents/caregivers
• Treat infections (esp respiratory tract) immediately w/appropriate antibiotics.
• All vaccines should be given.
• If aspiration occurs, consider placement of a permanent gastrostomy.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, spasticity.
OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, spasticity.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The father of an affected male will not have
In a family with more than one affected individual, the mother of an affected male is either an obligate heterozygote for an interstitial
Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous for a
In the majority of males who have an interstitial
Recommendations for the evaluation of the mother of a male proband include molecular genetic testing for the
Typically, mothers who are heterozygous for a
If the mother of the proband has an interstitial
Males who inherit the
Females who inherit the
If the mother of the proband has a balanced structural chromosome rearrangement involving the Xq28 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
If a male proband represents a simplex case (i.e., a single occurrence in a family) and if testing of maternal leukocyte DNA does not detect a
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the causative genetic alteration has been identified in the proband.
Note: Females who are heterozygous for a
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young females who are carriers or are at risk of being carriers.
Once the
Note: X-inactivation analysis of amniotic cells is not informative because the X-inactivation pattern in amniotic cells may not correlate with X inactivation in the fetal body and brain.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have
• In a family with more than one affected individual, the mother of an affected male is either an obligate heterozygote for an interstitial
• Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous for a
• In the majority of males who have an interstitial
• Recommendations for the evaluation of the mother of a male proband include molecular genetic testing for the
• Typically, mothers who are heterozygous for a
• If the mother of the proband has an interstitial
• Males who inherit the
• Females who inherit the
• Males who inherit the
• Females who inherit the
• If the mother of the proband has a balanced structural chromosome rearrangement involving the Xq28 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• If a male proband represents a simplex case (i.e., a single occurrence in a family) and if testing of maternal leukocyte DNA does not detect a
• Males who inherit the
• Females who inherit the
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young females who are carriers or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The father of an affected male will not have
In a family with more than one affected individual, the mother of an affected male is either an obligate heterozygote for an interstitial
Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous for a
In the majority of males who have an interstitial
Recommendations for the evaluation of the mother of a male proband include molecular genetic testing for the
Typically, mothers who are heterozygous for a
If the mother of the proband has an interstitial
Males who inherit the
Females who inherit the
If the mother of the proband has a balanced structural chromosome rearrangement involving the Xq28 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
If a male proband represents a simplex case (i.e., a single occurrence in a family) and if testing of maternal leukocyte DNA does not detect a
• The father of an affected male will not have
• In a family with more than one affected individual, the mother of an affected male is either an obligate heterozygote for an interstitial
• Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous for a
• In the majority of males who have an interstitial
• Recommendations for the evaluation of the mother of a male proband include molecular genetic testing for the
• Typically, mothers who are heterozygous for a
• If the mother of the proband has an interstitial
• Males who inherit the
• Females who inherit the
• Males who inherit the
• Females who inherit the
• If the mother of the proband has a balanced structural chromosome rearrangement involving the Xq28 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• If a male proband represents a simplex case (i.e., a single occurrence in a family) and if testing of maternal leukocyte DNA does not detect a
• Males who inherit the
• Females who inherit the
## Heterozygote Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the causative genetic alteration has been identified in the proband.
Note: Females who are heterozygous for a
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young females who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young females who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Note: X-inactivation analysis of amniotic cells is not informative because the X-inactivation pattern in amniotic cells may not correlate with X inactivation in the fetal body and brain.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Netherlands
United Kingdom
•
• Netherlands
•
•
•
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
MECP2 Duplication Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MECP2 Duplication Syndrome (
Overexpression of the MeCP2 protein could have detrimental effects on brain development and function as shown in mouse models [
## Molecular Pathogenesis
Overexpression of the MeCP2 protein could have detrimental effects on brain development and function as shown in mouse models [
## Chapter Notes
Hilde Van Esch is a clinical geneticist and researcher with focus on genetics of intellectual disability and brain malformations.
The author's research has received funding from Fonds voor Wetenschappelijk Onderzoek, Vlaanderen.
21 May 2020 (sw) Comprehensive update posted live
9 October 2014 (me) Comprehensive update posted live
24 June 2010 (me) Comprehensive update posted live
18 January 2008 (me) Review posted live
12 October 2007 (hve) Original submission
• 21 May 2020 (sw) Comprehensive update posted live
• 9 October 2014 (me) Comprehensive update posted live
• 24 June 2010 (me) Comprehensive update posted live
• 18 January 2008 (me) Review posted live
• 12 October 2007 (hve) Original submission
## Author Notes
Hilde Van Esch is a clinical geneticist and researcher with focus on genetics of intellectual disability and brain malformations.
## Acknowledgments
The author's research has received funding from Fonds voor Wetenschappelijk Onderzoek, Vlaanderen.
## Revision History
21 May 2020 (sw) Comprehensive update posted live
9 October 2014 (me) Comprehensive update posted live
24 June 2010 (me) Comprehensive update posted live
18 January 2008 (me) Review posted live
12 October 2007 (hve) Original submission
• 21 May 2020 (sw) Comprehensive update posted live
• 9 October 2014 (me) Comprehensive update posted live
• 24 June 2010 (me) Comprehensive update posted live
• 18 January 2008 (me) Review posted live
• 12 October 2007 (hve) Original submission
## References
## Literature Cited
|
[
"EK Bijlsma, A Collins, FT Papa, MI Tejada, P Wheeler, EA Peeters, AC Gijsbers, JM van de Kamp, M Kriek, M Losekoot, AJ Broekma, JA Crolla, M Pollazzon, M Mucciolo, E Katzaki, V Disciglio, MI Ferreri, A Marozza, MA Mencarelli, C Castagnini, L Dosa, F Ariani, F Mari, R Canitano, G Hayek, MP Botella, B Gener, M Mínguez, A Renieri, CA Ruivenkamp. Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation.. Eur J Med Genet. 2012;55:404-13",
"AM Breman, MB Ramocki, SH Kang, M Williams, D Freedenberg, A Patel, PI Bader, SW Cheung. MECP2 duplications in six patients with complex sex chromosome rearrangements.. Eur J Hum Genet. 2011;19:409-15",
"M Chahrour, SY Jung, C Shaw, X Zhou, ST Wong, J Qin, HY Zoghbi. MeCP2, a key contributor to neurological disease, activates and represses transcription.. Science. 2008;320:1224-9",
"AL Collins, JM Levenson, AP Vilaythong, R Richman, DL Armstrong, JL Noebels, J David Sweatt, HY Zoghbi. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice.. Hum Mol Genet. 2004;13:2679-89",
"DR Connolly, Z Zhou. Genomic insights into MeCP2 function: a role for the maintenance of chromatin architecture.. Curr Opin Neurobiol. 2019;59:174-9",
"J Clayton-Smith, S Walters, E Hobson, E Burkitt-Wright, R Smith, A Toutain, J Amiel, S Lyonnet, S Mansour, D Fitzpatrick, R Ciccone, I Ricca, O Zuffardi, D. Donnai. Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance.. Eur J Hum Genet. 2009;17:434-43",
"D del Gaudio, P Fang, F Scaglia, PA Ward, WJ Craigen, DG Glaze, JL Neul, A Patel, JA Lee, M Irons, SA Berry, AA Pursley, TA Grebe, D Freedenberg, RA Martin, GE Hsich, JR Khera, NR Friedman, HY Zoghbi, CM Eng, JR Lupski, SW Beaudet al Cheung, BB Roa. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males.. Genet Med. 2006;8:784-92",
"B Echenne, A Roubertie, D Lugtenberg, T Kleefstra, BC Hamel, H Van Bokhoven, D Lacombe, C Philippe, P Jonveaux, AP de Brouwer. Neurologic aspects of MECP2 gene duplication in male patients.. Pediatr Neurol. 2009;41:187-91",
"S El Chehadeh, L Faivre, AL Mosca-Boidron, V Malan, J Amiel, M Nizon, R Touraine, F Prieur, L Pasquier, P Callier, M Lefebvre, N Marle, C Dubourg, S Julia, C Sarret, C Francannet, F Laffargue, O Boespflug-Tanguy, A David, B Isidor, C Le Caignec, J Vigneron, B Leheup, L Lambert, C Philippe, JM Cuisset, J Andrieux, G Plessis, A Toutain, A Goldenberg, V Cormier-Daire, M Rio, JP Bonnefont, J Thevenon, B Echenne, H Journel, A Afenjar, L Burglen, T Bienvenu, MC Addor, S Lebon, D Martinet, C Baumann, L Perrin, S Drunat, PS Jouk, F Devillard, C Coutton, D Lacombe, MA Delrue, N Philip, A Moncla, C Badens, N Perreton, A Masurel, C Thauvin-Robinet, V Des Portes, L Guibaud. Large national series of patients with Xq28 duplication involving MECP2: delineation of brain MRI abnormalities in 30 affected patients.. Am J Med Genet A. 2016;170A:116-29",
"S El Chehadeh, R Touraine, F Prieur, W Reardon, T Bienvenu, S Chantot-Bastaraud, M Doco-Fenzy, E Landais, C Philippe, N Marle, P Callier, AL Mosca-Boidron, F Mugneret, N Le Meur, A Goldenberg, AM Guerrot, P Chambon, V Satre, C Coutton, PS Jouk, F Devillard, K Dieterich, A Afenjar, L Burglen, ML Moutard, MC Addor, S Lebon, D Martinet, JL Alessandri, B Doray, M Miguet, D Devys, P Saugier-Veber, S Drunat, B Aral, V Kremer, S Rondeau, AC Tabet, J Thevenon, C Thauvin-Robinet, N Perreton, V Des Portes, L Faivre. Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?. Clin Genet. 2017;91:576-88",
"N Fieremans, M Bauters, S Belet, J Verbeeck, AC Jansen, S Seneca, F Roelens, E De Baere, P Marynen, G Froyen. De novo MECP2 duplications in two females with intellectual disability and unfavorable complete skewed X-inactivation.. Hum Genet. 2014;133:1359-67",
"MJ Friez, JR Jones, K Clarkson, H Lubs, D Abuelo, JA Bier, S Pai, R Simensen, C Williams, PF Giampietro, CE Schwartz, RE Stevenson. Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28.. Pediatrics. 2006;118:e1687-95",
"P Giudice-Nairn, J Downs, K Wong, D Wilson, D Ta, M Gattas, D Amor, E Thompson, C Kirrali-Borri, C Ellaway, H Leonard. The incidence, prevalence and clinical features of MECP2 duplication syndrome in Australian children.. J Paediatr Child Health. 2019;55:1315-22",
"S Honda, S Satomura, S Hayashi, I Imoto, E Nakagawa, Y Goto, J Inazawa. Concomitant microduplications of MECP2 and ATRX in male patients with severe mental retardation.. J Hum Genet. 2012;57:73-7",
"EP Kirk, V Malaty-Brevaud, N Martini, C Lacoste, N Levy, K Maclean, L Davies, N Philip, C Badens. The clinical variability of the MECP2 duplication syndrome: description of two families with duplications excluding L1CAM and FLNA.. Clin Genet. 2009;75:301-3",
"KL Lachlan, MN Collinson, RO Sandford, B van Zyl, PA Jacobs, NS Thomas. Functional disomy resulting from duplications of distal Xq in four unrelated patients.. Hum Genet. 2004;115:399-408",
"Z Lim, J Downs, K Wong, C Ellaway, H Leonard. Expanding the clinical picture of the MECP2 duplication syndrome.. Clin Genet. 2017;91:557-63",
"D Lugtenberg, T Kleefstra, AR Oudakker, WM Nillesen, HG Yntema, A Tzschach, M Raynaud, D Rating, H Journel, J Chelly, C Goizet, D Lacombe, JM Pedespan, B Echenne, G Tariverdian, D O'Rourke, MD King, A Green, M van Kogelenberg, H Van Esch, J Gecz, BC Hamel, H van Bokhoven, AP de Brouwer. Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy.. Eur J Hum Genet. 2009;17:444-53",
"D Marafi, B Suter, R Schultz, D Glaze, VN Pavlik, AM Goldman. Spectrum and time course of epilepsy and the associated cognitive decline in. Neurology. 2019;92:e108-e114",
"M Meins, J Lehmann, F Gerresheim, J Herchenbach, M Hagedorn, K Hameister, JT Epplen. Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome.. J Med Genet. 2005;42",
"M Miguet, L Faivre, J Amiel, M Nizon, R Touraine, F Prieur, L Pasquier, M Lefebvre, J Thevenon, C Dubourg, S Julia, C Sarret, G Remerand, C Francannet, F Laffargue, O Boespflug-Tanguy, A David, B Isidor, J Vigneron, B Leheup, L Lambert, C Philippe, M Béri-Dexheimer, JM Cuisset, J Andrieux, G Plessis, A Toutain, L Guibaud, V Cormier-Daire, M Rio, JP Bonnefont, B Echenne, H Journel, L Burglen, S Chantot-Bastaraud, T Bienvenu, C Baumann, L Perrin, S Drunat, PS Jouk, K Dieterich, F Devillard, D Lacombe, N Philip, S Sigaudy, A Moncla, C Missirian, C Badens, N Perreton, C Thauvin-Robinet. AChro-Puce R, Pedespan JM, Rooryck C, Goizet C, Vincent-Delorme C, Duban-Bedu B, Bahi-Buisson N, Afenjar A, Maincent K, Héron D, Alessandri JL, Martin-Coignard D, Lesca G, Rossi M, Raynaud M, Callier P, Mosca-Boidron AL, Marle N, Coutton C, Satre V, Caignec CL, Malan V, Romana S, Keren B, Tabet AC, Kremer V, Scheidecker S, Vigouroux A, Lackmy-Port-Lis M, Sanlaville D, Till M, Carneiro M, Gilbert-Dussardier B, Willems M, Van Esch H, Portes VD, El Chehadeh S. Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features.. J Med Genet. 2018;55:359-71",
"S Nageshappa, C Carromeu, CA Trujillo, P Mesci, I Espuny-Camacho, E Pasciuto, P Vanderhaeghen, CM Verfaillie, S Raitano, A Kumar, CM Carvalho, C Bagni, MB Ramocki, BH Araujo, LB Torres, JR Lupski, H Van Esch, AR Muotri. Altered neuronal network and rescue in a human MECP2 duplication model.. Mol Psychiatry. 2016;21:178-88",
"F Novara, A Simonati, F Sicca, R Battini, S Fiori, A Contaldo, L Criscuolo, O Zuffardi, R. Ciccone. MECP2 duplication phenotype in symptomatic females: report of three further cases.. Mol Cytogenet. 2014;7:10",
"A Pascual-Alonso, L Blasco, S Vidal, E Gean, P Rubio, M O'Callaghan, AF Martínez-Monseny, AA Castells, C Xiol, V Català, N Brandi, P Pacheco, C Ros, M Del Campo, E Guillén, S Ibañez, MJ Sánchez, P Lapunzina, J Nevado, F Santos, E Lloveras, JD Ortigoza-Escobar, MI Tejada, H Maortua, F Martínez, C Orellana, M Roselló, MA Mesas, M Obón, A Plaja, JA Fernández-Ramos, E Tizzano, R Marín, JL Peña-Segura, S Alcántara, J Armstrong. Molecular characterization of Spanish patients with MECP2 duplication syndrome.. Clin Genet. 2020;97:610-20",
"O Philippe, M Rio, V Malan, H Van Esch, G Baujat, N Bahi-Buisson, V Valayannopoulos, R Gesny, JP Bonnefont, A Munnich, G Froyen, J Amiel, N Boddaert, L Colleaux. NF-κB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications.. Eur J Hum Genet. 2013;21:195-9",
"TE Prescott, OK Rødningen, A Bjørnstad, A Stray-Pedersen. Two brothers with a microduplication including the MECP2 gene: rapid head growth in infancy and resolution of susceptibility to infection.. Clin Dysmorphol. 2009;18:78-82",
"MB Ramocki, HY Zoghbi. Failure of neuronal homeostasis results in common neuropsychiatric phenotypes.. Nature 2008;455:912-8",
"MB Ramocki, SU Peters, YJ Tavyev, F Zhang, CM Carvalho, CP Schaaf, R Richman, P Fang, DG Glaze, JR Lupski, HY Zoghbi. Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome.. Ann Neurol. 2009;66:771-82",
"V San Antonio-Arce, M Fenollar-Cortés, R Oancea Ionescu, T DeSantos-Moreno, J Gallego-Merlo, FJ Illana Cámara, MC Cotarelo Pérez. Child Neurol Open. 2016:3",
"D Sanlaville, M Prieur, MC de Blois, D Genevieve, JM Lapierre, C Ozilou, M Picq, P Gosset, N Morichon-Delvallez, A Munnich, V Cormier-Daire, G Baujat, S Romana, M Vekemans, C Turleau. Functional disomy of the Xq28 chromosome region.. Eur J Hum Genet 2005;13:579-85",
"JN Sanmann, DL Bishay, LJ Starr, CA Bell, DL Pickering, JM Stevens, SG Kahler, AH Olney, GB Schaefer, WG Sanger. Characterization of six novel patients with MECP2 duplications due to unbalanced rearrangements of the X chromosome.. Am J Med Genet A. 2012;158A:1285-91",
"J Scott Schwoerer, J Laffin, J Haun, G Raca, MJ Friez, PF Giampietro. MECP2 duplication: possible cause of severe phenotype in females.. Am J Med Genet A. 2014;164A:1029-34",
"MD Shahbazian, HY Zoghbi. Rett syndrome and MeCP2: linking epigenetics and neuronal function.. Am J Hum Genet. 2002;71:1259-72",
"S Shimada, N Okamoto, M Ito, Y Arai, K Momosaki, M Togawa, Y Maegaki, M Sugawara, K Shimojima, M Osawa, T. Yamamoto. MECP2 duplication syndrome in both genders.. Brain Dev. 2013;35:411-9",
"PJ Skene, RS Illingworth, S Webb, AR Kerr, KD James, DJ Turner, R Andrews, AP Bird. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state.. Mol Cell. 2010;37:457-68",
"M Smyk, E Obersztyn, B Nowakowska, M Nawara, SW Cheung, T Mazurczak, P Stankiewicz, E Bocian. Different-sized duplications of Xq28, including MECP2, in three males with mental retardation, absent or delayed speech, and recurrent infections.. Am J Med Genet B Neuropsychiatr Genet 2008;147B:799-806",
"SS Tang, D Fernandez, LP Lazarou, R Singh, P Fallon. MECP2 triplication in 3 brothers - a rarely described cause of familial neurological regression in boys.. Eur J Paediatr Neurol. 2012;16:209-12",
"H Van Esch, M Bauters, J Ignatius, M Jansen, M Raynaud, K Hollanders, D Lugtenberg, T Bienvenu, LR Jensen, J Gecz, C Moraine, P Marynen, JP Fryns, G Froyen. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males.. Am J Hum Genet 2005;77:442-53",
"M Velinov, A Novelli, H Gu, M Fenko, N Dolzhanskaya, L Bernardini, A Capalbo, B Dallapiccola, ES Jenkins, WT Brown. De novo 2.15 Mb terminal Xq duplication involving MECP2 but not L1CAM gene in a male patient with mental retardation.. Clin Dysmorphol 2009;18:9-12"
] |
18/1/2008
|
21/5/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mecr-dis
|
mecr-dis
|
[
"Mitochondrial Enoyl CoA Reductase Protein-Associated Neurodegeneration (MEPAN)",
"Mitochondrial Enoyl CoA Reductase Protein-Associated Neurodegeneration (MEPAN)",
"Enoyl-[acyl-carrier-protein] reductase, mitochondrial",
"MECR",
"MECR-Related Neurologic Disorder"
] |
Gali Heimer, Allison Gregory, Penelope Hogarth, Susan Hayflick, Bruria Ben Zeev
|
Summary The diagnosis of
|
## Diagnosis
To date no formal diagnostic criteria have been published for
Childhood-onset dystonia, chorea, and other movement disorders: ages 1-6.5 years
Childhood-onset optic atrophy: typically ages 4-12 years. Note that optic atrophy is not necessary to consider the diagnosis of
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and imaging findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other disorders of childhood-onset dystonia,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
n = 5 [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Childhood-onset dystonia, chorea, and other movement disorders: ages 1-6.5 years
• Childhood-onset optic atrophy: typically ages 4-12 years. Note that optic atrophy is not necessary to consider the diagnosis of
• For an introduction to multigene panels click
## Suggestive Findings
Childhood-onset dystonia, chorea, and other movement disorders: ages 1-6.5 years
Childhood-onset optic atrophy: typically ages 4-12 years. Note that optic atrophy is not necessary to consider the diagnosis of
• Childhood-onset dystonia, chorea, and other movement disorders: ages 1-6.5 years
• Childhood-onset optic atrophy: typically ages 4-12 years. Note that optic atrophy is not necessary to consider the diagnosis of
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and imaging findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other disorders of childhood-onset dystonia,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
n = 5 [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and imaging findings suggest the diagnosis of
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other disorders of childhood-onset dystonia,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
n = 5 [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
To date, the authors know of 13 individuals with
The motor disability and dysarthria progress with time. Severity may vary between affected individuals, even within the same family.
In a different family of two affected brothers (ages 5 and 6 years), one had progressive dystonia, spasticity, and ataxia whereas the other had predominantly hypotonia and neck muscle weakness; neither has walked independently [Family F; Author, unpublished observations].
In a third family with three affected sisters, the oldest (currently age 15 years) started walking at about age two years, then exhibited pronounced chorea from age 5.5 years and dystonia from age 12 years. The youngest (currently age 4 years) exhibited arm dystonia at age one year, walked independently at age 22 months, and currently manifests dystonia of all limbs and facial chorea. In contrast, the middle sister (currently age 5.5 years) started walking at age 12 months; neurologic examination revealed minimal dystonia of the left leg of which the parents had previously been unaware [Family G; Author, unpublished observations].
Onset of the movement disorder is during early childhood (12 months–6.5 years). However, a history of hypotonia, increased laxity, and delayed motor development from the first year of life is possible.
The motor disability gradually progresses; over time, some affected individuals require a walker or wheelchair for ambulation. Some with earlier onset and more rapid progression may never walk independently.
Speech fluency and intelligibility are progressively impaired due to dysarthria. In some cases (e.g., the three sisters in Family G) articulation may be impaired at onset of speech, whereas in other children (e.g., the two brothers in Family F) speech may never develop despite relative preservation of receptive language.
Cognition was unaffected or relatively spared in five of the seven reported by
Although the oldest of the three sisters in Family G was suspected of having polyneuropathy (areflexia and decreased sensation noted around age two years), these findings were not evident on more recent examination. Furthermore, conflicting results of two nerve conduction velocity (NCV) tests several years apart cast doubt on whether these findings resulted from polyneuropathy or were other manifestations of
To date, seizures and encephalopathy have not been reported.
Abnormal eye movements (nystagmus or roving eye movements) can also be seen.
No clear genotype-phenotype correlations have been observed. Of the 13 currently known affected individuals, 12 are compound heterozygotes with various combinations of a missense variant and nonsense variant, and one is a homozygote for a missense variant [
To the authors' knowledge, only 13 individuals from eight families have been diagnosed with
Unpublished results based on the
## Clinical Description
To date, the authors know of 13 individuals with
The motor disability and dysarthria progress with time. Severity may vary between affected individuals, even within the same family.
In a different family of two affected brothers (ages 5 and 6 years), one had progressive dystonia, spasticity, and ataxia whereas the other had predominantly hypotonia and neck muscle weakness; neither has walked independently [Family F; Author, unpublished observations].
In a third family with three affected sisters, the oldest (currently age 15 years) started walking at about age two years, then exhibited pronounced chorea from age 5.5 years and dystonia from age 12 years. The youngest (currently age 4 years) exhibited arm dystonia at age one year, walked independently at age 22 months, and currently manifests dystonia of all limbs and facial chorea. In contrast, the middle sister (currently age 5.5 years) started walking at age 12 months; neurologic examination revealed minimal dystonia of the left leg of which the parents had previously been unaware [Family G; Author, unpublished observations].
Onset of the movement disorder is during early childhood (12 months–6.5 years). However, a history of hypotonia, increased laxity, and delayed motor development from the first year of life is possible.
The motor disability gradually progresses; over time, some affected individuals require a walker or wheelchair for ambulation. Some with earlier onset and more rapid progression may never walk independently.
Speech fluency and intelligibility are progressively impaired due to dysarthria. In some cases (e.g., the three sisters in Family G) articulation may be impaired at onset of speech, whereas in other children (e.g., the two brothers in Family F) speech may never develop despite relative preservation of receptive language.
Cognition was unaffected or relatively spared in five of the seven reported by
Although the oldest of the three sisters in Family G was suspected of having polyneuropathy (areflexia and decreased sensation noted around age two years), these findings were not evident on more recent examination. Furthermore, conflicting results of two nerve conduction velocity (NCV) tests several years apart cast doubt on whether these findings resulted from polyneuropathy or were other manifestations of
To date, seizures and encephalopathy have not been reported.
Abnormal eye movements (nystagmus or roving eye movements) can also be seen.
## Genotype-Phenotype Correlations
No clear genotype-phenotype correlations have been observed. Of the 13 currently known affected individuals, 12 are compound heterozygotes with various combinations of a missense variant and nonsense variant, and one is a homozygote for a missense variant [
## Prevalence
To the authors' knowledge, only 13 individuals from eight families have been diagnosed with
Unpublished results based on the
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The differential diagnosis of
Disorders with Dystonia and MRI Signal Abnormality in the Basal Ganglia to Consider in the Differential Diagnosis of
Optic atrophy may develop.
Symptoms may worsen following febrile illness.
Seizures, encephalopathy, cognitive regression
↑ blood/CNS lactate
Signal abnormality in brain stem in addition to basal ganglia lesions
Cognition may be preserved.
Symptoms may worsen following febrile illness.
Macrocephaly & widening of Sylvian fissures on MRI
Episodes of acute encephalopathy w/dystonic crises
↑ urine glutaric acid & 3-OH-glutaric acid
Seizures, cardiomyopathy, cognitive regression
↑ urine D-2-hydroxyglutaric acid
Subependymal cysts on MRI
↑ blood/CNS lactate
Encephalopathy
Good response to high doses of biotin & thiamine
Signal abnormality in the brain stem on MRI
Characteristic MRI feature: caudate head atrophy
Parkinsonism common in juvenile form
Onset after 3rd decade (although childhood onset has been reported)
Cognitive & behavioral changes
Caudate atrophy on MRI (characteristic feature)
↑ creatine kinase & acanthocytes
Seizures (in almost half of affected persons)
Myoclonic epilepsy, behavioral changes, dementia
Atrophic changes in cerebellum & brain stem on MRI
Tremor, parkinsonism, behavioral changes
Liver disease
Kayser-Fleischer ring
Low serum ceruloplasmin & high urinary copper
Dysarthria is common.
Optic atrophy may be present.
Hyperintense T
Parkinsonism & neuropsychiatric abnormalities
Brain iron accumulations & (in some cases) accompanying cerebral & cerebellar atrophy on MRI
AD = autosomal dominant; AR = autosomal recessive; Mit = mitochondrial; MOI = mode of inheritance; XL = X-linked
In addition to dystonia and MRI findings of signal abnormality in the basal ganglia
Leigh syndrome, a heterogeneous group of disorders, is associated with pathogenic variants in more than 70 genes (nuclear and mitochondrial).
Pathogenic variants in
Huntington disease is caused by an expansion of 36 or more CAG trinucleotide repeats in
DRPLA = dentatorubral-pallidoluysian atrophy
NBIA = neurodegeneration with brain iron accumulation
NBIA is a heterogeneous group of disorders associated with pathogenic variants in at least ten genes (see
• Optic atrophy may develop.
• Symptoms may worsen following febrile illness.
• Seizures, encephalopathy, cognitive regression
• ↑ blood/CNS lactate
• Signal abnormality in brain stem in addition to basal ganglia lesions
• Cognition may be preserved.
• Symptoms may worsen following febrile illness.
• Macrocephaly & widening of Sylvian fissures on MRI
• Episodes of acute encephalopathy w/dystonic crises
• ↑ urine glutaric acid & 3-OH-glutaric acid
• Seizures, cardiomyopathy, cognitive regression
• ↑ urine D-2-hydroxyglutaric acid
• Subependymal cysts on MRI
• ↑ blood/CNS lactate
• Encephalopathy
• Good response to high doses of biotin & thiamine
• Signal abnormality in the brain stem on MRI
• Characteristic MRI feature: caudate head atrophy
• Parkinsonism common in juvenile form
• Onset after 3rd decade (although childhood onset has been reported)
• Cognitive & behavioral changes
• Caudate atrophy on MRI (characteristic feature)
• ↑ creatine kinase & acanthocytes
• Seizures (in almost half of affected persons)
• Myoclonic epilepsy, behavioral changes, dementia
• Atrophic changes in cerebellum & brain stem on MRI
• Tremor, parkinsonism, behavioral changes
• Liver disease
• Kayser-Fleischer ring
• Low serum ceruloplasmin & high urinary copper
• Dysarthria is common.
• Optic atrophy may be present.
• Hyperintense T
• Parkinsonism & neuropsychiatric abnormalities
• Brain iron accumulations & (in some cases) accompanying cerebral & cerebellar atrophy on MRI
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis
Incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
Medication management for dystonia
Rehab w/therapies & equipment needs assessment for dystonia, chorea, &/or ataxia
Incl eval of motor, speech/language, general cognitive, & vocational skills
Speech therapy & augmentative communication consultation for dysarthria
OT = occupational therapy; PT = physical therapy
The following are appropriate:
Visual aids can be used in cases of decreased visual acuity due to optic atrophy.
Physiotherapy can be used to maintain range of movement.
Occupational therapy can be used as appropriate to develop and maintain skills related to activities of daily living, which will vary across the life span.
Special aids such as braces, walkers, and wheelchairs can maintain/improve mobility.
Speech therapy, if speech dysarthria is present, and assessment for augmentative communication devices
Medications that may relieve dystonia, such as anticholinergic agents, baclofen, and benzodiazepines, can be considered.
Anticholinergic agents act peripherally on the neuromuscular junction, but can have a variety of adverse central nervous system (CNS) effects.
Baclofen, which works on GABA
Benzodiazepines, which are GABA
Deep brain stimulation (DBS): While some patients with severe dystonia are treated with DBS, experience with
Of the three sisters (Family G; Author, unpublished observations), two are treated for ADHD: one with Vyvanse® (lisdexamfetamine dimesylate), which seems to also improve her dystonia and dysarthria; the other with Adderall, which seems to improve her dystonia and balance.
The following are recommended:
Yearly eye examination to determine need for additional visual aids
Yearly neurologic assessment to determine need for additional interventions, including speech therapy
Disease progression is presumed to be exacerbated by stress or febrile illness; therefore, prevention of these – to the extent possible – is recommended.
One patient reported onset of significant new, long-term motor symptoms following extended anesthesia with propofol. As with other mitochondrial disorders, anesthetic considerations should be discussed with a patient's medical team prior to any surgical procedure [
In one of the sisters (Family G), a test dose of dopamine worsened her chorea significantly.
See
The pathomechanism of
Search
• Incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
• Medication management for dystonia
• Rehab w/therapies & equipment needs assessment for dystonia, chorea, &/or ataxia
• Incl eval of motor, speech/language, general cognitive, & vocational skills
• Speech therapy & augmentative communication consultation for dysarthria
• Visual aids can be used in cases of decreased visual acuity due to optic atrophy.
• Physiotherapy can be used to maintain range of movement.
• Occupational therapy can be used as appropriate to develop and maintain skills related to activities of daily living, which will vary across the life span.
• Special aids such as braces, walkers, and wheelchairs can maintain/improve mobility.
• Speech therapy, if speech dysarthria is present, and assessment for augmentative communication devices
• Medications that may relieve dystonia, such as anticholinergic agents, baclofen, and benzodiazepines, can be considered.
• Anticholinergic agents act peripherally on the neuromuscular junction, but can have a variety of adverse central nervous system (CNS) effects.
• Baclofen, which works on GABA
• Benzodiazepines, which are GABA
• Anticholinergic agents act peripherally on the neuromuscular junction, but can have a variety of adverse central nervous system (CNS) effects.
• Baclofen, which works on GABA
• Benzodiazepines, which are GABA
• Deep brain stimulation (DBS): While some patients with severe dystonia are treated with DBS, experience with
• Of the three sisters (Family G; Author, unpublished observations), two are treated for ADHD: one with Vyvanse® (lisdexamfetamine dimesylate), which seems to also improve her dystonia and dysarthria; the other with Adderall, which seems to improve her dystonia and balance.
• Anticholinergic agents act peripherally on the neuromuscular junction, but can have a variety of adverse central nervous system (CNS) effects.
• Baclofen, which works on GABA
• Benzodiazepines, which are GABA
• Yearly eye examination to determine need for additional visual aids
• Yearly neurologic assessment to determine need for additional interventions, including speech therapy
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis
Incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
Medication management for dystonia
Rehab w/therapies & equipment needs assessment for dystonia, chorea, &/or ataxia
Incl eval of motor, speech/language, general cognitive, & vocational skills
Speech therapy & augmentative communication consultation for dysarthria
OT = occupational therapy; PT = physical therapy
• Incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
• Medication management for dystonia
• Rehab w/therapies & equipment needs assessment for dystonia, chorea, &/or ataxia
• Incl eval of motor, speech/language, general cognitive, & vocational skills
• Speech therapy & augmentative communication consultation for dysarthria
## Treatment of Manifestations
The following are appropriate:
Visual aids can be used in cases of decreased visual acuity due to optic atrophy.
Physiotherapy can be used to maintain range of movement.
Occupational therapy can be used as appropriate to develop and maintain skills related to activities of daily living, which will vary across the life span.
Special aids such as braces, walkers, and wheelchairs can maintain/improve mobility.
Speech therapy, if speech dysarthria is present, and assessment for augmentative communication devices
Medications that may relieve dystonia, such as anticholinergic agents, baclofen, and benzodiazepines, can be considered.
Anticholinergic agents act peripherally on the neuromuscular junction, but can have a variety of adverse central nervous system (CNS) effects.
Baclofen, which works on GABA
Benzodiazepines, which are GABA
Deep brain stimulation (DBS): While some patients with severe dystonia are treated with DBS, experience with
Of the three sisters (Family G; Author, unpublished observations), two are treated for ADHD: one with Vyvanse® (lisdexamfetamine dimesylate), which seems to also improve her dystonia and dysarthria; the other with Adderall, which seems to improve her dystonia and balance.
• Visual aids can be used in cases of decreased visual acuity due to optic atrophy.
• Physiotherapy can be used to maintain range of movement.
• Occupational therapy can be used as appropriate to develop and maintain skills related to activities of daily living, which will vary across the life span.
• Special aids such as braces, walkers, and wheelchairs can maintain/improve mobility.
• Speech therapy, if speech dysarthria is present, and assessment for augmentative communication devices
• Medications that may relieve dystonia, such as anticholinergic agents, baclofen, and benzodiazepines, can be considered.
• Anticholinergic agents act peripherally on the neuromuscular junction, but can have a variety of adverse central nervous system (CNS) effects.
• Baclofen, which works on GABA
• Benzodiazepines, which are GABA
• Anticholinergic agents act peripherally on the neuromuscular junction, but can have a variety of adverse central nervous system (CNS) effects.
• Baclofen, which works on GABA
• Benzodiazepines, which are GABA
• Deep brain stimulation (DBS): While some patients with severe dystonia are treated with DBS, experience with
• Of the three sisters (Family G; Author, unpublished observations), two are treated for ADHD: one with Vyvanse® (lisdexamfetamine dimesylate), which seems to also improve her dystonia and dysarthria; the other with Adderall, which seems to improve her dystonia and balance.
• Anticholinergic agents act peripherally on the neuromuscular junction, but can have a variety of adverse central nervous system (CNS) effects.
• Baclofen, which works on GABA
• Benzodiazepines, which are GABA
## Surveillance
The following are recommended:
Yearly eye examination to determine need for additional visual aids
Yearly neurologic assessment to determine need for additional interventions, including speech therapy
• Yearly eye examination to determine need for additional visual aids
• Yearly neurologic assessment to determine need for additional interventions, including speech therapy
## Agents/Circumstances to Avoid
Disease progression is presumed to be exacerbated by stress or febrile illness; therefore, prevention of these – to the extent possible – is recommended.
One patient reported onset of significant new, long-term motor symptoms following extended anesthesia with propofol. As with other mitochondrial disorders, anesthetic considerations should be discussed with a patient's medical team prior to any surgical procedure [
In one of the sisters (Family G), a test dose of dopamine worsened her chorea significantly.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
The pathomechanism of
Search
## Genetic Counseling
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
MECR-Related Neurologic Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MECR-Related Neurologic Disorder (
Variants listed in the table have been provided by the authors.
See
## Chapter Notes
Dr Gali Heimer is a Senior Pediatric Neurologist and Director of the Angelman Clinic in the Pediatric Neurology Unit of the Edmond and Lily Safra Children's Hospital, and a member of the Talpiot Medical Leadership Program at the Sheba Medical Center.
Her clinical work and research focuses on neurogenetics: diagnosing known and novel genetic causes of rare neurologic diseases of childhood with emphasis on unraveling their pathomechanism and searching for therapeutic strategies.
The authors plan to test the effect of LA/C8 on cell lines from individuals with
9 May 2019 (bp) Review posted live
12 June 2017 (gh) Original submission
• 9 May 2019 (bp) Review posted live
• 12 June 2017 (gh) Original submission
## Author Notes
Dr Gali Heimer is a Senior Pediatric Neurologist and Director of the Angelman Clinic in the Pediatric Neurology Unit of the Edmond and Lily Safra Children's Hospital, and a member of the Talpiot Medical Leadership Program at the Sheba Medical Center.
Her clinical work and research focuses on neurogenetics: diagnosing known and novel genetic causes of rare neurologic diseases of childhood with emphasis on unraveling their pathomechanism and searching for therapeutic strategies.
The authors plan to test the effect of LA/C8 on cell lines from individuals with
## Revision History
9 May 2019 (bp) Review posted live
12 June 2017 (gh) Original submission
• 9 May 2019 (bp) Review posted live
• 12 June 2017 (gh) Original submission
## References
## Literature Cited
Magnetic resonance imaging of individuals with
A. T
B. T
C. Flair axial section demonstrating hyperintense signal in both putamen and caudate (arrows) (Family C, Patient II:8) [
|
[
"G Heimer, JM Kerätär, LG Riley, S Balasubramaniam, E Eyal, LP Pietikäinen, JK Hiltunen, D Marek-Yagel, J Hamada, A Gregory, C Rogers, P Hogarth, MA Nance, N Shalva, A Veber, M Tzadok, A Nissenkorn, D Tonduti, F Renaldo, I Kraoua, C Panteghini, L Valletta, B Garavaglia, MJ Cowley, V Gayevskiy, T Roscioli, JM Silberstein, C Hoffmann, A Raas-Rothschild, V Tiranti, Y Anikster, J Christodoulou, AJ Kastaniotis, B Ben-Zeev, SJ Hayflick. MECR mutations cause childhood-onset dystonia and optic atrophy, a mitochondrial fatty acid synthesis disorder.. Am J Hum Genet. 2016;99:1229-44",
"JK Hiltunen, MS Schonauer, KJ Autio, TM Mittelmeier, AJ Kastaniotis, CL Dieckmann. Mitochondrial fatty acid synthesis type II: more than just fatty acids.. J Biol Chem. 2009;284:9011-5",
"VA Kursu, LP Pietikäinen, F Fontanesi, MJ Aaltonen, F Suomi, R Raghavan Nair, MS Schonauer, CL Dieckmann, A Barrientos, JK Hiltunen, AJ Kastaniotis. Defects in mitochondrial fatty acid synthesis result in failure of multiple aspects of mitochondrial biogenesis in Saccharomyces cerevisiae.. Mol Microbiol. 2013;90:824-40",
"J Niezgoda, PG Morgan. Anesthetic considerations in patients with mitochondrial defects.. Paediatr Anaesth. 2013;23:785-93",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24"
] |
9/5/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
med13l
|
med13l
|
[
"MED13L Haploinsufficiency Syndrome",
"MED13L-Related Intellectual Disability",
"MED13L Haploinsufficiency Syndrome",
"MED13L-Related Intellectual Disability",
"Mediator of RNA polymerase II transcription subunit 13-like",
"MED13L",
"MED13L Syndrome"
] |
Alicia Nicole Campbell, Jennifer Bain, Steven James Doyle
|
Summary The diagnosis of
|
## Diagnosis
Mild-to-profound developmental delay
Intellectual disability of variable degree
Hypotonia
Neurobehavioral manifestations
Facial dysmorphisms. Depressed nasal bridge and bulbous nose, broad forehead, frontal bossing, up- or down-slanted palpebral fissures, large, low-set ears with prominent antihelix stem, short and deep philtrum, exaggerated Cupid's bow, macroglossia with hypotonic open mouth and/or tongue protrusion, and cleft or highly arched palate (See
Musculoskeletal features, ophthalmologic involvement, congenital heart defects, and seizures in some individuals
Ventriculomegaly (9/62 individuals)
Delayed or lack of myelination (6/62)
Thin or absent corpus callosum (5/62)
Periventricular foci and subcortical white matter abnormalities (7/62)
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
A few additional individuals with contiguous gene deletions and whole-gene duplications (not included in these calculations) have been reported (see
• Mild-to-profound developmental delay
• Intellectual disability of variable degree
• Hypotonia
• Neurobehavioral manifestations
• Facial dysmorphisms. Depressed nasal bridge and bulbous nose, broad forehead, frontal bossing, up- or down-slanted palpebral fissures, large, low-set ears with prominent antihelix stem, short and deep philtrum, exaggerated Cupid's bow, macroglossia with hypotonic open mouth and/or tongue protrusion, and cleft or highly arched palate (See
• Musculoskeletal features, ophthalmologic involvement, congenital heart defects, and seizures in some individuals
• Ventriculomegaly (9/62 individuals)
• Delayed or lack of myelination (6/62)
• Thin or absent corpus callosum (5/62)
• Periventricular foci and subcortical white matter abnormalities (7/62)
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Suggestive Findings
Mild-to-profound developmental delay
Intellectual disability of variable degree
Hypotonia
Neurobehavioral manifestations
Facial dysmorphisms. Depressed nasal bridge and bulbous nose, broad forehead, frontal bossing, up- or down-slanted palpebral fissures, large, low-set ears with prominent antihelix stem, short and deep philtrum, exaggerated Cupid's bow, macroglossia with hypotonic open mouth and/or tongue protrusion, and cleft or highly arched palate (See
Musculoskeletal features, ophthalmologic involvement, congenital heart defects, and seizures in some individuals
Ventriculomegaly (9/62 individuals)
Delayed or lack of myelination (6/62)
Thin or absent corpus callosum (5/62)
Periventricular foci and subcortical white matter abnormalities (7/62)
• Mild-to-profound developmental delay
• Intellectual disability of variable degree
• Hypotonia
• Neurobehavioral manifestations
• Facial dysmorphisms. Depressed nasal bridge and bulbous nose, broad forehead, frontal bossing, up- or down-slanted palpebral fissures, large, low-set ears with prominent antihelix stem, short and deep philtrum, exaggerated Cupid's bow, macroglossia with hypotonic open mouth and/or tongue protrusion, and cleft or highly arched palate (See
• Musculoskeletal features, ophthalmologic involvement, congenital heart defects, and seizures in some individuals
• Ventriculomegaly (9/62 individuals)
• Delayed or lack of myelination (6/62)
• Thin or absent corpus callosum (5/62)
• Periventricular foci and subcortical white matter abnormalities (7/62)
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
A few additional individuals with contiguous gene deletions and whole-gene duplications (not included in these calculations) have been reported (see
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Clinical Characteristics
Based on
PFO = patent foramen ovale; dTGA = dextro-loop transposition of the great arteries; CoA = coarctation of the aorta; pVSD = perimembranous ventricular septal defect
Hypotonia is common. Some individuals have facial hypotonia, including an open mouth and protruding tongue [
Speech and language development is delayed or completely lacking in most individuals (99%). Several individuals are able to follow short commands but lack expressive language [
No genotype-phenotype correlations have been identified; however, pathogenic missense variants appear to be associated with more severe manifestations, including severe motor delay, seizures, and autism / behavioral issues. A higher likelihood of absent speech (5/9), absent ambulation (4/9), seizures (5/9), and autistic features (5/8) were reported in individuals with
There are no reported individuals with a
To date, more than 100 published individuals have been identified with a pathogenic variant in
## Clinical Description
Based on
PFO = patent foramen ovale; dTGA = dextro-loop transposition of the great arteries; CoA = coarctation of the aorta; pVSD = perimembranous ventricular septal defect
Hypotonia is common. Some individuals have facial hypotonia, including an open mouth and protruding tongue [
Speech and language development is delayed or completely lacking in most individuals (99%). Several individuals are able to follow short commands but lack expressive language [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified; however, pathogenic missense variants appear to be associated with more severe manifestations, including severe motor delay, seizures, and autism / behavioral issues. A higher likelihood of absent speech (5/9), absent ambulation (4/9), seizures (5/9), and autistic features (5/8) were reported in individuals with
## Penetrance
There are no reported individuals with a
## Prevalence
To date, more than 100 published individuals have been identified with a pathogenic variant in
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
The phenotypic features associated with
Overlap in clinical features has been noted between
Selected Disorders in the Differential Diagnosis of
Bulbous nose w/depressed nasal bridge & deep philtrum
ID, speech delay
Hypotonia
ASD
Seizures
Structural abnormalities of brain
Macroglossia
ID, speech delay
Hypotonia
Congenital heart defects
Autistic features
Seizures
DD
Congenital heart defects
AD = autosomal dominant; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance
• Bulbous nose w/depressed nasal bridge & deep philtrum
• ID, speech delay
• Hypotonia
• ASD
• Seizures
• Structural abnormalities of brain
• Macroglossia
• ID, speech delay
• Hypotonia
• Congenital heart defects
• Autistic features
• Seizures
• DD
• Congenital heart defects
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI.
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Radial clubhand, clubfoot, metatarsus varus, & scoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
For congenital heart defects
To incl echocardiogram
To incl eval of aspiration risk & nutritional status
Assess impact of facial hypotonia, macroglossia, &/or protruding tongue on feeding.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Assess for hernia.
Assess for cryptorchidism &/or micropenis.
Referral to urologist &/or endocrinologist as needed
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatric/adult neurology, occupational therapy, audiology, speech-language pathology, clinical genetics, orthopedics, physical therapy, and mental health (see
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Gastronomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Physical medicine, OT/PT assessment of mobility, self-help skills
Clinical assessment for scoliosis w/radiographs as needed
ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider brain MRI.
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Radial clubhand, clubfoot, metatarsus varus, & scoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• For congenital heart defects
• To incl echocardiogram
• To incl eval of aspiration risk & nutritional status
• Assess impact of facial hypotonia, macroglossia, &/or protruding tongue on feeding.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Assess for hernia.
• Assess for cryptorchidism &/or micropenis.
• Referral to urologist &/or endocrinologist as needed
• Community or
• Social work involvement for parental support
• Home nursing referral
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Gastronomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Clinical assessment for scoliosis w/radiographs as needed
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI.
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Radial clubhand, clubfoot, metatarsus varus, & scoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
For congenital heart defects
To incl echocardiogram
To incl eval of aspiration risk & nutritional status
Assess impact of facial hypotonia, macroglossia, &/or protruding tongue on feeding.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Assess for hernia.
Assess for cryptorchidism &/or micropenis.
Referral to urologist &/or endocrinologist as needed
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider brain MRI.
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Radial clubhand, clubfoot, metatarsus varus, & scoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• For congenital heart defects
• To incl echocardiogram
• To incl eval of aspiration risk & nutritional status
• Assess impact of facial hypotonia, macroglossia, &/or protruding tongue on feeding.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Assess for hernia.
• Assess for cryptorchidism &/or micropenis.
• Referral to urologist &/or endocrinologist as needed
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatric/adult neurology, occupational therapy, audiology, speech-language pathology, clinical genetics, orthopedics, physical therapy, and mental health (see
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Gastronomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Gastronomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Neurobehavioral/Psychiatric Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Physical medicine, OT/PT assessment of mobility, self-help skills
Clinical assessment for scoliosis w/radiographs as needed
ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Clinical assessment for scoliosis w/radiographs as needed
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The majority of probands reported to date with
Rarely, individuals diagnosed with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and gonadal mosaicism for an
If a parent of the proband is known to have the
If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The majority of probands reported to date with
• Rarely, individuals diagnosed with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• If a parent of the proband is known to have the
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
The majority of probands reported to date with
Rarely, individuals diagnosed with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and gonadal mosaicism for an
If a parent of the proband is known to have the
If the
• The majority of probands reported to date with
• Rarely, individuals diagnosed with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• If a parent of the proband is known to have the
• If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
## Molecular Genetics
MED13L Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MED13L Syndrome (
Studies have also shown that
## Molecular Pathogenesis
Studies have also shown that
## Chapter Notes
Dr Alicia Campbell is actively involved in clinical and molecular biology research regarding individuals with
If there are questions related to diagnosis/management of
Additionally, contact Dr Reza Asadollahi (
Contact any of those listed above to inquire about review of
The authors would like to acknowledge the
10 April 2025 (sw) Review posted live
2 May 2024 (ac) Original submission
• 10 April 2025 (sw) Review posted live
• 2 May 2024 (ac) Original submission
## Author Notes
Dr Alicia Campbell is actively involved in clinical and molecular biology research regarding individuals with
If there are questions related to diagnosis/management of
Additionally, contact Dr Reza Asadollahi (
Contact any of those listed above to inquire about review of
## Acknowledgments
The authors would like to acknowledge the
## Revision History
10 April 2025 (sw) Review posted live
2 May 2024 (ac) Original submission
• 10 April 2025 (sw) Review posted live
• 2 May 2024 (ac) Original submission
## References
## Literature Cited
Characteristic facial features of individuals with
(a, b) Female age 22 years with low columella, short philtrum, retrognathia, and prominent antihelix stem
(c, d) Male age 33 years with mild bitemporal narrowing, upslanted palpebral fissures, midface retrusion, depressed nasal bridge, long nasal ridge, short philtrum, and micrognathia
(e, f) Female with similar facial features as that of her brother (c, d)
Reproduced with permission from
|
[] |
10/4/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
mef2c-dis
|
mef2c-dis
|
[
"MEF2C Deficiency",
"MEF2C Haploinsufficiency Syndrome (MCHS)",
"MEF2C-Related Neurodevelopmental Disorder",
"MEF2C-Related Syndrome",
"Neurodevelopmental Disorder with Hypotonia, Stereotypic Hand Movements, and Impaired Language (NEDHSIL)",
"MEF2C Deficiency",
"MEF2C Haploinsufficiency Syndrome (MCHS)",
"MEF2C-Related Neurodevelopmental Disorder",
"MEF2C-Related Syndrome",
"Neurodevelopmental Disorder with Hypotonia, Stereotypic Hand Movements, and Impaired Language (NEDHSIL)",
"Myocyte-specific enhancer factor 2C",
"MEF2C",
"MEF2C-Related Disorder"
] |
Jessica Cooley Coleman, Steven A Skinner
|
Summary The diagnosis of
|
## Diagnosis
Moderate-to-profound developmental delay (including lack of speech in 95% and inability to walk independently in 50%)
Profound intellectual disability
Hypotonia
Feeding/gastrointestinal issues (constipation, gastroesophageal reflux disease, feeding difficulties)
Dysmorphic facial features (broad forehead, prominent philtrum, tented upper lip, widely spaced teeth, large ears)
Seizures (febrile, infantile spasms, generalized tonic-clonic, myoclonic, and focal)
Neurobehavioral/psychiatric manifestations, including autistic features (decreased social interaction, stereotypic movements particularly of the hands, repetitive rocking and head shaking, hyperkinesis), bruxism, agitation, sleep issues, and high pain tolerance
Cardiac manifestations (ventricular septal defect, double outlet right ventricle, patent ductus arteriosus, pulmonary stenosis, and adult-onset dilated cardiomyopathy)
Vision issues (strabismus, refractive errors)
Hypoplastic corpus callosum
Mild thinning of the cortical white matter
Enlarged ventricles and other cerebrospinal fluid spaces (including the subarachnoid space and cortical sulcus)
Delay in myelination and mild undermyelination
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Sixty-four additional individuals with contiguous
• Moderate-to-profound developmental delay (including lack of speech in 95% and inability to walk independently in 50%)
• Profound intellectual disability
• Hypotonia
• Feeding/gastrointestinal issues (constipation, gastroesophageal reflux disease, feeding difficulties)
• Dysmorphic facial features (broad forehead, prominent philtrum, tented upper lip, widely spaced teeth, large ears)
• Seizures (febrile, infantile spasms, generalized tonic-clonic, myoclonic, and focal)
• Neurobehavioral/psychiatric manifestations, including autistic features (decreased social interaction, stereotypic movements particularly of the hands, repetitive rocking and head shaking, hyperkinesis), bruxism, agitation, sleep issues, and high pain tolerance
• Cardiac manifestations (ventricular septal defect, double outlet right ventricle, patent ductus arteriosus, pulmonary stenosis, and adult-onset dilated cardiomyopathy)
• Vision issues (strabismus, refractive errors)
• Hypoplastic corpus callosum
• Mild thinning of the cortical white matter
• Enlarged ventricles and other cerebrospinal fluid spaces (including the subarachnoid space and cortical sulcus)
• Delay in myelination and mild undermyelination
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Suggestive Findings
Moderate-to-profound developmental delay (including lack of speech in 95% and inability to walk independently in 50%)
Profound intellectual disability
Hypotonia
Feeding/gastrointestinal issues (constipation, gastroesophageal reflux disease, feeding difficulties)
Dysmorphic facial features (broad forehead, prominent philtrum, tented upper lip, widely spaced teeth, large ears)
Seizures (febrile, infantile spasms, generalized tonic-clonic, myoclonic, and focal)
Neurobehavioral/psychiatric manifestations, including autistic features (decreased social interaction, stereotypic movements particularly of the hands, repetitive rocking and head shaking, hyperkinesis), bruxism, agitation, sleep issues, and high pain tolerance
Cardiac manifestations (ventricular septal defect, double outlet right ventricle, patent ductus arteriosus, pulmonary stenosis, and adult-onset dilated cardiomyopathy)
Vision issues (strabismus, refractive errors)
Hypoplastic corpus callosum
Mild thinning of the cortical white matter
Enlarged ventricles and other cerebrospinal fluid spaces (including the subarachnoid space and cortical sulcus)
Delay in myelination and mild undermyelination
• Moderate-to-profound developmental delay (including lack of speech in 95% and inability to walk independently in 50%)
• Profound intellectual disability
• Hypotonia
• Feeding/gastrointestinal issues (constipation, gastroesophageal reflux disease, feeding difficulties)
• Dysmorphic facial features (broad forehead, prominent philtrum, tented upper lip, widely spaced teeth, large ears)
• Seizures (febrile, infantile spasms, generalized tonic-clonic, myoclonic, and focal)
• Neurobehavioral/psychiatric manifestations, including autistic features (decreased social interaction, stereotypic movements particularly of the hands, repetitive rocking and head shaking, hyperkinesis), bruxism, agitation, sleep issues, and high pain tolerance
• Cardiac manifestations (ventricular septal defect, double outlet right ventricle, patent ductus arteriosus, pulmonary stenosis, and adult-onset dilated cardiomyopathy)
• Vision issues (strabismus, refractive errors)
• Hypoplastic corpus callosum
• Mild thinning of the cortical white matter
• Enlarged ventricles and other cerebrospinal fluid spaces (including the subarachnoid space and cortical sulcus)
• Delay in myelination and mild undermyelination
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Sixty-four additional individuals with contiguous
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Clinical Characteristics
Select Features of
Based on
DCM = dilated cardiomyopathy; GERD = gastroesophageal reflux disease; PDA = patent ductus arteriosus; PFO = persistent foramen ovale; PS = pulmonary stenosis; VSD = ventricular septal defect
Regression after acquiring milestones is not common in individuals with
Duplex left kidney [
Tremors [
At least two individuals with a deletion encompassing only
Individuals with pathogenic variants affecting the proximal region of the MEF2C protein (e.g., within the MADS or MEF2 domains) may be more severely affected than individuals with more distal pathogenic variants [
Possible genotype-phenotype correlations associated with
Penetrance is 100%; all individuals who have a
The term "
The prevalence of
• Duplex left kidney [
• Tremors [
## Clinical Description
Select Features of
Based on
DCM = dilated cardiomyopathy; GERD = gastroesophageal reflux disease; PDA = patent ductus arteriosus; PFO = persistent foramen ovale; PS = pulmonary stenosis; VSD = ventricular septal defect
Regression after acquiring milestones is not common in individuals with
Duplex left kidney [
Tremors [
• Duplex left kidney [
• Tremors [
## Genotype-Phenotype Correlations
At least two individuals with a deletion encompassing only
Individuals with pathogenic variants affecting the proximal region of the MEF2C protein (e.g., within the MADS or MEF2 domains) may be more severely affected than individuals with more distal pathogenic variants [
Possible genotype-phenotype correlations associated with
## Penetrance
Penetrance is 100%; all individuals who have a
## Nomenclature
The term "
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The phenotypic features associated with
Classic Rett syndrome and Angelman syndrome can be considered in individuals presenting with stereotypic hand movements, intellectual disability, and seizures (see
Genes of Interest in the Differential Diagnosis of
Normal development for 1st 6-18 mos of life followed by regression
Absence of brain structural abnormalities on MRI
Persons w/Angelman syndrome seek eye contact.
Cardiac abnormalities are not typically reported.
DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
The risk to sibs of a proband depends on the genetic mechanism leading to the loss of
•
•
•
•
• Normal development for 1st 6-18 mos of life followed by regression
• Absence of brain structural abnormalities on MRI
• Persons w/Angelman syndrome seek eye contact.
• Cardiac abnormalities are not typically reported.
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Neurologic eval
Cognitive assessment
To incl brain MRI
Consider EEG if seizures are a concern.
To incl eval of aspiration risk & nutritional status
Assess for GERD & constipation.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Assess for recurrent respiratory infections &/or recurrent otitis.
Hearing eval in those w/recurrent otitis
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Many ASMs may be effective; Keppra
Education of parents/caregivers
Treatment per ophthalmologist for refractive errors, strabismus
Treatment per ophthalmic subspecialist for more complex findings
Antibiotics as needed for recurrent respiratory infections & recurrent otitis media
Referral to ENT for tympanostomy tubes as needed for recurrent otitis
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; H2 = histamine type 2; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Assess for recurrent respiratory infections &/or recurrent otitis media.
Hearing eval in those w/recurrent otitis
ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Neurologic eval
• Cognitive assessment
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl eval of aspiration risk & nutritional status
• Assess for GERD & constipation.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Assess for recurrent respiratory infections &/or recurrent otitis.
• Hearing eval in those w/recurrent otitis
• Community or
• Social work involvement for parental support
• Home nursing referral
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Many ASMs may be effective; Keppra
• Education of parents/caregivers
• Treatment per ophthalmologist for refractive errors, strabismus
• Treatment per ophthalmic subspecialist for more complex findings
• Antibiotics as needed for recurrent respiratory infections & recurrent otitis media
• Referral to ENT for tympanostomy tubes as needed for recurrent otitis
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Assess for recurrent respiratory infections &/or recurrent otitis media.
• Hearing eval in those w/recurrent otitis
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Neurologic eval
Cognitive assessment
To incl brain MRI
Consider EEG if seizures are a concern.
To incl eval of aspiration risk & nutritional status
Assess for GERD & constipation.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Assess for recurrent respiratory infections &/or recurrent otitis.
Hearing eval in those w/recurrent otitis
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Neurologic eval
• Cognitive assessment
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl eval of aspiration risk & nutritional status
• Assess for GERD & constipation.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Assess for recurrent respiratory infections &/or recurrent otitis.
• Hearing eval in those w/recurrent otitis
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Many ASMs may be effective; Keppra
Education of parents/caregivers
Treatment per ophthalmologist for refractive errors, strabismus
Treatment per ophthalmic subspecialist for more complex findings
Antibiotics as needed for recurrent respiratory infections & recurrent otitis media
Referral to ENT for tympanostomy tubes as needed for recurrent otitis
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; H2 = histamine type 2; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Many ASMs may be effective; Keppra
• Education of parents/caregivers
• Treatment per ophthalmologist for refractive errors, strabismus
• Treatment per ophthalmic subspecialist for more complex findings
• Antibiotics as needed for recurrent respiratory infections & recurrent otitis media
• Referral to ENT for tympanostomy tubes as needed for recurrent otitis
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Neurobehavioral/Psychiatric Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Assess for recurrent respiratory infections &/or recurrent otitis media.
Hearing eval in those w/recurrent otitis
ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Assess for recurrent respiratory infections &/or recurrent otitis media.
• Hearing eval in those w/recurrent otitis
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most probands reported to date with
Rarely, a proband diagnosed with
Heterozygous parent. Transmission of a
Parent with gonadal (or somatic and gonadal) mosaicism. Transmission of an
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
If a parent of the proband is known to have the
If the
Each child of an individual with
The majority of individuals with
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most probands reported to date with
• Rarely, a proband diagnosed with
• Heterozygous parent. Transmission of a
• Parent with gonadal (or somatic and gonadal) mosaicism. Transmission of an
• Heterozygous parent. Transmission of a
• Parent with gonadal (or somatic and gonadal) mosaicism. Transmission of an
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• Heterozygous parent. Transmission of a
• Parent with gonadal (or somatic and gonadal) mosaicism. Transmission of an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is known to have the
• If the
• Each child of an individual with
• The majority of individuals with
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
Most probands reported to date with
Rarely, a proband diagnosed with
Heterozygous parent. Transmission of a
Parent with gonadal (or somatic and gonadal) mosaicism. Transmission of an
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
If a parent of the proband is known to have the
If the
Each child of an individual with
The majority of individuals with
• Most probands reported to date with
• Rarely, a proband diagnosed with
• Heterozygous parent. Transmission of a
• Parent with gonadal (or somatic and gonadal) mosaicism. Transmission of an
• Heterozygous parent. Transmission of a
• Parent with gonadal (or somatic and gonadal) mosaicism. Transmission of an
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• Heterozygous parent. Transmission of a
• Parent with gonadal (or somatic and gonadal) mosaicism. Transmission of an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is known to have the
• If the
• Each child of an individual with
• The majority of individuals with
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
MEF2C-Related Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MEF2C-Related Disorder (
## Molecular Pathogenesis
## Chapter Notes
Dr Jessica Cooley Coleman (
Dr Steven A Skinner (
Contact Dr Cooley Coleman to inquire about review of
The authors would like to thank all individuals with
## Author Notes
Dr Jessica Cooley Coleman (
Dr Steven A Skinner (
Contact Dr Cooley Coleman to inquire about review of
## Acknowledgments
The authors would like to thank all individuals with
## References
## Literature Cited
|
[] |
12/12/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
megdel
|
megdel
|
[
"3-Methylglutaconic Aciduria with Deafness, Encephalopathy, and Leigh-like Syndrome",
"MEGDHEL Syndrome",
"SERAC1 Defect",
"MEGD(H)EL Syndrome (3-Methylglutaconic Aciduria with Deafness-Dystonia, [Hepatopathy], Encephalopathy, and Leigh-Like Syndrome)",
"Juvenile-Onset Complicated Hereditary Spastic Paraplegia (cHSP) with Mild Nonprogressive Intellectual Disability",
"SERAC1 Adult-Onset Generalized Dystonia",
"Protein SERAC1",
"SERAC1",
"SERAC1 Deficiency"
] |
SERAC1 Deficiency
|
Saskia B Wortmann, Arjan PM de Brouwer, Ron A Wevers, Eva Morava
|
Summary The phenotypic spectrum of SERAC1 deficiency comprises MEGD(H)EL syndrome (3- The diagnosis of SERAC1 deficiency is established in a proband with suggestive clinical and metabolic (3-methylglutaconic aciduria) findings and biallelic pathogenic variants in SERAC1 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the
|
MEGD(H)EL syndrome (3-
Juvenile-onset complicated hereditary spastic paraplegia (cHSP) with mild nonprogressive intellectual disability
Adult-onset generalized dystonia
For other genetic causes of these phenotypes, see
• MEGD(H)EL syndrome (3-
• Juvenile-onset complicated hereditary spastic paraplegia (cHSP) with mild nonprogressive intellectual disability
• Adult-onset generalized dystonia
## Diagnosis
SERAC1 deficiency
Transient hypoglycemia
Sepsis-like episodes without infection
Transient liver involvement ranging from undulating elevation of transaminases to prolonged hyperbilirubinemia and hyperammonemia and near-fatal liver failure
Feeding problems
Failure to thrive
Optic atrophy
Developmental delay followed by motor and cognitive regression
Progressive sensorineural hearing loss
Progressive dystonia
Progressive spasticity
Laboratory findings:
Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
Urinary Concentration of 3-MGA in MEGD(H)EL Syndrome
Reference range as used at the Laboratory for Genetic Endocrine and Metabolic Diseases (LGEM), Department of Laboratory Medicine, Radboud UMC Nijmegen, Nijmegen, the Netherlands
Cognitive delay
Spasticity manifesting as slowly progressive lower limb spasticity beginning in adolescence
Laboratory findings: 3-MGA excretion
Cognitive delay
Progressive generalized hyperkinetic movement disorder beginning in early adulthood (3rd decade)
Laboratory findings: variable degree of 3-MGA excretion
Bilateral basal ganglia involvement is seen on brain MRI (comparable to
Stage 0. Normal MRI
Stage 1. T
Stage 2. Swelling of the putamen and caudate nucleus. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease.
Stage 3. The putaminal eye increases, reflecting progressive putaminal involvement. This "eye" was found in all individuals with MEGD(H)EL syndrome during a specific age range (>1-4 years), and has not been reported in other disorders, making it pathognomonic for MEGD(H)EL syndrome and allowing diagnosis based on MRI findings.
Stage 4. Basal ganglia degeneration until near loss; cortical and cerebellar atrophy
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
The diagnosis of SERAC1 deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive laboratory findings described in
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SERAC1 Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A deletion of exons 5-8 has been reported [
• Transient hypoglycemia
• Sepsis-like episodes without infection
• Transient liver involvement ranging from undulating elevation of transaminases to prolonged hyperbilirubinemia and hyperammonemia and near-fatal liver failure
• Feeding problems
• Failure to thrive
• Optic atrophy
• Developmental delay followed by motor and cognitive regression
• Progressive sensorineural hearing loss
• Progressive dystonia
• Progressive spasticity
• Laboratory findings:
• Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
• Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
• Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
• Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
• Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
• Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
• Cognitive delay
• Spasticity manifesting as slowly progressive lower limb spasticity beginning in adolescence
• Laboratory findings: 3-MGA excretion
• Cognitive delay
• Progressive generalized hyperkinetic movement disorder beginning in early adulthood (3rd decade)
• Laboratory findings: variable degree of 3-MGA excretion
• Stage 0. Normal MRI
• Stage 1. T
• Stage 2. Swelling of the putamen and caudate nucleus. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease.
• Stage 3. The putaminal eye increases, reflecting progressive putaminal involvement. This "eye" was found in all individuals with MEGD(H)EL syndrome during a specific age range (>1-4 years), and has not been reported in other disorders, making it pathognomonic for MEGD(H)EL syndrome and allowing diagnosis based on MRI findings.
• Stage 4. Basal ganglia degeneration until near loss; cortical and cerebellar atrophy
## Suggestive Findings
SERAC1 deficiency
Transient hypoglycemia
Sepsis-like episodes without infection
Transient liver involvement ranging from undulating elevation of transaminases to prolonged hyperbilirubinemia and hyperammonemia and near-fatal liver failure
Feeding problems
Failure to thrive
Optic atrophy
Developmental delay followed by motor and cognitive regression
Progressive sensorineural hearing loss
Progressive dystonia
Progressive spasticity
Laboratory findings:
Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
Urinary Concentration of 3-MGA in MEGD(H)EL Syndrome
Reference range as used at the Laboratory for Genetic Endocrine and Metabolic Diseases (LGEM), Department of Laboratory Medicine, Radboud UMC Nijmegen, Nijmegen, the Netherlands
Cognitive delay
Spasticity manifesting as slowly progressive lower limb spasticity beginning in adolescence
Laboratory findings: 3-MGA excretion
Cognitive delay
Progressive generalized hyperkinetic movement disorder beginning in early adulthood (3rd decade)
Laboratory findings: variable degree of 3-MGA excretion
Bilateral basal ganglia involvement is seen on brain MRI (comparable to
Stage 0. Normal MRI
Stage 1. T
Stage 2. Swelling of the putamen and caudate nucleus. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease.
Stage 3. The putaminal eye increases, reflecting progressive putaminal involvement. This "eye" was found in all individuals with MEGD(H)EL syndrome during a specific age range (>1-4 years), and has not been reported in other disorders, making it pathognomonic for MEGD(H)EL syndrome and allowing diagnosis based on MRI findings.
Stage 4. Basal ganglia degeneration until near loss; cortical and cerebellar atrophy
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
• Transient hypoglycemia
• Sepsis-like episodes without infection
• Transient liver involvement ranging from undulating elevation of transaminases to prolonged hyperbilirubinemia and hyperammonemia and near-fatal liver failure
• Feeding problems
• Failure to thrive
• Optic atrophy
• Developmental delay followed by motor and cognitive regression
• Progressive sensorineural hearing loss
• Progressive dystonia
• Progressive spasticity
• Laboratory findings:
• Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
• Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
• Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
• Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
• Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
• Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
• Cognitive delay
• Spasticity manifesting as slowly progressive lower limb spasticity beginning in adolescence
• Laboratory findings: 3-MGA excretion
• Cognitive delay
• Progressive generalized hyperkinetic movement disorder beginning in early adulthood (3rd decade)
• Laboratory findings: variable degree of 3-MGA excretion
• Stage 0. Normal MRI
• Stage 1. T
• Stage 2. Swelling of the putamen and caudate nucleus. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease.
• Stage 3. The putaminal eye increases, reflecting progressive putaminal involvement. This "eye" was found in all individuals with MEGD(H)EL syndrome during a specific age range (>1-4 years), and has not been reported in other disorders, making it pathognomonic for MEGD(H)EL syndrome and allowing diagnosis based on MRI findings.
• Stage 4. Basal ganglia degeneration until near loss; cortical and cerebellar atrophy
## Three Main Clinical Phenotypes
Transient hypoglycemia
Sepsis-like episodes without infection
Transient liver involvement ranging from undulating elevation of transaminases to prolonged hyperbilirubinemia and hyperammonemia and near-fatal liver failure
Feeding problems
Failure to thrive
Optic atrophy
Developmental delay followed by motor and cognitive regression
Progressive sensorineural hearing loss
Progressive dystonia
Progressive spasticity
Laboratory findings:
Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
Urinary Concentration of 3-MGA in MEGD(H)EL Syndrome
Reference range as used at the Laboratory for Genetic Endocrine and Metabolic Diseases (LGEM), Department of Laboratory Medicine, Radboud UMC Nijmegen, Nijmegen, the Netherlands
Cognitive delay
Spasticity manifesting as slowly progressive lower limb spasticity beginning in adolescence
Laboratory findings: 3-MGA excretion
Cognitive delay
Progressive generalized hyperkinetic movement disorder beginning in early adulthood (3rd decade)
Laboratory findings: variable degree of 3-MGA excretion
• Transient hypoglycemia
• Sepsis-like episodes without infection
• Transient liver involvement ranging from undulating elevation of transaminases to prolonged hyperbilirubinemia and hyperammonemia and near-fatal liver failure
• Feeding problems
• Failure to thrive
• Optic atrophy
• Developmental delay followed by motor and cognitive regression
• Progressive sensorineural hearing loss
• Progressive dystonia
• Progressive spasticity
• Laboratory findings:
• Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
• Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
• Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
• Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
• Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see
• Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [
• Cognitive delay
• Spasticity manifesting as slowly progressive lower limb spasticity beginning in adolescence
• Laboratory findings: 3-MGA excretion
• Cognitive delay
• Progressive generalized hyperkinetic movement disorder beginning in early adulthood (3rd decade)
• Laboratory findings: variable degree of 3-MGA excretion
## Brain MRI
Bilateral basal ganglia involvement is seen on brain MRI (comparable to
Stage 0. Normal MRI
Stage 1. T
Stage 2. Swelling of the putamen and caudate nucleus. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease.
Stage 3. The putaminal eye increases, reflecting progressive putaminal involvement. This "eye" was found in all individuals with MEGD(H)EL syndrome during a specific age range (>1-4 years), and has not been reported in other disorders, making it pathognomonic for MEGD(H)EL syndrome and allowing diagnosis based on MRI findings.
Stage 4. Basal ganglia degeneration until near loss; cortical and cerebellar atrophy
• Stage 0. Normal MRI
• Stage 1. T
• Stage 2. Swelling of the putamen and caudate nucleus. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease.
• Stage 3. The putaminal eye increases, reflecting progressive putaminal involvement. This "eye" was found in all individuals with MEGD(H)EL syndrome during a specific age range (>1-4 years), and has not been reported in other disorders, making it pathognomonic for MEGD(H)EL syndrome and allowing diagnosis based on MRI findings.
• Stage 4. Basal ganglia degeneration until near loss; cortical and cerebellar atrophy
## Family History
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
## Establishing the Diagnosis
The diagnosis of SERAC1 deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive laboratory findings described in
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SERAC1 Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A deletion of exons 5-8 has been reported [
## Option 1
For an introduction to multigene panels click
## Option 2
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SERAC1 Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A deletion of exons 5-8 has been reported [
## Clinical Characteristics
To date, SERAC1 deficiency has been identified in more than 67 individuals with MEGD(H)EL syndrome (3-
Select Features of SERAC1 Deficiency
68% of affected persons never learn to walk.
58% never learn to speak.
Based on
The following clinical findings of SERAC1 deficiency are based on the combined personal experience of the authors as well as published data [
Most children with MEGD(H)EL syndrome present in the
During the
By
The
Communication is limited to the expression of comfort and discomfort; speech is absent.
Feeding is complicated by the movement disorder and often also by excessive drooling, often requiring tube feeding.
Some affected individuals have epilepsy which occurs either in the neonatal period or later in the disease course.
The length of survival varies. Some do not survive the neonatal period due to multiorgan failure, some succumb to liver failure in infancy, and others to (pulmonary) infections later in life. The oldest living affected individual is older than age 24 years.
Juvenile-onset paraspasticity, complicated by nonprogressive mild cognitive deficits, was observed in one family in which five of six affected sibs were homozygous for the splice site variant c.91+6T>C [
Three had a relatively benign cHSP disease course. Cognitive delay was detected at school age. None had a history of infantile feeding problems, liver failure, hearing loss, or truncal hypotonia. All were still able to walk several miles without assistance at age ten to 20 years, and the youngest sib did not show any motor problems at age ten years.
Only one of six, who was the most severely affected, showed signs of dystonia.
A man age 31 years (compound heterozygous for c.1347-1350dupATCT [p.Val451fs] and c.1598C.T [p.Pro533Leu]) is the only person with SERAC1 deficiency with this phenotype described to date [
Currently, no clear relationship exists between the type and position of the
The level of 3-methylglutaconic aciduria does not correlate with the clinical course.
The prevalence of MEGD(H)EL syndrome is estimated at 0.09:100,000 [
• 68% of affected persons never learn to walk.
• 58% never learn to speak.
• Three had a relatively benign cHSP disease course. Cognitive delay was detected at school age. None had a history of infantile feeding problems, liver failure, hearing loss, or truncal hypotonia. All were still able to walk several miles without assistance at age ten to 20 years, and the youngest sib did not show any motor problems at age ten years.
• Only one of six, who was the most severely affected, showed signs of dystonia.
## Clinical Description
To date, SERAC1 deficiency has been identified in more than 67 individuals with MEGD(H)EL syndrome (3-
Select Features of SERAC1 Deficiency
68% of affected persons never learn to walk.
58% never learn to speak.
Based on
The following clinical findings of SERAC1 deficiency are based on the combined personal experience of the authors as well as published data [
Most children with MEGD(H)EL syndrome present in the
During the
By
The
Communication is limited to the expression of comfort and discomfort; speech is absent.
Feeding is complicated by the movement disorder and often also by excessive drooling, often requiring tube feeding.
Some affected individuals have epilepsy which occurs either in the neonatal period or later in the disease course.
The length of survival varies. Some do not survive the neonatal period due to multiorgan failure, some succumb to liver failure in infancy, and others to (pulmonary) infections later in life. The oldest living affected individual is older than age 24 years.
Juvenile-onset paraspasticity, complicated by nonprogressive mild cognitive deficits, was observed in one family in which five of six affected sibs were homozygous for the splice site variant c.91+6T>C [
Three had a relatively benign cHSP disease course. Cognitive delay was detected at school age. None had a history of infantile feeding problems, liver failure, hearing loss, or truncal hypotonia. All were still able to walk several miles without assistance at age ten to 20 years, and the youngest sib did not show any motor problems at age ten years.
Only one of six, who was the most severely affected, showed signs of dystonia.
A man age 31 years (compound heterozygous for c.1347-1350dupATCT [p.Val451fs] and c.1598C.T [p.Pro533Leu]) is the only person with SERAC1 deficiency with this phenotype described to date [
• 68% of affected persons never learn to walk.
• 58% never learn to speak.
• Three had a relatively benign cHSP disease course. Cognitive delay was detected at school age. None had a history of infantile feeding problems, liver failure, hearing loss, or truncal hypotonia. All were still able to walk several miles without assistance at age ten to 20 years, and the youngest sib did not show any motor problems at age ten years.
• Only one of six, who was the most severely affected, showed signs of dystonia.
## Infantile, Severe MEGD(H)EL Syndrome
Most children with MEGD(H)EL syndrome present in the
During the
By
The
Communication is limited to the expression of comfort and discomfort; speech is absent.
Feeding is complicated by the movement disorder and often also by excessive drooling, often requiring tube feeding.
Some affected individuals have epilepsy which occurs either in the neonatal period or later in the disease course.
The length of survival varies. Some do not survive the neonatal period due to multiorgan failure, some succumb to liver failure in infancy, and others to (pulmonary) infections later in life. The oldest living affected individual is older than age 24 years.
## Milder Juvenile-Onset Complicated Hereditary Spastic Paraplegia (cHSP)
Juvenile-onset paraspasticity, complicated by nonprogressive mild cognitive deficits, was observed in one family in which five of six affected sibs were homozygous for the splice site variant c.91+6T>C [
Three had a relatively benign cHSP disease course. Cognitive delay was detected at school age. None had a history of infantile feeding problems, liver failure, hearing loss, or truncal hypotonia. All were still able to walk several miles without assistance at age ten to 20 years, and the youngest sib did not show any motor problems at age ten years.
Only one of six, who was the most severely affected, showed signs of dystonia.
• Three had a relatively benign cHSP disease course. Cognitive delay was detected at school age. None had a history of infantile feeding problems, liver failure, hearing loss, or truncal hypotonia. All were still able to walk several miles without assistance at age ten to 20 years, and the youngest sib did not show any motor problems at age ten years.
• Only one of six, who was the most severely affected, showed signs of dystonia.
## Adult-Onset Generalized Dystonia
A man age 31 years (compound heterozygous for c.1347-1350dupATCT [p.Val451fs] and c.1598C.T [p.Pro533Leu]) is the only person with SERAC1 deficiency with this phenotype described to date [
## Genotype-Phenotype Correlations
Currently, no clear relationship exists between the type and position of the
The level of 3-methylglutaconic aciduria does not correlate with the clinical course.
## Prevalence
The prevalence of MEGD(H)EL syndrome is estimated at 0.09:100,000 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of SERAC1 Deficiency
Early-onset dystonia, deafness, severe failure to thrive
Basal ganglia involvement visible on brain MRI in some
Movement disorder, epilepsy, 3-MGA-uria, & ↑ serum lactate common.
Characteristic metabolite profile: mild ↑ in urinary methylmalonic acid & serum acyl-carnitine ester abnormalities
Progressive deafness in infancy
Dystonia develops later in life; may develop in adulthood.
Basal ganglia lesions can be found on brain MRI.
Typically neonatal onset w/muscular hypotonia, hypertrophic cardiomyopathy, psychomotor disability, hyperammonemia, & lactic acidosis
Children surviving neonatal period later show DD.
Phenotypic spectrum is variable.
3-MGA-uria = 3-methylglutaconic aciduria; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
See also
* 3-MGA-uria is a discriminative feature of this disorder.
Seen in some affected persons
AUH defect is the only one of the five inborn errors of metabolism with 3-MGA-uria with a distinct biochemical finding: elevated urinary excretion of 3-hydroxyisovaleric acid (3-HIVA).
Increased C3- & C4-dicarboxyli-carnitine esters.
The phenotypic spectrum of TMEM70 defect is variable and becoming broader as more affected individuals are reported. At this time no specific syndromic presentation is evident.
3-MGA-uria is common in mitochondrial disorders [
• Early-onset dystonia, deafness, severe failure to thrive
• Basal ganglia involvement visible on brain MRI in some
• Movement disorder, epilepsy, 3-MGA-uria, & ↑ serum lactate common.
• Characteristic metabolite profile: mild ↑ in urinary methylmalonic acid & serum acyl-carnitine ester abnormalities
• Progressive deafness in infancy
• Dystonia develops later in life; may develop in adulthood.
• Basal ganglia lesions can be found on brain MRI.
• Typically neonatal onset w/muscular hypotonia, hypertrophic cardiomyopathy, psychomotor disability, hyperammonemia, & lactic acidosis
• Children surviving neonatal period later show DD.
• Phenotypic spectrum is variable.
## Management
To establish the extent of disease and needs in an individual diagnosed with SERAC1 deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SERAC1 Deficiency
Spasticity
Dystonia
Possible seizures, incl EEG
MRI if not performed previously
Motor, adaptive, cognitive, & speech/language
Need for early intervention / special education
Gross motor & fine motor skills;
Contractures, scoliosis;
Mobility, ADLs, & need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
Incl eval of aspiration risk & nutritional status.
Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
Community resources &
Social work involvement for parental support;
Home nursing referral.
ADLs = activities of daily living; ALAT = alanine aminotransferase; ASAT = aspartate aminotransferase; BAEP = brain stem auditory evoked potentials; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment is supportive. Care is best provided by a multidisciplinary team including a metabolic pediatrician, pediatric neurologist, dietician, and physical therapist when possible.
Treatment of Manifestations in Individuals with SERAC1 Deficiency
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Recommended Surveillance for Individuals with SERAC1 Deficiency
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Monitor developmental progress incl possibility of cognitive decline.
Monitor educational needs.
Medications known to impair mitochondrial function (e.g., valproic acid) should be avoided.
See
Search
• Spasticity
• Dystonia
• Possible seizures, incl EEG
• MRI if not performed previously
• Motor, adaptive, cognitive, & speech/language
• Need for early intervention / special education
• Gross motor & fine motor skills;
• Contractures, scoliosis;
• Mobility, ADLs, & need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• Incl eval of aspiration risk & nutritional status.
• Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
• Community resources &
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Monitor developmental progress incl possibility of cognitive decline.
• Monitor educational needs.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SERAC1 deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SERAC1 Deficiency
Spasticity
Dystonia
Possible seizures, incl EEG
MRI if not performed previously
Motor, adaptive, cognitive, & speech/language
Need for early intervention / special education
Gross motor & fine motor skills;
Contractures, scoliosis;
Mobility, ADLs, & need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
Incl eval of aspiration risk & nutritional status.
Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
Community resources &
Social work involvement for parental support;
Home nursing referral.
ADLs = activities of daily living; ALAT = alanine aminotransferase; ASAT = aspartate aminotransferase; BAEP = brain stem auditory evoked potentials; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Spasticity
• Dystonia
• Possible seizures, incl EEG
• MRI if not performed previously
• Motor, adaptive, cognitive, & speech/language
• Need for early intervention / special education
• Gross motor & fine motor skills;
• Contractures, scoliosis;
• Mobility, ADLs, & need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• Incl eval of aspiration risk & nutritional status.
• Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
• Community resources &
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment is supportive. Care is best provided by a multidisciplinary team including a metabolic pediatrician, pediatric neurologist, dietician, and physical therapist when possible.
Treatment of Manifestations in Individuals with SERAC1 Deficiency
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Surveillance
Recommended Surveillance for Individuals with SERAC1 Deficiency
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Monitor developmental progress incl possibility of cognitive decline.
Monitor educational needs.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Monitor developmental progress incl possibility of cognitive decline.
• Monitor educational needs.
## Agents/Circumstances to Avoid
Medications known to impair mitochondrial function (e.g., valproic acid) should be avoided.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
SERAC1 deficiency is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
To date, individuals with MEGD(H)EL syndrome are not known to reproduce.
Unless an affected individual's reproductive partner also has
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• To date, individuals with MEGD(H)EL syndrome are not known to reproduce.
• Unless an affected individual's reproductive partner also has
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
SERAC1 deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
To date, individuals with MEGD(H)EL syndrome are not known to reproduce.
Unless an affected individual's reproductive partner also has
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• To date, individuals with MEGD(H)EL syndrome are not known to reproduce.
• Unless an affected individual's reproductive partner also has
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
SERAC1 Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SERAC1 Deficiency (
Loss of SERAC1 in phospholipid remodeling has consequences for mitochondrial function and intracellular cholesterol trafficking. SERAC1 is involved in remodeling phosphatidylglycerol-34:1 (PG-34:1) to phosphatidylglycerol-36:1 (PG-36:1). PG-36:1 is the precursor for bis(monoacylglycerol)phosphate (BMP) and a precursor to cardiolipin-68:5. Loss of SERAC1 reduces PG-36:1 and lowers concentrations of BMP, leading to the accumulation of intracellular free cholesterol. In addition, the altered cardiolipin species distribution in the mitochondrial membranes likely causes the mitochondrial dysfunction.
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Loss of SERAC1 in phospholipid remodeling has consequences for mitochondrial function and intracellular cholesterol trafficking. SERAC1 is involved in remodeling phosphatidylglycerol-34:1 (PG-34:1) to phosphatidylglycerol-36:1 (PG-36:1). PG-36:1 is the precursor for bis(monoacylglycerol)phosphate (BMP) and a precursor to cardiolipin-68:5. Loss of SERAC1 reduces PG-36:1 and lowers concentrations of BMP, leading to the accumulation of intracellular free cholesterol. In addition, the altered cardiolipin species distribution in the mitochondrial membranes likely causes the mitochondrial dysfunction.
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Dr SB Wortmann and Prof RA Wevers are interested in patients with elevated urinary excretion of 3-methylglutaconic acid. Combining the clinical, biochemical, and neuroradiologic findings of these patients, they are able to define homogeneous subgroups on which they perform next-generation sequencing to unravel the underlying genetic disorders. This is followed by biochemical investigations to characterize the function of the affected protein.
23 July 2020 (bp) Comprehensive update posted live
17 April 2014 (me) Review posted live
17 January 2014 (adb) Original submission
• 23 July 2020 (bp) Comprehensive update posted live
• 17 April 2014 (me) Review posted live
• 17 January 2014 (adb) Original submission
## Author Notes
Dr SB Wortmann and Prof RA Wevers are interested in patients with elevated urinary excretion of 3-methylglutaconic acid. Combining the clinical, biochemical, and neuroradiologic findings of these patients, they are able to define homogeneous subgroups on which they perform next-generation sequencing to unravel the underlying genetic disorders. This is followed by biochemical investigations to characterize the function of the affected protein.
## Revision History
23 July 2020 (bp) Comprehensive update posted live
17 April 2014 (me) Review posted live
17 January 2014 (adb) Original submission
• 23 July 2020 (bp) Comprehensive update posted live
• 17 April 2014 (me) Review posted live
• 17 January 2014 (adb) Original submission
## References
## Literature Cited
|
[
"C Giron, E Roze, B Degos, A Méneret, C Jardel, A Lannuzel, F Mochel. Adult-onset generalized dystonia as the main manifestation of MEGDEL syndrome.. Tremor Other Hyperkinet Mov (N Y) 2018;8:554",
"T Harel, WH Yoon, C Garone, S Gu, Z Coban-Akdemir, MK Eldomery, JE Posey, SN Jhangiani, JA Rosenfeld, MT Cho, S Fox, M Withers, SM Brooks, T Chiang, L Duraine, S Erdin, B Yuan, Y Shao, E Moussallem, C Lamperti, MA Donati, JD Smith, HM McLaughlin, CM Eng, M Walkiewicz, F Xia, T Pippucci, P Magini, M Seri, M Zeviani, M Hirano, JV Hunter, M Srour, S Zanigni, RA Lewis, DM Muzny, TE Lotze, E Boerwinkle, RA Gibbs, SE Hickey, BH Graham, Y Yang, D Buhas, DM Martin, L Potocki, C Graziano, HJ Bellen, JR Lupski. Recurrent de novo and biallelic variation of ATAD3A, encoding a mitochondrial membrane protein, results in distinct neurological syndromes.. Am J Hum Genet. 2016;99:831-45",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"R Kovacs-Nagy, G Morin, MA Nouri, O Brandau, NW Saadi, MA Nouri, F van den Broek, H Prokisch, JA Mayr, SB Wortmann. HTRA2 defect: a recognizable inborn error of metabolism with 3-methylglutaconic aciduria as discriminating feature characterized by neonatal movement disorder and epilepsy-report of 11 patients.. Neuropediatrics. 2018;49:373-8",
"RR Maas, K Iwanicka-Pronicka, S Kalkan Ucar, B Alhaddad, M AlSayed, MA Al-Owain, HI Al-Zaidan, S Balasubramaniam, I Barić, DK Bubshait, A Burlina, J Christodoulou, WK Chung, R Colombo, N Darin, P Freisinger, MT Garcia Silva, S Grunewald, TB Haack, PM van Hasselt, O Hikmat, F Hörster, P Isohanni, K Ramzan, R Kovacs-Nagy, Z Krumina, E Martin-Hernandez, JA Mayr, P McClean, L De Meirleir, K Naess, LH Ngu, M Pajdowska, S Rahman, G Riordan, L Riley, B Roeben, F Rutsch, R Santer, M Schiff, M Seders, S Sequeira, W Sperl, C Staufner, M Synofzik, RW Taylor, J Trubicka, K Tsiakas, O Unal, E Wassmer, Y Wedatilake, T Wolff, H Prokisch, E Morava, E Pronicka, RA Wevers, AP de Brouwer, SB Wortmann. Progressive deafness-dystonia due to SERAC1 mutations: a study of 67 cases.. Ann Neurol. 2017;82:1004-15",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"B Roeben, R Schüle, S Ruf, B Bender, B Alhaddad, T Benkert, T Meitinger, S Reich, J Böhringer, CD Langhans, FM Vaz, SB Wortmann, T Marquardt, TB Haack, I Krägeloh-Mann, L Schöls, M Synofzik. SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family.. J Med Genet. 2018;55:39-47",
"O Sarig, D Goldsher, J Nousbeck, D Fuchs-Telem, K Cohen-Katsenelson, TC Iancu, I Manov, A Saada, E Sprecher, H Mandel. Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1.. Am J Med Genet A. 2013;161A:2204-15",
"J Tan, M Wagner, SL Stenton, TM Strom, SB Wortmann, H Prokisch, T Meitinger, K Oexle, T Klopstock. Lifetime risk of autosomal recessive mitochondrial disorders calculated from genetic databases.. EBioMedicine. 2020;54",
"F Tort, MT García-Silva, X Ferrer-Cortès, A Navarro-Sastre, J Garcia-Villoria, MJ Coll, E Vidal, J Jiménez-Almazán, J Dopazo, P Briones, O Elpeleg, A Ribes. Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.. Mol Genet Metab. 2013;110:73-7",
"S Wortmann, RJ Rodenburg, M Huizing, FJ Loupatty, T de Koning, LA Kluijtmans, U Engelke, R Wevers, JA Smeitink, E Morava. Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation.. Mol Genet Metab. 2006;88:47-52",
"SB Wortmann, M Duran, Y Anikster, PG Barth, W Sperl, J Zschocke, E Morava, RA Wevers. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature.. J Inherit Metab Dis. 2013a;36:923-8",
"SB Wortmann, LA Kluijtmans, UF Engelke, RA Wevers, E Morava. The 3-methylglutaconic acidurias: what's new?. J Inherit Metab Dis. 2012a;35:13-22",
"SB Wortmann, LA Kluijtmans, RJ Rodenburg, JO Sass, J Nouws, EP van Kaauwen, T Kleefstra, L Tranebjaerg, MC de Vries, P Isohanni, K Walter, FS Alkuraya, I Smuts, CJ Reinecke, FH van der Westhuizen, D Thorburn, JA Smeitink, E Morava, RA Wevers. 3-Methylglutaconic aciduria--lessons from 50 genes and 977 patients.. J Inherit Metab Dis. 2013b;36:913-21",
"SB Wortmann, BH Kremer, A Graham, MA Willemsen, FJ Loupatty, SL Hogg, UF Engelke, LA Kluijtmans, RJ Wanders, S Illsinger, B Wilcken, JR Cruysberg, AM Das, E Morava, RA Wevers. 3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy.. Neurology. 2010;75:1079-83",
"SB Wortmann, JA Mayr, JM Nuoffer, H Prokisch, W Sperl. A guideline for the diagnosis of pediatric mitochondrial disease: the value of muscle and skin biopsies in the genetics era.. Neuropediatrics. 2017;48:309-14",
"SB Wortmann, RJ Rodenburg, A Jonckheere, MC de Vries, M Huizing, K Heldt, LP van den Heuvel, U Wendel, LA Kluijtmans, UF Engelke, RA Wevers, JA Smeitink, E Morava. Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy.. Brain. 2009;132:136-46",
"SB Wortmann, PM van Hasselt, I Barić, A Burlina, N Darin, F Hörster, M Coker, SK Ucar, Z Krumina, K Naess, LH Ngu, E Pronicka, G Riordan, R Santer, E Wassmer, J Zschocke, M Schiff, L de Meirleir, MA Alowain, JA Smeitink, E Morava, T Kozicz, RA Wevers, NI Wolf, MA Willemsen. Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome.. Neuropediatrics. 2015;46:98-103",
"SB Wortmann, FM Vaz, T Gardeitchik, LE Vissers, GH Renkema, JH Schuurs-Hoeijmakers, W Kulik, M Lammens, C Christin, LA Kluijtmans, RJ Rodenburg, LG Nijtmans, A Grünewald, C Klein, JM Gerhold, T Kozicz, PM van Hasselt, M Harakalova, W Kloosterman, I Barić, E Pronicka, SK Ucar, K Naess, KK Singhal, Z Krumina, C Gilissen, H van Bokhoven, JA Veltman, JA Smeitink, DJ Lefeber, JN Spelbrink, RA Wevers, E Morava, AP de Brouwer. Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.. Nat Genet. 2012b;44:797-802"
] |
17/4/2014
|
23/7/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
melas
|
melas
|
[
"Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes",
"MELAS, MT-ND6-Related",
"MELAS, MT-ND1-Related",
"MELAS, MT-TK-Related",
"MELAS, MT-TS1-Related",
"MELAS, MT-ND5-Related",
"MELAS, MT-TL1-Related",
"MELAS, MT-TS2-Related",
"MELAS, MT-TF-Related",
"MELAS, MT-TQ-Related",
"MELAS, MT-TH-Related",
"Cytochrome b",
"Cytochrome c oxidase subunit 2",
"Cytochrome c oxidase subunit 3",
"NADH-ubiquinone oxidoreductase chain 1",
"NADH-ubiquinone oxidoreductase chain 5",
"NADH-ubiquinone oxidoreductase chain 6",
"Not applicable",
"MT-CO2",
"MT-CO3",
"MT-CYB",
"MT-ND1",
"MT-ND5",
"MT-ND6",
"MT-TC",
"MT-TF",
"MT-TH",
"MT-TK",
"MT-TL1",
"MT-TL2",
"MT-TQ",
"MT-TS1",
"MT-TS2",
"MT-TV",
"MT-TW",
"MELAS"
] |
MELAS
|
Ayman W El-Hattab, Mohammed Almannai, Fernando Scaglia
|
Summary MELAS ( The diagnosis of MELAS is based on meeting clinical diagnostic criteria and identifying a pathogenic variant in one of the genes associated with MELAS. The m.3243A>G pathogenic variant in the mitochondrial gene MELAS is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance. The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. A man with a mtDNA pathogenic variant cannot transmit the variant to any of his offspring. A woman with a mtDNA pathogenic variant (whether symptomatic or asymptomatic) transmits the variant to all of her offspring. Prenatal testing and preimplantation genetic testing for MELAS is possible if a mtDNA pathogenic variant has been detected in the mother. However, because the mutational load in embryonic and fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of all fetal tissues, and because the mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation, prediction of the phenotype from prenatal studies cannot be made with certainty.
|
## Diagnosis
Clinical diagnostic criteria for MELAS (
MELAS (
Stroke-like episodes before the age of 40 years
Acquired encephalopathy with seizures and/or dementia
Recurrent headaches
Muscle weakness and exercise intolerance
Cortical vision loss
Hemiparesis
Recurrent vomiting
Short stature
Hearing impairment
Normal early psychomotor development
Peripheral neuropathy
Learning disability
During the stroke-like episodes, the affected areas:
Have increased T
Do not correspond to the classic vascular distribution (hence the term "stroke-like");
Are asymmetric;
Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
Can be restricted to cortical areas or involve subcortical white matter [
Slow spreading of the stroke-like lesions occurs in the weeks following the first symptoms, typically documented by T
Diffusion-weighted MRI shows increased apparent diffusion coefficient (ADC) in the stroke-like lesions of MELAS, in contrast to the decreased ADC seen in ischemic strokes [
MR angiography is usually normal and MR spectroscopy shows decreased N-acetylaspartate signals and accumulation of lactate [
Findings are consistent with a myopathic process, but neuropathy may coexist. Neuropathy can be axonal or mixed axonal and demyelinating [
Lactic acidemia is not specific for MELAS syndrome as it can occur in other mitochondrial diseases, metabolic diseases, and systemic illness. Other situations (unrelated to the diagnosis of MELAS) in which lactate can be elevated are acute neurologic events such as seizure or stroke. On the other hand, lactate level can be normal in a minority of individuals with MELAS syndrome [
Ragged red fibers (RRFs) with the modified Gomori trichrome stain, which represent mitochondrial proliferation below the plasma membrane of the muscular fibers causing the contour of the muscle fiber to become irregular. These proliferated mitochondria also stain strongly with the succinate dehydrogenase (SDH) stain giving the appearance of ragged blue fibers.
Although RRFs are present in many other mitochondrial diseases e.g., MERRF (myoclonic epilepsy with ragged red fibers), most of the RRFs in MELAS stain positively with the cytochrome
An overabundance of mitochondria in smooth muscle and endothelial cells of intramuscular blood vessels, best revealed with the SDH stain ("strongly succinate dehydrogenase-reactive blood vessels," or SSVs)
Respiratory chain studies on muscle tissue: typically multiple partial defects, especially involving complex I and/or complex IV. However, biochemical results can also be normal.
Note: Muscle biopsy is not required to make this diagnosis; molecular genetic testing is frequently used in lieu of muscle biopsy to
Two sets of clinical diagnostic criteria for MELAS (
A clinical diagnosis of MELAS can be made if the following three criteria are met [
Stroke-like episodes before age 40 years
Encephalopathy characterized by seizures and/or dementia
Mitochondrial myopathy is evident by the presence of lactic acidosis and/or ragged-red fibers (RRFs) on muscle biopsy.
Normal early psychomotor development
Recurrent headaches
Recurrent vomiting episodes
A clinical diagnosis of MELAS can also be made in an individual with at least two category A
Headaches with vomiting
Seizures
Hemiplegia
Cortical blindness
Acute focal lesions on neuroimaging (See Suggestive Findings,
High plasma or cerebrospinal fluid (CSF) lactate
Mitochondrial abnormalities on muscle biopsy (See Suggestive Findings,
A MELAS-related pathogenic variant (See
The diagnosis of MELAS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of MELAS, molecular genetic testing approaches can include
Typically, blood leukocyte DNA is initially tested for the
If this is normal, targeted testing for the pathogenic variants
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and weakness,
For an introduction to comprehensive genomic testing click
Genetic Causes of MELAS
Pathogenic variants of any one of the genes included in this table account for >1% of MELAS.
Genes are listed from most frequent to least frequent genetic cause of MELAS.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
• Stroke-like episodes before the age of 40 years
• Acquired encephalopathy with seizures and/or dementia
• Recurrent headaches
• Muscle weakness and exercise intolerance
• Cortical vision loss
• Hemiparesis
• Recurrent vomiting
• Short stature
• Hearing impairment
• Normal early psychomotor development
• Peripheral neuropathy
• Learning disability
• During the stroke-like episodes, the affected areas:
• Have increased T
• Do not correspond to the classic vascular distribution (hence the term "stroke-like");
• Are asymmetric;
• Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
• Can be restricted to cortical areas or involve subcortical white matter [
• Have increased T
• Do not correspond to the classic vascular distribution (hence the term "stroke-like");
• Are asymmetric;
• Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
• Can be restricted to cortical areas or involve subcortical white matter [
• Slow spreading of the stroke-like lesions occurs in the weeks following the first symptoms, typically documented by T
• Diffusion-weighted MRI shows increased apparent diffusion coefficient (ADC) in the stroke-like lesions of MELAS, in contrast to the decreased ADC seen in ischemic strokes [
• MR angiography is usually normal and MR spectroscopy shows decreased N-acetylaspartate signals and accumulation of lactate [
• Have increased T
• Do not correspond to the classic vascular distribution (hence the term "stroke-like");
• Are asymmetric;
• Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
• Can be restricted to cortical areas or involve subcortical white matter [
• Ragged red fibers (RRFs) with the modified Gomori trichrome stain, which represent mitochondrial proliferation below the plasma membrane of the muscular fibers causing the contour of the muscle fiber to become irregular. These proliferated mitochondria also stain strongly with the succinate dehydrogenase (SDH) stain giving the appearance of ragged blue fibers.
• Although RRFs are present in many other mitochondrial diseases e.g., MERRF (myoclonic epilepsy with ragged red fibers), most of the RRFs in MELAS stain positively with the cytochrome
• An overabundance of mitochondria in smooth muscle and endothelial cells of intramuscular blood vessels, best revealed with the SDH stain ("strongly succinate dehydrogenase-reactive blood vessels," or SSVs)
• Respiratory chain studies on muscle tissue: typically multiple partial defects, especially involving complex I and/or complex IV. However, biochemical results can also be normal.
• A clinical diagnosis of MELAS can be made if the following three criteria are met [
• Stroke-like episodes before age 40 years
• Encephalopathy characterized by seizures and/or dementia
• Mitochondrial myopathy is evident by the presence of lactic acidosis and/or ragged-red fibers (RRFs) on muscle biopsy.
• Normal early psychomotor development
• Recurrent headaches
• Recurrent vomiting episodes
• Stroke-like episodes before age 40 years
• Encephalopathy characterized by seizures and/or dementia
• Mitochondrial myopathy is evident by the presence of lactic acidosis and/or ragged-red fibers (RRFs) on muscle biopsy.
• Normal early psychomotor development
• Recurrent headaches
• Recurrent vomiting episodes
• A clinical diagnosis of MELAS can also be made in an individual with at least two category A
•
• Headaches with vomiting
• Seizures
• Hemiplegia
• Cortical blindness
• Acute focal lesions on neuroimaging (See Suggestive Findings,
•
• High plasma or cerebrospinal fluid (CSF) lactate
• Mitochondrial abnormalities on muscle biopsy (See Suggestive Findings,
• A MELAS-related pathogenic variant (See
• Headaches with vomiting
• Seizures
• Hemiplegia
• Cortical blindness
• Acute focal lesions on neuroimaging (See Suggestive Findings,
• High plasma or cerebrospinal fluid (CSF) lactate
• Mitochondrial abnormalities on muscle biopsy (See Suggestive Findings,
• A MELAS-related pathogenic variant (See
• Stroke-like episodes before age 40 years
• Encephalopathy characterized by seizures and/or dementia
• Mitochondrial myopathy is evident by the presence of lactic acidosis and/or ragged-red fibers (RRFs) on muscle biopsy.
• Normal early psychomotor development
• Recurrent headaches
• Recurrent vomiting episodes
• Headaches with vomiting
• Seizures
• Hemiplegia
• Cortical blindness
• Acute focal lesions on neuroimaging (See Suggestive Findings,
• High plasma or cerebrospinal fluid (CSF) lactate
• Mitochondrial abnormalities on muscle biopsy (See Suggestive Findings,
• A MELAS-related pathogenic variant (See
• Typically, blood leukocyte DNA is initially tested for the
• If this is normal, targeted testing for the pathogenic variants
## Suggestive Findings
MELAS (
Stroke-like episodes before the age of 40 years
Acquired encephalopathy with seizures and/or dementia
Recurrent headaches
Muscle weakness and exercise intolerance
Cortical vision loss
Hemiparesis
Recurrent vomiting
Short stature
Hearing impairment
Normal early psychomotor development
Peripheral neuropathy
Learning disability
During the stroke-like episodes, the affected areas:
Have increased T
Do not correspond to the classic vascular distribution (hence the term "stroke-like");
Are asymmetric;
Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
Can be restricted to cortical areas or involve subcortical white matter [
Slow spreading of the stroke-like lesions occurs in the weeks following the first symptoms, typically documented by T
Diffusion-weighted MRI shows increased apparent diffusion coefficient (ADC) in the stroke-like lesions of MELAS, in contrast to the decreased ADC seen in ischemic strokes [
MR angiography is usually normal and MR spectroscopy shows decreased N-acetylaspartate signals and accumulation of lactate [
Findings are consistent with a myopathic process, but neuropathy may coexist. Neuropathy can be axonal or mixed axonal and demyelinating [
Lactic acidemia is not specific for MELAS syndrome as it can occur in other mitochondrial diseases, metabolic diseases, and systemic illness. Other situations (unrelated to the diagnosis of MELAS) in which lactate can be elevated are acute neurologic events such as seizure or stroke. On the other hand, lactate level can be normal in a minority of individuals with MELAS syndrome [
Ragged red fibers (RRFs) with the modified Gomori trichrome stain, which represent mitochondrial proliferation below the plasma membrane of the muscular fibers causing the contour of the muscle fiber to become irregular. These proliferated mitochondria also stain strongly with the succinate dehydrogenase (SDH) stain giving the appearance of ragged blue fibers.
Although RRFs are present in many other mitochondrial diseases e.g., MERRF (myoclonic epilepsy with ragged red fibers), most of the RRFs in MELAS stain positively with the cytochrome
An overabundance of mitochondria in smooth muscle and endothelial cells of intramuscular blood vessels, best revealed with the SDH stain ("strongly succinate dehydrogenase-reactive blood vessels," or SSVs)
Respiratory chain studies on muscle tissue: typically multiple partial defects, especially involving complex I and/or complex IV. However, biochemical results can also be normal.
Note: Muscle biopsy is not required to make this diagnosis; molecular genetic testing is frequently used in lieu of muscle biopsy to
• Stroke-like episodes before the age of 40 years
• Acquired encephalopathy with seizures and/or dementia
• Recurrent headaches
• Muscle weakness and exercise intolerance
• Cortical vision loss
• Hemiparesis
• Recurrent vomiting
• Short stature
• Hearing impairment
• Normal early psychomotor development
• Peripheral neuropathy
• Learning disability
• During the stroke-like episodes, the affected areas:
• Have increased T
• Do not correspond to the classic vascular distribution (hence the term "stroke-like");
• Are asymmetric;
• Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
• Can be restricted to cortical areas or involve subcortical white matter [
• Have increased T
• Do not correspond to the classic vascular distribution (hence the term "stroke-like");
• Are asymmetric;
• Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
• Can be restricted to cortical areas or involve subcortical white matter [
• Slow spreading of the stroke-like lesions occurs in the weeks following the first symptoms, typically documented by T
• Diffusion-weighted MRI shows increased apparent diffusion coefficient (ADC) in the stroke-like lesions of MELAS, in contrast to the decreased ADC seen in ischemic strokes [
• MR angiography is usually normal and MR spectroscopy shows decreased N-acetylaspartate signals and accumulation of lactate [
• Have increased T
• Do not correspond to the classic vascular distribution (hence the term "stroke-like");
• Are asymmetric;
• Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
• Can be restricted to cortical areas or involve subcortical white matter [
• Ragged red fibers (RRFs) with the modified Gomori trichrome stain, which represent mitochondrial proliferation below the plasma membrane of the muscular fibers causing the contour of the muscle fiber to become irregular. These proliferated mitochondria also stain strongly with the succinate dehydrogenase (SDH) stain giving the appearance of ragged blue fibers.
• Although RRFs are present in many other mitochondrial diseases e.g., MERRF (myoclonic epilepsy with ragged red fibers), most of the RRFs in MELAS stain positively with the cytochrome
• An overabundance of mitochondria in smooth muscle and endothelial cells of intramuscular blood vessels, best revealed with the SDH stain ("strongly succinate dehydrogenase-reactive blood vessels," or SSVs)
• Respiratory chain studies on muscle tissue: typically multiple partial defects, especially involving complex I and/or complex IV. However, biochemical results can also be normal.
## Clinical Features
Stroke-like episodes before the age of 40 years
Acquired encephalopathy with seizures and/or dementia
Recurrent headaches
Muscle weakness and exercise intolerance
Cortical vision loss
Hemiparesis
Recurrent vomiting
Short stature
Hearing impairment
Normal early psychomotor development
Peripheral neuropathy
Learning disability
• Stroke-like episodes before the age of 40 years
• Acquired encephalopathy with seizures and/or dementia
• Recurrent headaches
• Muscle weakness and exercise intolerance
• Cortical vision loss
• Hemiparesis
• Recurrent vomiting
• Short stature
• Hearing impairment
• Normal early psychomotor development
• Peripheral neuropathy
• Learning disability
## Brain Imaging
During the stroke-like episodes, the affected areas:
Have increased T
Do not correspond to the classic vascular distribution (hence the term "stroke-like");
Are asymmetric;
Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
Can be restricted to cortical areas or involve subcortical white matter [
Slow spreading of the stroke-like lesions occurs in the weeks following the first symptoms, typically documented by T
Diffusion-weighted MRI shows increased apparent diffusion coefficient (ADC) in the stroke-like lesions of MELAS, in contrast to the decreased ADC seen in ischemic strokes [
MR angiography is usually normal and MR spectroscopy shows decreased N-acetylaspartate signals and accumulation of lactate [
• During the stroke-like episodes, the affected areas:
• Have increased T
• Do not correspond to the classic vascular distribution (hence the term "stroke-like");
• Are asymmetric;
• Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
• Can be restricted to cortical areas or involve subcortical white matter [
• Have increased T
• Do not correspond to the classic vascular distribution (hence the term "stroke-like");
• Are asymmetric;
• Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
• Can be restricted to cortical areas or involve subcortical white matter [
• Slow spreading of the stroke-like lesions occurs in the weeks following the first symptoms, typically documented by T
• Diffusion-weighted MRI shows increased apparent diffusion coefficient (ADC) in the stroke-like lesions of MELAS, in contrast to the decreased ADC seen in ischemic strokes [
• MR angiography is usually normal and MR spectroscopy shows decreased N-acetylaspartate signals and accumulation of lactate [
• Have increased T
• Do not correspond to the classic vascular distribution (hence the term "stroke-like");
• Are asymmetric;
• Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);
• Can be restricted to cortical areas or involve subcortical white matter [
## Electromyography and Nerve Conduction Studies
Findings are consistent with a myopathic process, but neuropathy may coexist. Neuropathy can be axonal or mixed axonal and demyelinating [
## Suggestive Laboratory Findings
Lactic acidemia is not specific for MELAS syndrome as it can occur in other mitochondrial diseases, metabolic diseases, and systemic illness. Other situations (unrelated to the diagnosis of MELAS) in which lactate can be elevated are acute neurologic events such as seizure or stroke. On the other hand, lactate level can be normal in a minority of individuals with MELAS syndrome [
Ragged red fibers (RRFs) with the modified Gomori trichrome stain, which represent mitochondrial proliferation below the plasma membrane of the muscular fibers causing the contour of the muscle fiber to become irregular. These proliferated mitochondria also stain strongly with the succinate dehydrogenase (SDH) stain giving the appearance of ragged blue fibers.
Although RRFs are present in many other mitochondrial diseases e.g., MERRF (myoclonic epilepsy with ragged red fibers), most of the RRFs in MELAS stain positively with the cytochrome
An overabundance of mitochondria in smooth muscle and endothelial cells of intramuscular blood vessels, best revealed with the SDH stain ("strongly succinate dehydrogenase-reactive blood vessels," or SSVs)
Respiratory chain studies on muscle tissue: typically multiple partial defects, especially involving complex I and/or complex IV. However, biochemical results can also be normal.
Note: Muscle biopsy is not required to make this diagnosis; molecular genetic testing is frequently used in lieu of muscle biopsy to
• Ragged red fibers (RRFs) with the modified Gomori trichrome stain, which represent mitochondrial proliferation below the plasma membrane of the muscular fibers causing the contour of the muscle fiber to become irregular. These proliferated mitochondria also stain strongly with the succinate dehydrogenase (SDH) stain giving the appearance of ragged blue fibers.
• Although RRFs are present in many other mitochondrial diseases e.g., MERRF (myoclonic epilepsy with ragged red fibers), most of the RRFs in MELAS stain positively with the cytochrome
• An overabundance of mitochondria in smooth muscle and endothelial cells of intramuscular blood vessels, best revealed with the SDH stain ("strongly succinate dehydrogenase-reactive blood vessels," or SSVs)
• Respiratory chain studies on muscle tissue: typically multiple partial defects, especially involving complex I and/or complex IV. However, biochemical results can also be normal.
## Establishing the Diagnosis
Two sets of clinical diagnostic criteria for MELAS (
A clinical diagnosis of MELAS can be made if the following three criteria are met [
Stroke-like episodes before age 40 years
Encephalopathy characterized by seizures and/or dementia
Mitochondrial myopathy is evident by the presence of lactic acidosis and/or ragged-red fibers (RRFs) on muscle biopsy.
Normal early psychomotor development
Recurrent headaches
Recurrent vomiting episodes
A clinical diagnosis of MELAS can also be made in an individual with at least two category A
Headaches with vomiting
Seizures
Hemiplegia
Cortical blindness
Acute focal lesions on neuroimaging (See Suggestive Findings,
High plasma or cerebrospinal fluid (CSF) lactate
Mitochondrial abnormalities on muscle biopsy (See Suggestive Findings,
A MELAS-related pathogenic variant (See
The diagnosis of MELAS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of MELAS, molecular genetic testing approaches can include
Typically, blood leukocyte DNA is initially tested for the
If this is normal, targeted testing for the pathogenic variants
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and weakness,
For an introduction to comprehensive genomic testing click
Genetic Causes of MELAS
Pathogenic variants of any one of the genes included in this table account for >1% of MELAS.
Genes are listed from most frequent to least frequent genetic cause of MELAS.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
• A clinical diagnosis of MELAS can be made if the following three criteria are met [
• Stroke-like episodes before age 40 years
• Encephalopathy characterized by seizures and/or dementia
• Mitochondrial myopathy is evident by the presence of lactic acidosis and/or ragged-red fibers (RRFs) on muscle biopsy.
• Normal early psychomotor development
• Recurrent headaches
• Recurrent vomiting episodes
• Stroke-like episodes before age 40 years
• Encephalopathy characterized by seizures and/or dementia
• Mitochondrial myopathy is evident by the presence of lactic acidosis and/or ragged-red fibers (RRFs) on muscle biopsy.
• Normal early psychomotor development
• Recurrent headaches
• Recurrent vomiting episodes
• A clinical diagnosis of MELAS can also be made in an individual with at least two category A
•
• Headaches with vomiting
• Seizures
• Hemiplegia
• Cortical blindness
• Acute focal lesions on neuroimaging (See Suggestive Findings,
•
• High plasma or cerebrospinal fluid (CSF) lactate
• Mitochondrial abnormalities on muscle biopsy (See Suggestive Findings,
• A MELAS-related pathogenic variant (See
• Headaches with vomiting
• Seizures
• Hemiplegia
• Cortical blindness
• Acute focal lesions on neuroimaging (See Suggestive Findings,
• High plasma or cerebrospinal fluid (CSF) lactate
• Mitochondrial abnormalities on muscle biopsy (See Suggestive Findings,
• A MELAS-related pathogenic variant (See
• Stroke-like episodes before age 40 years
• Encephalopathy characterized by seizures and/or dementia
• Mitochondrial myopathy is evident by the presence of lactic acidosis and/or ragged-red fibers (RRFs) on muscle biopsy.
• Normal early psychomotor development
• Recurrent headaches
• Recurrent vomiting episodes
• Headaches with vomiting
• Seizures
• Hemiplegia
• Cortical blindness
• Acute focal lesions on neuroimaging (See Suggestive Findings,
• High plasma or cerebrospinal fluid (CSF) lactate
• Mitochondrial abnormalities on muscle biopsy (See Suggestive Findings,
• A MELAS-related pathogenic variant (See
• Typically, blood leukocyte DNA is initially tested for the
• If this is normal, targeted testing for the pathogenic variants
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of MELAS, molecular genetic testing approaches can include
Typically, blood leukocyte DNA is initially tested for the
If this is normal, targeted testing for the pathogenic variants
For an introduction to multigene panels click
• Typically, blood leukocyte DNA is initially tested for the
• If this is normal, targeted testing for the pathogenic variants
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and weakness,
For an introduction to comprehensive genomic testing click
Genetic Causes of MELAS
Pathogenic variants of any one of the genes included in this table account for >1% of MELAS.
Genes are listed from most frequent to least frequent genetic cause of MELAS.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
## Clinical Characteristics
MELAS is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Childhood is the typical age of onset with 65%-76% of affected individuals presenting at or before age 20 years. Onset of symptoms before age two years or after age 40 years is uncommon (age40 years: 1%-6% of individuals).
Individuals with MELAS frequently present with more than one initial clinical manifestation. The most common initial symptoms are seizures, recurrent headaches, stroke-like episodes, cortical vision loss, muscle weakness, recurrent vomiting, and short stature (
MELAS: Initial Clinical Manifestations
Seizures
Recurrent headaches
Stroke-like episodes
Cortical vision loss
Muscle weakness
Recurrent vomiting
Short stature
Altered consciousness
Impaired mentation
Hearing impairment
Diabetes mellitus (type 1 or 2)
Developmental delay
Fever
MELAS: Additional Clinical Manifestations
Stroke-like episodes
Dementia
Epilepsy
Lactic acidemia
Ragged red fibers (RRFs) on muscle biopsy
Hemiparesis
Cortical vision loss
Recurrent headaches
Hearing impairment
Muscle weakness
Peripheral neuropathy
Learning disability
Memory impairment
Recurrent vomiting
Short stature
Basal ganglia calcification
Myoclonus
Ataxia
Episodic altered consciousness
Gait disturbance
Depression
Anxiety
Psychotic disorders
Diabetes mellitus (type 1 or 2)
Optic atrophy
Pigmentary retinopathy
Progressive external ophthalmoplegia
Motor developmental delay
Cardiomyopathy
Cardiac conduction abnormalities
Nephropathy
Vitiligo
Both the underlying neurologic dysfunction and the accumulating cortical injuries due to stroke-like episodes contribute to dementia.
Executive function deficits have been observed despite the relative sparing of the frontal lobe on neuroimaging, indicating an additional diffuse neurodegenerative process in addition to the damage caused by the stroke-like episodes [
Focal and primary generalized seizures can occur.
Primary generalized seizures in MELAS can occur in the context of normal neuroimaging or be accompanied by neuroimaging abnormalities including stroke-like episodes, white matter lesions, cortical atrophy, and corpus callosum agenesis or hypogenesis (see Suggestive Findings,
Seizures can occur in MELAS as a manifestation of a stroke-like episode or independently, and may even induce a stroke-like episode [
Both dilated and hypertrophic cardiomyopathy have been observed, however, the more typical is a non-obstructive concentric hypertrophy [
Cardiac conduction abnormalities including Wolff-Parkinson-White syndrome has been reported occasionally [
In a cohort of 33 adults with the pathogenic m.3243A>G variant in
In a natural history study of 31 individuals with MELAS and 54 symptomatic and asymptomatic obligate carrier relatives over a follow-up period of up to 10.6 years, neurologic examination, neuropsychological testing, and daily living scores significantly declined in all affected individuals with MELAS, whereas no significant deterioration occurred in carrier relatives.
The death rate was more than 17-fold higher in fully symptomatic individuals compared to carrier relatives. The average observed age at death in the affected MELAS group was 34.5±19 years (range 10.2-81.8 years). Of the deaths, 22% occurred in those younger than 18 years.
The estimated overall median survival time based on fully symptomatic individuals was 16.9 years from onset of focal neurologic disease [
A Japanese prospective cohort study of 96 individuals with MELAS confirmed a rapidly progressive course within a five-year interval, with 20.8% of affected individuals dying within a median time of 7.3 years from diagnosis [
For all mtDNA pathogenic variants, clinical expression depends on three factors:
While the tissue vulnerability threshold probably does not vary substantially among individuals, mutational load and tissue distribution do vary and may account for the clinical diversity seen in individuals with MELAS. Correlations between the frequency of the more common clinical features and the level of mutated mtDNA in muscle, but not in leukocytes, have been observed [
The m.3243A>G pathogenic variant, the most frequent variant associated with MELAS, is associated with diverse clinical manifestations (i.e., progressive external ophthalmoplegia, diabetes mellitus, cardiomyopathy, deafness) that collectively constitute a wide spectrum ranging from MELAS at the severe end to asymptomatic carrier status. More severe phenotypes may be the result of a higher abundance of the pathogenic variant in affected organs [
No clear genotype-phenotype correlations have been identified (see
In mtDNA-related disorders, penetrance typically depends on mutational load and tissue distribution, which show random variation within families (see
Typically designated by the acronym MELAS, this disorder may also be referred to as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.
The prevalence of MELAS has been estimated to be 0.2:100,000 in Japan [
• Seizures
• Recurrent headaches
• Stroke-like episodes
• Cortical vision loss
• Muscle weakness
• Recurrent vomiting
• Short stature
• Altered consciousness
• Impaired mentation
• Hearing impairment
• Diabetes mellitus (type 1 or 2)
• Developmental delay
• Fever
• Stroke-like episodes
• Dementia
• Epilepsy
• Lactic acidemia
• Ragged red fibers (RRFs) on muscle biopsy
• Hemiparesis
• Cortical vision loss
• Recurrent headaches
• Hearing impairment
• Muscle weakness
• Peripheral neuropathy
• Learning disability
• Memory impairment
• Recurrent vomiting
• Short stature
• Basal ganglia calcification
• Myoclonus
• Ataxia
• Episodic altered consciousness
• Gait disturbance
• Depression
• Anxiety
• Psychotic disorders
• Diabetes mellitus (type 1 or 2)
• Optic atrophy
• Pigmentary retinopathy
• Progressive external ophthalmoplegia
• Motor developmental delay
• Cardiomyopathy
• Cardiac conduction abnormalities
• Nephropathy
• Vitiligo
• Both the underlying neurologic dysfunction and the accumulating cortical injuries due to stroke-like episodes contribute to dementia.
• Executive function deficits have been observed despite the relative sparing of the frontal lobe on neuroimaging, indicating an additional diffuse neurodegenerative process in addition to the damage caused by the stroke-like episodes [
• Both the underlying neurologic dysfunction and the accumulating cortical injuries due to stroke-like episodes contribute to dementia.
• Executive function deficits have been observed despite the relative sparing of the frontal lobe on neuroimaging, indicating an additional diffuse neurodegenerative process in addition to the damage caused by the stroke-like episodes [
•
• Focal and primary generalized seizures can occur.
• Primary generalized seizures in MELAS can occur in the context of normal neuroimaging or be accompanied by neuroimaging abnormalities including stroke-like episodes, white matter lesions, cortical atrophy, and corpus callosum agenesis or hypogenesis (see Suggestive Findings,
• Seizures can occur in MELAS as a manifestation of a stroke-like episode or independently, and may even induce a stroke-like episode [
• Focal and primary generalized seizures can occur.
• Primary generalized seizures in MELAS can occur in the context of normal neuroimaging or be accompanied by neuroimaging abnormalities including stroke-like episodes, white matter lesions, cortical atrophy, and corpus callosum agenesis or hypogenesis (see Suggestive Findings,
• Seizures can occur in MELAS as a manifestation of a stroke-like episode or independently, and may even induce a stroke-like episode [
• Both the underlying neurologic dysfunction and the accumulating cortical injuries due to stroke-like episodes contribute to dementia.
• Executive function deficits have been observed despite the relative sparing of the frontal lobe on neuroimaging, indicating an additional diffuse neurodegenerative process in addition to the damage caused by the stroke-like episodes [
• Focal and primary generalized seizures can occur.
• Primary generalized seizures in MELAS can occur in the context of normal neuroimaging or be accompanied by neuroimaging abnormalities including stroke-like episodes, white matter lesions, cortical atrophy, and corpus callosum agenesis or hypogenesis (see Suggestive Findings,
• Seizures can occur in MELAS as a manifestation of a stroke-like episode or independently, and may even induce a stroke-like episode [
• Both dilated and hypertrophic cardiomyopathy have been observed, however, the more typical is a non-obstructive concentric hypertrophy [
• Cardiac conduction abnormalities including Wolff-Parkinson-White syndrome has been reported occasionally [
• In a cohort of 33 adults with the pathogenic m.3243A>G variant in
• In a natural history study of 31 individuals with MELAS and 54 symptomatic and asymptomatic obligate carrier relatives over a follow-up period of up to 10.6 years, neurologic examination, neuropsychological testing, and daily living scores significantly declined in all affected individuals with MELAS, whereas no significant deterioration occurred in carrier relatives.
• The death rate was more than 17-fold higher in fully symptomatic individuals compared to carrier relatives. The average observed age at death in the affected MELAS group was 34.5±19 years (range 10.2-81.8 years). Of the deaths, 22% occurred in those younger than 18 years.
• The estimated overall median survival time based on fully symptomatic individuals was 16.9 years from onset of focal neurologic disease [
• A Japanese prospective cohort study of 96 individuals with MELAS confirmed a rapidly progressive course within a five-year interval, with 20.8% of affected individuals dying within a median time of 7.3 years from diagnosis [
## Clinical Description
MELAS is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Childhood is the typical age of onset with 65%-76% of affected individuals presenting at or before age 20 years. Onset of symptoms before age two years or after age 40 years is uncommon (age40 years: 1%-6% of individuals).
Individuals with MELAS frequently present with more than one initial clinical manifestation. The most common initial symptoms are seizures, recurrent headaches, stroke-like episodes, cortical vision loss, muscle weakness, recurrent vomiting, and short stature (
MELAS: Initial Clinical Manifestations
Seizures
Recurrent headaches
Stroke-like episodes
Cortical vision loss
Muscle weakness
Recurrent vomiting
Short stature
Altered consciousness
Impaired mentation
Hearing impairment
Diabetes mellitus (type 1 or 2)
Developmental delay
Fever
MELAS: Additional Clinical Manifestations
Stroke-like episodes
Dementia
Epilepsy
Lactic acidemia
Ragged red fibers (RRFs) on muscle biopsy
Hemiparesis
Cortical vision loss
Recurrent headaches
Hearing impairment
Muscle weakness
Peripheral neuropathy
Learning disability
Memory impairment
Recurrent vomiting
Short stature
Basal ganglia calcification
Myoclonus
Ataxia
Episodic altered consciousness
Gait disturbance
Depression
Anxiety
Psychotic disorders
Diabetes mellitus (type 1 or 2)
Optic atrophy
Pigmentary retinopathy
Progressive external ophthalmoplegia
Motor developmental delay
Cardiomyopathy
Cardiac conduction abnormalities
Nephropathy
Vitiligo
Both the underlying neurologic dysfunction and the accumulating cortical injuries due to stroke-like episodes contribute to dementia.
Executive function deficits have been observed despite the relative sparing of the frontal lobe on neuroimaging, indicating an additional diffuse neurodegenerative process in addition to the damage caused by the stroke-like episodes [
Focal and primary generalized seizures can occur.
Primary generalized seizures in MELAS can occur in the context of normal neuroimaging or be accompanied by neuroimaging abnormalities including stroke-like episodes, white matter lesions, cortical atrophy, and corpus callosum agenesis or hypogenesis (see Suggestive Findings,
Seizures can occur in MELAS as a manifestation of a stroke-like episode or independently, and may even induce a stroke-like episode [
Both dilated and hypertrophic cardiomyopathy have been observed, however, the more typical is a non-obstructive concentric hypertrophy [
Cardiac conduction abnormalities including Wolff-Parkinson-White syndrome has been reported occasionally [
In a cohort of 33 adults with the pathogenic m.3243A>G variant in
In a natural history study of 31 individuals with MELAS and 54 symptomatic and asymptomatic obligate carrier relatives over a follow-up period of up to 10.6 years, neurologic examination, neuropsychological testing, and daily living scores significantly declined in all affected individuals with MELAS, whereas no significant deterioration occurred in carrier relatives.
The death rate was more than 17-fold higher in fully symptomatic individuals compared to carrier relatives. The average observed age at death in the affected MELAS group was 34.5±19 years (range 10.2-81.8 years). Of the deaths, 22% occurred in those younger than 18 years.
The estimated overall median survival time based on fully symptomatic individuals was 16.9 years from onset of focal neurologic disease [
A Japanese prospective cohort study of 96 individuals with MELAS confirmed a rapidly progressive course within a five-year interval, with 20.8% of affected individuals dying within a median time of 7.3 years from diagnosis [
• Seizures
• Recurrent headaches
• Stroke-like episodes
• Cortical vision loss
• Muscle weakness
• Recurrent vomiting
• Short stature
• Altered consciousness
• Impaired mentation
• Hearing impairment
• Diabetes mellitus (type 1 or 2)
• Developmental delay
• Fever
• Stroke-like episodes
• Dementia
• Epilepsy
• Lactic acidemia
• Ragged red fibers (RRFs) on muscle biopsy
• Hemiparesis
• Cortical vision loss
• Recurrent headaches
• Hearing impairment
• Muscle weakness
• Peripheral neuropathy
• Learning disability
• Memory impairment
• Recurrent vomiting
• Short stature
• Basal ganglia calcification
• Myoclonus
• Ataxia
• Episodic altered consciousness
• Gait disturbance
• Depression
• Anxiety
• Psychotic disorders
• Diabetes mellitus (type 1 or 2)
• Optic atrophy
• Pigmentary retinopathy
• Progressive external ophthalmoplegia
• Motor developmental delay
• Cardiomyopathy
• Cardiac conduction abnormalities
• Nephropathy
• Vitiligo
• Both the underlying neurologic dysfunction and the accumulating cortical injuries due to stroke-like episodes contribute to dementia.
• Executive function deficits have been observed despite the relative sparing of the frontal lobe on neuroimaging, indicating an additional diffuse neurodegenerative process in addition to the damage caused by the stroke-like episodes [
• Both the underlying neurologic dysfunction and the accumulating cortical injuries due to stroke-like episodes contribute to dementia.
• Executive function deficits have been observed despite the relative sparing of the frontal lobe on neuroimaging, indicating an additional diffuse neurodegenerative process in addition to the damage caused by the stroke-like episodes [
•
• Focal and primary generalized seizures can occur.
• Primary generalized seizures in MELAS can occur in the context of normal neuroimaging or be accompanied by neuroimaging abnormalities including stroke-like episodes, white matter lesions, cortical atrophy, and corpus callosum agenesis or hypogenesis (see Suggestive Findings,
• Seizures can occur in MELAS as a manifestation of a stroke-like episode or independently, and may even induce a stroke-like episode [
• Focal and primary generalized seizures can occur.
• Primary generalized seizures in MELAS can occur in the context of normal neuroimaging or be accompanied by neuroimaging abnormalities including stroke-like episodes, white matter lesions, cortical atrophy, and corpus callosum agenesis or hypogenesis (see Suggestive Findings,
• Seizures can occur in MELAS as a manifestation of a stroke-like episode or independently, and may even induce a stroke-like episode [
• Both the underlying neurologic dysfunction and the accumulating cortical injuries due to stroke-like episodes contribute to dementia.
• Executive function deficits have been observed despite the relative sparing of the frontal lobe on neuroimaging, indicating an additional diffuse neurodegenerative process in addition to the damage caused by the stroke-like episodes [
• Focal and primary generalized seizures can occur.
• Primary generalized seizures in MELAS can occur in the context of normal neuroimaging or be accompanied by neuroimaging abnormalities including stroke-like episodes, white matter lesions, cortical atrophy, and corpus callosum agenesis or hypogenesis (see Suggestive Findings,
• Seizures can occur in MELAS as a manifestation of a stroke-like episode or independently, and may even induce a stroke-like episode [
• Both dilated and hypertrophic cardiomyopathy have been observed, however, the more typical is a non-obstructive concentric hypertrophy [
• Cardiac conduction abnormalities including Wolff-Parkinson-White syndrome has been reported occasionally [
• In a cohort of 33 adults with the pathogenic m.3243A>G variant in
• In a natural history study of 31 individuals with MELAS and 54 symptomatic and asymptomatic obligate carrier relatives over a follow-up period of up to 10.6 years, neurologic examination, neuropsychological testing, and daily living scores significantly declined in all affected individuals with MELAS, whereas no significant deterioration occurred in carrier relatives.
• The death rate was more than 17-fold higher in fully symptomatic individuals compared to carrier relatives. The average observed age at death in the affected MELAS group was 34.5±19 years (range 10.2-81.8 years). Of the deaths, 22% occurred in those younger than 18 years.
• The estimated overall median survival time based on fully symptomatic individuals was 16.9 years from onset of focal neurologic disease [
• A Japanese prospective cohort study of 96 individuals with MELAS confirmed a rapidly progressive course within a five-year interval, with 20.8% of affected individuals dying within a median time of 7.3 years from diagnosis [
## Causes of Phenotypic Variability
For all mtDNA pathogenic variants, clinical expression depends on three factors:
While the tissue vulnerability threshold probably does not vary substantially among individuals, mutational load and tissue distribution do vary and may account for the clinical diversity seen in individuals with MELAS. Correlations between the frequency of the more common clinical features and the level of mutated mtDNA in muscle, but not in leukocytes, have been observed [
The m.3243A>G pathogenic variant, the most frequent variant associated with MELAS, is associated with diverse clinical manifestations (i.e., progressive external ophthalmoplegia, diabetes mellitus, cardiomyopathy, deafness) that collectively constitute a wide spectrum ranging from MELAS at the severe end to asymptomatic carrier status. More severe phenotypes may be the result of a higher abundance of the pathogenic variant in affected organs [
## Genotype-Phenotype Correlations
No clear genotype-phenotype correlations have been identified (see
## Penetrance
In mtDNA-related disorders, penetrance typically depends on mutational load and tissue distribution, which show random variation within families (see
## Nomenclature
Typically designated by the acronym MELAS, this disorder may also be referred to as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.
## Prevalence
The prevalence of MELAS has been estimated to be 0.2:100,000 in Japan [
## Genetically Related (Allelic) Disorders
Pathogenic variants in mtDNA genes known to be associated with MELAS can also be associated with a variety of other mitochondrial disorders. See
Selected Allelic Disorders
See hyperlinked
## Differential Diagnosis
Clinical manifestations of MELAS can be seen in a wide variety of mitochondrial diseases (see
The differential diagnosis of acute stroke includes other causes of stroke in a young person: heart disease, carotid or vertebral diseases,
A MELAS-like phenotype with defects in nuclear genes including
## Management
To establish the extent of disease and needs in an individual diagnosed with MELAS, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Recommended Evaluations Following Initial Diagnosis in Individuals with MELAS
OT = occupational therapy; PT = physical therapy
Consider referral to a cardiologist.
Consider referral to a neurologist.
Consider referral to an endocrinologist.
Treatment for MELAS is primarily supportive.
Treatment of Manifestations in Individuals with MELAS
Children: 5-10 mg/kg/day
Adults: 200–400 mg/day in 3 divided doses
Children: 100 mg/kg/day
Adults: 3 g/day in 3 divided doses
Children: 100 mg/kg/day
Adults: 2-5 g/day in 3 divided doses
CoQ
Individuals with MELAS can be suitable candidates for cardiac transplantation. Before transplantation, however, careful consideration of the multisystemic nature of the disease is indicated to determine the suitability of candidates [
Diabetes can be type 1 or type 2
Typically sulfonylureas
Once an individual with MELAS has the first stroke-like episode, arginine should be administered prophylactically to reduce the risk of recurrent stroke-like episodes. A daily dose of 150 to 300 mg/kg/day oral arginine in three divided doses is recommended [
Because febrile illnesses may trigger acute exacerbations, individuals with MELAS should receive standard childhood vaccinations, flu vaccine, and pneumococcal vaccine.
Affected individuals and their at-risk relatives should be followed at regular intervals to monitor progression and the appearance of new symptoms.
Recommended Annual Surveillance for Individuals with MELAS
Individuals with MELAS should avoid mitochondrial toxins such as: aminoglycoside antibiotics, linezolid, cigarettes, and alcohol. Valproic acid should be avoided in the treatment of seizures [
Metformin should also be avoided because of its propensity to cause lactic acidosis [
Dichloroacetate, which reduces lactate by activating the pyruvate dehydrogenase enzyme, should be avoided in MELAS syndrome. A study evaluating the effect of dichloroacetate in individuals with MELAS syndrome was terminated because of onset or worsening of peripheral neuropathy, indicating that dichloroacetate can be associated with peripheral nerve toxicity [
Molecular genetic testing of at-risk maternal relatives may reveal individuals who have high mutational loads and are thus at risk of developing symptoms. No proven disease-modifying intervention exists at present. However, asymptomatic individuals can undergo regular surveillance for early detection of complications.
See
Infertility may preclude pregnancy in some affected individuals. Women with MELAS should receive genetic counseling prior to pregnancy. During pregnancy, affected or at-risk women should be monitored for the development of diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions [
The transfer of nuclear DNA from fertilized oocytes or zygotes containing a mtDNA pathogenic variant to an enucleated recipient cell could theoretically prevent transmission of mtDNA diseases; proof of this concept has been demonstrated in pronuclear transfers from abnormally fertilized zygotes [
Search
• Children: 5-10 mg/kg/day
• Adults: 200–400 mg/day in 3 divided doses
• Children: 100 mg/kg/day
• Adults: 3 g/day in 3 divided doses
• Children: 100 mg/kg/day
• Adults: 2-5 g/day in 3 divided doses
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MELAS, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Recommended Evaluations Following Initial Diagnosis in Individuals with MELAS
OT = occupational therapy; PT = physical therapy
Consider referral to a cardiologist.
Consider referral to a neurologist.
Consider referral to an endocrinologist.
## Treatment of Manifestations
Treatment for MELAS is primarily supportive.
Treatment of Manifestations in Individuals with MELAS
Children: 5-10 mg/kg/day
Adults: 200–400 mg/day in 3 divided doses
Children: 100 mg/kg/day
Adults: 3 g/day in 3 divided doses
Children: 100 mg/kg/day
Adults: 2-5 g/day in 3 divided doses
CoQ
Individuals with MELAS can be suitable candidates for cardiac transplantation. Before transplantation, however, careful consideration of the multisystemic nature of the disease is indicated to determine the suitability of candidates [
Diabetes can be type 1 or type 2
Typically sulfonylureas
• Children: 5-10 mg/kg/day
• Adults: 200–400 mg/day in 3 divided doses
• Children: 100 mg/kg/day
• Adults: 3 g/day in 3 divided doses
• Children: 100 mg/kg/day
• Adults: 2-5 g/day in 3 divided doses
## Prevention of Primary Manifestations
Once an individual with MELAS has the first stroke-like episode, arginine should be administered prophylactically to reduce the risk of recurrent stroke-like episodes. A daily dose of 150 to 300 mg/kg/day oral arginine in three divided doses is recommended [
## Prevention of Secondary Complications
Because febrile illnesses may trigger acute exacerbations, individuals with MELAS should receive standard childhood vaccinations, flu vaccine, and pneumococcal vaccine.
## Surveillance
Affected individuals and their at-risk relatives should be followed at regular intervals to monitor progression and the appearance of new symptoms.
Recommended Annual Surveillance for Individuals with MELAS
## Agents/Circumstances to Avoid
Individuals with MELAS should avoid mitochondrial toxins such as: aminoglycoside antibiotics, linezolid, cigarettes, and alcohol. Valproic acid should be avoided in the treatment of seizures [
Metformin should also be avoided because of its propensity to cause lactic acidosis [
Dichloroacetate, which reduces lactate by activating the pyruvate dehydrogenase enzyme, should be avoided in MELAS syndrome. A study evaluating the effect of dichloroacetate in individuals with MELAS syndrome was terminated because of onset or worsening of peripheral neuropathy, indicating that dichloroacetate can be associated with peripheral nerve toxicity [
## Evaluation of Relatives at Risk
Molecular genetic testing of at-risk maternal relatives may reveal individuals who have high mutational loads and are thus at risk of developing symptoms. No proven disease-modifying intervention exists at present. However, asymptomatic individuals can undergo regular surveillance for early detection of complications.
See
## Pregnancy Management
Infertility may preclude pregnancy in some affected individuals. Women with MELAS should receive genetic counseling prior to pregnancy. During pregnancy, affected or at-risk women should be monitored for the development of diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions [
## Therapies Under Investigation
The transfer of nuclear DNA from fertilized oocytes or zygotes containing a mtDNA pathogenic variant to an enucleated recipient cell could theoretically prevent transmission of mtDNA diseases; proof of this concept has been demonstrated in pronuclear transfers from abnormally fertilized zygotes [
Search
## Genetic Counseling
MELAS is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance.
The father of a proband does not have the mtDNA pathogenic variant.
The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. In some mothers, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
Alternatively, the proband may have a
The risk to the sibs depends on the genetic status of the mother.
If the mother has the mtDNA pathogenic variant, all the sibs of a proband will inherit the mtDNA pathogenic variant and may or may not have symptoms. Women with higher levels of mutated mtDNA in their blood may have a greater likelihood of having affected offspring [
All offspring of females with a mtDNA pathogenic variant will inherit the variant.
Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the variant.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the specific mtDNA pathogenic variant in the mother has been identified, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing (PGT) for MELAS are possible. However, prenatal testing for mtDNA pathogenic variants causing MELAS is of uncertain utility.
Changes in mutational load during pregnancy were evaluated in a small study of nine pregnancies in five women from families with the
Interpretation of prenatal testing results is complex for the following reasons:
The mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues.
The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.
Prediction of phenotype, age of onset, severity, or rate of progression is not possible.
• The father of a proband does not have the mtDNA pathogenic variant.
• The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. In some mothers, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
• Alternatively, the proband may have a
• The risk to the sibs depends on the genetic status of the mother.
• If the mother has the mtDNA pathogenic variant, all the sibs of a proband will inherit the mtDNA pathogenic variant and may or may not have symptoms. Women with higher levels of mutated mtDNA in their blood may have a greater likelihood of having affected offspring [
• All offspring of females with a mtDNA pathogenic variant will inherit the variant.
• Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the variant.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues.
• The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.
• Prediction of phenotype, age of onset, severity, or rate of progression is not possible.
## Mode of Inheritance
MELAS is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance.
## Risk to Family Members
The father of a proband does not have the mtDNA pathogenic variant.
The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. In some mothers, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
Alternatively, the proband may have a
The risk to the sibs depends on the genetic status of the mother.
If the mother has the mtDNA pathogenic variant, all the sibs of a proband will inherit the mtDNA pathogenic variant and may or may not have symptoms. Women with higher levels of mutated mtDNA in their blood may have a greater likelihood of having affected offspring [
All offspring of females with a mtDNA pathogenic variant will inherit the variant.
Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the variant.
• The father of a proband does not have the mtDNA pathogenic variant.
• The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. In some mothers, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
• Alternatively, the proband may have a
• The risk to the sibs depends on the genetic status of the mother.
• If the mother has the mtDNA pathogenic variant, all the sibs of a proband will inherit the mtDNA pathogenic variant and may or may not have symptoms. Women with higher levels of mutated mtDNA in their blood may have a greater likelihood of having affected offspring [
• All offspring of females with a mtDNA pathogenic variant will inherit the variant.
• Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the variant.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the specific mtDNA pathogenic variant in the mother has been identified, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing (PGT) for MELAS are possible. However, prenatal testing for mtDNA pathogenic variants causing MELAS is of uncertain utility.
Changes in mutational load during pregnancy were evaluated in a small study of nine pregnancies in five women from families with the
Interpretation of prenatal testing results is complex for the following reasons:
The mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues.
The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.
Prediction of phenotype, age of onset, severity, or rate of progression is not possible.
• The mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues.
• The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.
• Prediction of phenotype, age of onset, severity, or rate of progression is not possible.
## Resources
Australia
United Kingdom
•
•
•
•
•
•
•
• Australia
•
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
MELAS: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MELAS (
The pathogenesis of MELAS syndrome, which is not fully understood, is likely explained by several interacting mechanisms including impaired mitochondrial energy production, microvasculature angiopathy, and nitric oxide (NO) deficiency. The MELAS-associated variants typically result in impaired mitochondrial translation leading to decreased mitochondrial protein synthesis, which affects the electron transport chain (ETC) complex subunits. Decreased synthesis of ETC complexes results in impaired mitochondrial energy production. The inability of dysfunctional mitochondria to generate sufficient energy to meet the energy needs of various organs results in the multiorgan dysfunction observed in MELAS syndrome. Energy deficiency can also stimulate mitochondrial proliferation. Angiopathy due to mitochondrial proliferation in smooth muscle and endothelial cells of small blood vessels leads to impaired blood perfusion in microvasculature, contributing to the complications observed in MELAS – particularly stroke-like episodes. In addition, growing evidence suggests that NO deficiency occurs in MELAS and can contribute significantly to its complications [
Pathogenic Variants in Mitochondrial DNA Associated with MELAS
Variants listed in the table have been provided by the authors.
See
Numbering based on mitochondrial DNA reference sequence: AC_000021.2 and individual protein reference sequences
Six protein-encoding genes are also involved in MELAS.
## Molecular Pathogenesis
The pathogenesis of MELAS syndrome, which is not fully understood, is likely explained by several interacting mechanisms including impaired mitochondrial energy production, microvasculature angiopathy, and nitric oxide (NO) deficiency. The MELAS-associated variants typically result in impaired mitochondrial translation leading to decreased mitochondrial protein synthesis, which affects the electron transport chain (ETC) complex subunits. Decreased synthesis of ETC complexes results in impaired mitochondrial energy production. The inability of dysfunctional mitochondria to generate sufficient energy to meet the energy needs of various organs results in the multiorgan dysfunction observed in MELAS syndrome. Energy deficiency can also stimulate mitochondrial proliferation. Angiopathy due to mitochondrial proliferation in smooth muscle and endothelial cells of small blood vessels leads to impaired blood perfusion in microvasculature, contributing to the complications observed in MELAS – particularly stroke-like episodes. In addition, growing evidence suggests that NO deficiency occurs in MELAS and can contribute significantly to its complications [
Pathogenic Variants in Mitochondrial DNA Associated with MELAS
Variants listed in the table have been provided by the authors.
See
Numbering based on mitochondrial DNA reference sequence: AC_000021.2 and individual protein reference sequences
Six protein-encoding genes are also involved in MELAS.
## Chapter Notes
Mohammed Almannai, MD (2018-present)Salvatore DiMauro, MD; Columbia University (2001-2018)Ayman El-Hattab, MD (2018-present)Michio Hirano, MD; Columbia University (2001-2018)Fernando Scaglia, MD (2018-present)
29 November 2018 (ma) Comprehensive update posted live
21 November 2013 (me) Comprehensive update posted live
14 October 2010 (me) Comprehensive update posted live
13 October 2005 (me) Comprehensive update posted live
18 June 2003 (ca) Comprehensive update posted live
27 February 2001 (me) Review posted live
September 2000 (sdm) Original submission
• 29 November 2018 (ma) Comprehensive update posted live
• 21 November 2013 (me) Comprehensive update posted live
• 14 October 2010 (me) Comprehensive update posted live
• 13 October 2005 (me) Comprehensive update posted live
• 18 June 2003 (ca) Comprehensive update posted live
• 27 February 2001 (me) Review posted live
• September 2000 (sdm) Original submission
## Author History
Mohammed Almannai, MD (2018-present)Salvatore DiMauro, MD; Columbia University (2001-2018)Ayman El-Hattab, MD (2018-present)Michio Hirano, MD; Columbia University (2001-2018)Fernando Scaglia, MD (2018-present)
## Revision History
29 November 2018 (ma) Comprehensive update posted live
21 November 2013 (me) Comprehensive update posted live
14 October 2010 (me) Comprehensive update posted live
13 October 2005 (me) Comprehensive update posted live
18 June 2003 (ca) Comprehensive update posted live
27 February 2001 (me) Review posted live
September 2000 (sdm) Original submission
• 29 November 2018 (ma) Comprehensive update posted live
• 21 November 2013 (me) Comprehensive update posted live
• 14 October 2010 (me) Comprehensive update posted live
• 13 October 2005 (me) Comprehensive update posted live
• 18 June 2003 (ca) Comprehensive update posted live
• 27 February 2001 (me) Review posted live
• September 2000 (sdm) Original submission
## References
## Literature Cited
|
[] |
27/2/2001
|
29/11/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
men1
|
men1
|
[
"MEN1",
"MEN1 Syndrome",
"Multiple Endocrine Adenomatosis",
"Wermer Syndrome",
"MEN1",
"MEN1 Syndrome",
"Multiple Endocrine Adenomatosis",
"Wermer Syndrome",
"Menin",
"MEN1",
"Multiple Endocrine Neoplasia Type 1"
] |
Multiple Endocrine Neoplasia Type 1
|
Francesca Giusti, Francesca Marini, Maria Luisa Brandi
|
Summary Multiple endocrine neoplasia type 1 (MEN1) includes varying combinations of more than 20 endocrine and non-endocrine tumors. Endocrine tumors become evident either by overproduction of hormones by the tumor or by growth of the tumor itself. Non-endocrine tumors include facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas. The clinical diagnosis of MEN1 can be established in a proband with: Two or more endocrine tumors including parathyroid, anterior pituitary, and/or GEP tract tumors or one endocrine tumor (parathyroid, anterior pituitary, or GEP tract tumor); and A first-degree relative with MEN1. The molecular diagnosis can be established by identification of a heterozygous pathogenic variant in MEN1 is inherited in an autosomal dominant manner. Approximately 90% of individuals diagnosed with MEN1 have an affected parent; approximately 10% of individuals diagnosed with MEN1 have the disorder as the result of a
|
## Diagnosis
Multiple endocrine neoplasia type 1 (MEN1)
Prolactinomas (prolactin-secreting anterior pituitary adenomas) manifest as oligomenorrhea/amenorrhea and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
Growth hormone-secreting anterior pituitary adenomas cause gigantism in children and signs and symptoms of acromegaly in adults.
Growth hormone/prolactin (GH/PRL)-secreting anterior pituitary adenomas manifest as signs and symptoms of acromegaly, oligomenorrhea/amenorrhea, and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
Thyroid-stimulating hormone (TSH)-secreting anterior pituitary adenomas cause signs and symptoms of hyperthyroidism.
Adrenocorticotrophic hormone (ACTH)-secreting anterior pituitary adenomas are mostly associated with Cushing disease.
Nonfunctioning (nonsecreting) anterior pituitary adenomas manifest as enlarging tumors, compressing adjacent structures such as the optic chiasm with visual disturbances, and/or hypopituitarism.
Note: The imaging test of choice for all types of pituitary tumors is MRI.
Zollinger-Ellison syndrome (ZES) (i.e., peptic ulcer with or without chronic diarrhea) resulting from a gastrin-secreting duodenal mucosal tumor (gastrinoma)
Hypoglycemia resulting from an insulin-secreting pancreatic tumor (insulinoma)
Hyperglycemia, anorexia, glossitis, anemia, diarrhea, venous thrombosis, and skin rash (necrolytic migratory erythema) resulting from a glucagon-secreting pancreatic tumor (glucagonoma)
Watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome) resulting from a vasoactive intestinal peptide (VIP)-secreting tumor (VIPoma)
Note: (1) Nonfunctioning pancreatic endocrine tumors that are difficult to diagnose by biochemical and imaging tests are the most frequently seen tumors in MEN1 [
Cutaneous manifestations may be helpful in the diagnosis of individuals with MEN1 even before manifestations of hormone-secreting tumors appear.
The clinical diagnosis of MEN1 can be
Two or more endocrine tumors including parathyroid, anterior pituitary, and well-differentiated neuroendocrine tumors of the GEP tract; OR
One of three endocrine tumors (parathyroid, anterior pituitary, or well-differentiated neuroendocrine tumors of the GEP tract) and a first-degree relative with MEN1.
The molecular diagnosis can be established in a proband with a germline heterozygous
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other tumor predisposition disorders,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multiple Endocrine Neoplasia Type 1
familial = a proband meeting the diagnostic criteria of MEN1 plus a minimum of one first-degree relative with at least one of these tumors; simplex = a single occurrence of MEN1 in a family
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Prolactinomas (prolactin-secreting anterior pituitary adenomas) manifest as oligomenorrhea/amenorrhea and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
• Growth hormone-secreting anterior pituitary adenomas cause gigantism in children and signs and symptoms of acromegaly in adults.
• Growth hormone/prolactin (GH/PRL)-secreting anterior pituitary adenomas manifest as signs and symptoms of acromegaly, oligomenorrhea/amenorrhea, and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
• Thyroid-stimulating hormone (TSH)-secreting anterior pituitary adenomas cause signs and symptoms of hyperthyroidism.
• Adrenocorticotrophic hormone (ACTH)-secreting anterior pituitary adenomas are mostly associated with Cushing disease.
• Nonfunctioning (nonsecreting) anterior pituitary adenomas manifest as enlarging tumors, compressing adjacent structures such as the optic chiasm with visual disturbances, and/or hypopituitarism.
• Zollinger-Ellison syndrome (ZES) (i.e., peptic ulcer with or without chronic diarrhea) resulting from a gastrin-secreting duodenal mucosal tumor (gastrinoma)
• Hypoglycemia resulting from an insulin-secreting pancreatic tumor (insulinoma)
• Hyperglycemia, anorexia, glossitis, anemia, diarrhea, venous thrombosis, and skin rash (necrolytic migratory erythema) resulting from a glucagon-secreting pancreatic tumor (glucagonoma)
• Watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome) resulting from a vasoactive intestinal peptide (VIP)-secreting tumor (VIPoma)
• Two or more endocrine tumors including parathyroid, anterior pituitary, and well-differentiated neuroendocrine tumors of the GEP tract; OR
• One of three endocrine tumors (parathyroid, anterior pituitary, or well-differentiated neuroendocrine tumors of the GEP tract) and a first-degree relative with MEN1.
## Suggestive Findings
Multiple endocrine neoplasia type 1 (MEN1)
Prolactinomas (prolactin-secreting anterior pituitary adenomas) manifest as oligomenorrhea/amenorrhea and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
Growth hormone-secreting anterior pituitary adenomas cause gigantism in children and signs and symptoms of acromegaly in adults.
Growth hormone/prolactin (GH/PRL)-secreting anterior pituitary adenomas manifest as signs and symptoms of acromegaly, oligomenorrhea/amenorrhea, and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
Thyroid-stimulating hormone (TSH)-secreting anterior pituitary adenomas cause signs and symptoms of hyperthyroidism.
Adrenocorticotrophic hormone (ACTH)-secreting anterior pituitary adenomas are mostly associated with Cushing disease.
Nonfunctioning (nonsecreting) anterior pituitary adenomas manifest as enlarging tumors, compressing adjacent structures such as the optic chiasm with visual disturbances, and/or hypopituitarism.
Note: The imaging test of choice for all types of pituitary tumors is MRI.
Zollinger-Ellison syndrome (ZES) (i.e., peptic ulcer with or without chronic diarrhea) resulting from a gastrin-secreting duodenal mucosal tumor (gastrinoma)
Hypoglycemia resulting from an insulin-secreting pancreatic tumor (insulinoma)
Hyperglycemia, anorexia, glossitis, anemia, diarrhea, venous thrombosis, and skin rash (necrolytic migratory erythema) resulting from a glucagon-secreting pancreatic tumor (glucagonoma)
Watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome) resulting from a vasoactive intestinal peptide (VIP)-secreting tumor (VIPoma)
Note: (1) Nonfunctioning pancreatic endocrine tumors that are difficult to diagnose by biochemical and imaging tests are the most frequently seen tumors in MEN1 [
Cutaneous manifestations may be helpful in the diagnosis of individuals with MEN1 even before manifestations of hormone-secreting tumors appear.
• Prolactinomas (prolactin-secreting anterior pituitary adenomas) manifest as oligomenorrhea/amenorrhea and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
• Growth hormone-secreting anterior pituitary adenomas cause gigantism in children and signs and symptoms of acromegaly in adults.
• Growth hormone/prolactin (GH/PRL)-secreting anterior pituitary adenomas manifest as signs and symptoms of acromegaly, oligomenorrhea/amenorrhea, and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
• Thyroid-stimulating hormone (TSH)-secreting anterior pituitary adenomas cause signs and symptoms of hyperthyroidism.
• Adrenocorticotrophic hormone (ACTH)-secreting anterior pituitary adenomas are mostly associated with Cushing disease.
• Nonfunctioning (nonsecreting) anterior pituitary adenomas manifest as enlarging tumors, compressing adjacent structures such as the optic chiasm with visual disturbances, and/or hypopituitarism.
• Zollinger-Ellison syndrome (ZES) (i.e., peptic ulcer with or without chronic diarrhea) resulting from a gastrin-secreting duodenal mucosal tumor (gastrinoma)
• Hypoglycemia resulting from an insulin-secreting pancreatic tumor (insulinoma)
• Hyperglycemia, anorexia, glossitis, anemia, diarrhea, venous thrombosis, and skin rash (necrolytic migratory erythema) resulting from a glucagon-secreting pancreatic tumor (glucagonoma)
• Watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome) resulting from a vasoactive intestinal peptide (VIP)-secreting tumor (VIPoma)
## Establishing the Diagnosis
The clinical diagnosis of MEN1 can be
Two or more endocrine tumors including parathyroid, anterior pituitary, and well-differentiated neuroendocrine tumors of the GEP tract; OR
One of three endocrine tumors (parathyroid, anterior pituitary, or well-differentiated neuroendocrine tumors of the GEP tract) and a first-degree relative with MEN1.
The molecular diagnosis can be established in a proband with a germline heterozygous
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other tumor predisposition disorders,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multiple Endocrine Neoplasia Type 1
familial = a proband meeting the diagnostic criteria of MEN1 plus a minimum of one first-degree relative with at least one of these tumors; simplex = a single occurrence of MEN1 in a family
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Two or more endocrine tumors including parathyroid, anterior pituitary, and well-differentiated neuroendocrine tumors of the GEP tract; OR
• One of three endocrine tumors (parathyroid, anterior pituitary, or well-differentiated neuroendocrine tumors of the GEP tract) and a first-degree relative with MEN1.
## Option 1
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other tumor predisposition disorders,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multiple Endocrine Neoplasia Type 1
familial = a proband meeting the diagnostic criteria of MEN1 plus a minimum of one first-degree relative with at least one of these tumors; simplex = a single occurrence of MEN1 in a family
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Multiple endocrine neoplasia type 1 (MEN1) is characterized by varying combinations of more than 20 endocrine and non-endocrine tumors. Endocrine tumors occurring in individuals with MEN1 are shown in
Endocrine Tumor Types in Multiple Endocrine Neoplasia Type 1
ACTH = adrenocorticotrophic hormone; ECL = enterochromaffin-like; GEP = gastroenteropancreatic; GH = growth hormone; NA = not applicable; PHPT = primary hyperparathyroidism; PRL = prolactin; TSH = thyroid-stimulating hormone; VIPoma = vasoactive intestinal peptide-secreting tumor
Of note, MEN1-associated tumors are often clinically distinct from sporadically occurring tumors of the same tissue type (i.e., as single tumors in the absence of other findings of MEN1) (see
PHPT is often mild, with hypercalcemia often detected in asymptomatic individuals known to have or be at risk for MEN1. PHPT is the most common MEN1-associated endocrinopathy, and the first clinical feature in 90% of individuals. Onset is typically between ages 20 and 25 years. All individuals with MEN1 can be expected to have hypercalcemia by age 50 years [
Common clinical manifestations of hypercalcemia:
Hypercalcemia may increase the secretion of gastrin from a gastrinoma, precipitating and/or exacerbating symptoms of Zollinger-Ellison syndrome [
Pituitary adenomas are the first clinical manifestation of MEN1 in 25% of simplex cases (i.e., a single occurrence of MEN1 in a family) and in 10% of familial cases. The incidence of pituitary adenomas in MEN1 varies from 15% to 55% in different series [
Pituitary adenomas are usually solitary, although adenomas that produce more than one hormone have been reported (e.g., growth hormone [GH] and prolactin [PRL] with follicle-stimulating hormone [FSH], luteinizing hormone, or adrenocorticotropic hormone [ACTH]) [
Symptoms depend on the pituitary hormone produced:
Clinically significant symptoms such as nerve compression, headache, and hypopituitarism may also result from pituitary mass effects [
Pancreatic gastrinomas are more aggressive than duodenal gastrinomas, as suggested by their larger size and greater risk for hepatic metastasis. Among individuals with multiple pancreatic endocrine tumors, eight asymptomatic individuals operated on at a mean age of 33 years did not have metastases [
Thymic, bronchial, and type II gastric enterochromaffin-like (ECL) carcinoids occur in 3%-10% of individuals with MEN1. CT is useful in localizing occult bronchial tumors, while CT and MRI are equally sensitive in detecting thymic carcinoid tumors at initial evaluation [
Carcinoid tumors are the only MEN1-associated neoplasms currently known to exhibit an unequal male-to-female ratio: thymic carcinoids are more prevalent in males than in females with a male:female ratio of 20:1 and bronchial carcinoids occur predominantly in women (male:female ratio of 1:4) [
The clinical course of carcinoid tumors is often indolent but can also be aggressive and resistant to therapy [
The retrospective study of
The mean age at diagnosis of gastric carcinoids is 50 years [
Most bronchial carcinoids, in contrast to thymic carcinoids, behave indolently, albeit with the potential for local mass effect, metastasis, and recurrence after resection [
Therefore, the presence of thymic tumors is reported to be associated with a significantly increased risk of death in individuals with MEN1 (hazard or odds ratio = 4.29) – this is in contrast to the presence of bronchial carcinoids, which have not been associated with increased risk of death [
Adrenocortical tumors, involving one or both adrenal glands, have been described in a variable percentage (20%-73%) of individuals with MEN1, depending on the radiologic screening methods employed. Adrenocortical tumors are most often detected during CT screening.
Most of these tumors are nonfunctioning, and these include cortical adenomas, hyperplasia, multiple adenomas, nodular hyperplasia, cysts, or carcinomas; fewer than 10% of these tumors demonstrate hormonal hypersecretion, and, among these, adrenocortical tumors causing Cushing disease are the most common [
Rarely, adrenocortical tumors are associated with primary hypercortisolism or hyperaldosteronism [
Facial angiofibromas, benign tumors comprising blood vessels and connective tissue, are present in about 85% of affected individuals [
Collagenomas, present in about 70% of affected individuals, frequently present as multiple skin-colored, sometimes hypopigmented cutaneous nodules, symmetrically arranged on the trunk, neck, and upper limbs [
Lipomas are benign fatty tissue tumors found anywhere that fat is located and are present in about 30% of affected individuals [
Other skin findings include café au lait macules in 38% of affected individuals, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% [
Meningioma was reported in 8% of 74 individuals [
Ependymoma is present in about 1% of affected individuals.
Improved knowledge of MEN1-associated clinical manifestations, early diagnosis of MEN1-associated tumors, presymptomatic screening of at-risk children, and treatment of metabolic complications of MEN1 have virtually eliminated ZES and/or complicated PHPT as causes of death and decreased morbidity and mortality associated with MEN1-related tumors [
No direct genotype-phenotype correlations have been identified in MEN1 [
One study reported a twofold higher risk of death in individuals with a heterozygous
Although a trend (which did not reach statistical significance) suggested that the prevalence of truncating variants in
The only specific clustering of tumors within the MEN1 phenotype was reported in those with the Burin variant
The age-related penetrance for all clinical features surpasses 50% by age 20 years and 95% by age 40 years [
MEN1 has a prevalence of between 1:10,000 and 1:100,000 individuals. Geographic clustering as a consequence of founder effect has been reported [
• Pancreatic gastrinomas are more aggressive than duodenal gastrinomas, as suggested by their larger size and greater risk for hepatic metastasis. Among individuals with multiple pancreatic endocrine tumors, eight asymptomatic individuals operated on at a mean age of 33 years did not have metastases [
• Facial angiofibromas, benign tumors comprising blood vessels and connective tissue, are present in about 85% of affected individuals [
• Collagenomas, present in about 70% of affected individuals, frequently present as multiple skin-colored, sometimes hypopigmented cutaneous nodules, symmetrically arranged on the trunk, neck, and upper limbs [
• Lipomas are benign fatty tissue tumors found anywhere that fat is located and are present in about 30% of affected individuals [
• Other skin findings include café au lait macules in 38% of affected individuals, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% [
• Meningioma was reported in 8% of 74 individuals [
• Ependymoma is present in about 1% of affected individuals.
## Clinical Description
Multiple endocrine neoplasia type 1 (MEN1) is characterized by varying combinations of more than 20 endocrine and non-endocrine tumors. Endocrine tumors occurring in individuals with MEN1 are shown in
Endocrine Tumor Types in Multiple Endocrine Neoplasia Type 1
ACTH = adrenocorticotrophic hormone; ECL = enterochromaffin-like; GEP = gastroenteropancreatic; GH = growth hormone; NA = not applicable; PHPT = primary hyperparathyroidism; PRL = prolactin; TSH = thyroid-stimulating hormone; VIPoma = vasoactive intestinal peptide-secreting tumor
Of note, MEN1-associated tumors are often clinically distinct from sporadically occurring tumors of the same tissue type (i.e., as single tumors in the absence of other findings of MEN1) (see
PHPT is often mild, with hypercalcemia often detected in asymptomatic individuals known to have or be at risk for MEN1. PHPT is the most common MEN1-associated endocrinopathy, and the first clinical feature in 90% of individuals. Onset is typically between ages 20 and 25 years. All individuals with MEN1 can be expected to have hypercalcemia by age 50 years [
Common clinical manifestations of hypercalcemia:
Hypercalcemia may increase the secretion of gastrin from a gastrinoma, precipitating and/or exacerbating symptoms of Zollinger-Ellison syndrome [
Pituitary adenomas are the first clinical manifestation of MEN1 in 25% of simplex cases (i.e., a single occurrence of MEN1 in a family) and in 10% of familial cases. The incidence of pituitary adenomas in MEN1 varies from 15% to 55% in different series [
Pituitary adenomas are usually solitary, although adenomas that produce more than one hormone have been reported (e.g., growth hormone [GH] and prolactin [PRL] with follicle-stimulating hormone [FSH], luteinizing hormone, or adrenocorticotropic hormone [ACTH]) [
Symptoms depend on the pituitary hormone produced:
Clinically significant symptoms such as nerve compression, headache, and hypopituitarism may also result from pituitary mass effects [
Pancreatic gastrinomas are more aggressive than duodenal gastrinomas, as suggested by their larger size and greater risk for hepatic metastasis. Among individuals with multiple pancreatic endocrine tumors, eight asymptomatic individuals operated on at a mean age of 33 years did not have metastases [
Thymic, bronchial, and type II gastric enterochromaffin-like (ECL) carcinoids occur in 3%-10% of individuals with MEN1. CT is useful in localizing occult bronchial tumors, while CT and MRI are equally sensitive in detecting thymic carcinoid tumors at initial evaluation [
Carcinoid tumors are the only MEN1-associated neoplasms currently known to exhibit an unequal male-to-female ratio: thymic carcinoids are more prevalent in males than in females with a male:female ratio of 20:1 and bronchial carcinoids occur predominantly in women (male:female ratio of 1:4) [
The clinical course of carcinoid tumors is often indolent but can also be aggressive and resistant to therapy [
The retrospective study of
The mean age at diagnosis of gastric carcinoids is 50 years [
Most bronchial carcinoids, in contrast to thymic carcinoids, behave indolently, albeit with the potential for local mass effect, metastasis, and recurrence after resection [
Therefore, the presence of thymic tumors is reported to be associated with a significantly increased risk of death in individuals with MEN1 (hazard or odds ratio = 4.29) – this is in contrast to the presence of bronchial carcinoids, which have not been associated with increased risk of death [
Adrenocortical tumors, involving one or both adrenal glands, have been described in a variable percentage (20%-73%) of individuals with MEN1, depending on the radiologic screening methods employed. Adrenocortical tumors are most often detected during CT screening.
Most of these tumors are nonfunctioning, and these include cortical adenomas, hyperplasia, multiple adenomas, nodular hyperplasia, cysts, or carcinomas; fewer than 10% of these tumors demonstrate hormonal hypersecretion, and, among these, adrenocortical tumors causing Cushing disease are the most common [
Rarely, adrenocortical tumors are associated with primary hypercortisolism or hyperaldosteronism [
Facial angiofibromas, benign tumors comprising blood vessels and connective tissue, are present in about 85% of affected individuals [
Collagenomas, present in about 70% of affected individuals, frequently present as multiple skin-colored, sometimes hypopigmented cutaneous nodules, symmetrically arranged on the trunk, neck, and upper limbs [
Lipomas are benign fatty tissue tumors found anywhere that fat is located and are present in about 30% of affected individuals [
Other skin findings include café au lait macules in 38% of affected individuals, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% [
Meningioma was reported in 8% of 74 individuals [
Ependymoma is present in about 1% of affected individuals.
Improved knowledge of MEN1-associated clinical manifestations, early diagnosis of MEN1-associated tumors, presymptomatic screening of at-risk children, and treatment of metabolic complications of MEN1 have virtually eliminated ZES and/or complicated PHPT as causes of death and decreased morbidity and mortality associated with MEN1-related tumors [
• Pancreatic gastrinomas are more aggressive than duodenal gastrinomas, as suggested by their larger size and greater risk for hepatic metastasis. Among individuals with multiple pancreatic endocrine tumors, eight asymptomatic individuals operated on at a mean age of 33 years did not have metastases [
• Facial angiofibromas, benign tumors comprising blood vessels and connective tissue, are present in about 85% of affected individuals [
• Collagenomas, present in about 70% of affected individuals, frequently present as multiple skin-colored, sometimes hypopigmented cutaneous nodules, symmetrically arranged on the trunk, neck, and upper limbs [
• Lipomas are benign fatty tissue tumors found anywhere that fat is located and are present in about 30% of affected individuals [
• Other skin findings include café au lait macules in 38% of affected individuals, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% [
• Meningioma was reported in 8% of 74 individuals [
• Ependymoma is present in about 1% of affected individuals.
## Primary Hyperparathyroidism (PHPT)
PHPT is often mild, with hypercalcemia often detected in asymptomatic individuals known to have or be at risk for MEN1. PHPT is the most common MEN1-associated endocrinopathy, and the first clinical feature in 90% of individuals. Onset is typically between ages 20 and 25 years. All individuals with MEN1 can be expected to have hypercalcemia by age 50 years [
Common clinical manifestations of hypercalcemia:
Hypercalcemia may increase the secretion of gastrin from a gastrinoma, precipitating and/or exacerbating symptoms of Zollinger-Ellison syndrome [
## Anterior Pituitary Adenomas
Pituitary adenomas are the first clinical manifestation of MEN1 in 25% of simplex cases (i.e., a single occurrence of MEN1 in a family) and in 10% of familial cases. The incidence of pituitary adenomas in MEN1 varies from 15% to 55% in different series [
Pituitary adenomas are usually solitary, although adenomas that produce more than one hormone have been reported (e.g., growth hormone [GH] and prolactin [PRL] with follicle-stimulating hormone [FSH], luteinizing hormone, or adrenocorticotropic hormone [ACTH]) [
Symptoms depend on the pituitary hormone produced:
Clinically significant symptoms such as nerve compression, headache, and hypopituitarism may also result from pituitary mass effects [
## Well-Differentiated Endocrine Tumors of the Gastroenteropancreatic (GEP) Tract
Pancreatic gastrinomas are more aggressive than duodenal gastrinomas, as suggested by their larger size and greater risk for hepatic metastasis. Among individuals with multiple pancreatic endocrine tumors, eight asymptomatic individuals operated on at a mean age of 33 years did not have metastases [
• Pancreatic gastrinomas are more aggressive than duodenal gastrinomas, as suggested by their larger size and greater risk for hepatic metastasis. Among individuals with multiple pancreatic endocrine tumors, eight asymptomatic individuals operated on at a mean age of 33 years did not have metastases [
## Carcinoid Tumors
Thymic, bronchial, and type II gastric enterochromaffin-like (ECL) carcinoids occur in 3%-10% of individuals with MEN1. CT is useful in localizing occult bronchial tumors, while CT and MRI are equally sensitive in detecting thymic carcinoid tumors at initial evaluation [
Carcinoid tumors are the only MEN1-associated neoplasms currently known to exhibit an unequal male-to-female ratio: thymic carcinoids are more prevalent in males than in females with a male:female ratio of 20:1 and bronchial carcinoids occur predominantly in women (male:female ratio of 1:4) [
The clinical course of carcinoid tumors is often indolent but can also be aggressive and resistant to therapy [
The retrospective study of
The mean age at diagnosis of gastric carcinoids is 50 years [
Most bronchial carcinoids, in contrast to thymic carcinoids, behave indolently, albeit with the potential for local mass effect, metastasis, and recurrence after resection [
Therefore, the presence of thymic tumors is reported to be associated with a significantly increased risk of death in individuals with MEN1 (hazard or odds ratio = 4.29) – this is in contrast to the presence of bronchial carcinoids, which have not been associated with increased risk of death [
## Adrenocortical Tumors
Adrenocortical tumors, involving one or both adrenal glands, have been described in a variable percentage (20%-73%) of individuals with MEN1, depending on the radiologic screening methods employed. Adrenocortical tumors are most often detected during CT screening.
Most of these tumors are nonfunctioning, and these include cortical adenomas, hyperplasia, multiple adenomas, nodular hyperplasia, cysts, or carcinomas; fewer than 10% of these tumors demonstrate hormonal hypersecretion, and, among these, adrenocortical tumors causing Cushing disease are the most common [
Rarely, adrenocortical tumors are associated with primary hypercortisolism or hyperaldosteronism [
## Non-Endocrine Tumors Associated with MEN1
Facial angiofibromas, benign tumors comprising blood vessels and connective tissue, are present in about 85% of affected individuals [
Collagenomas, present in about 70% of affected individuals, frequently present as multiple skin-colored, sometimes hypopigmented cutaneous nodules, symmetrically arranged on the trunk, neck, and upper limbs [
Lipomas are benign fatty tissue tumors found anywhere that fat is located and are present in about 30% of affected individuals [
Other skin findings include café au lait macules in 38% of affected individuals, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% [
Meningioma was reported in 8% of 74 individuals [
Ependymoma is present in about 1% of affected individuals.
• Facial angiofibromas, benign tumors comprising blood vessels and connective tissue, are present in about 85% of affected individuals [
• Collagenomas, present in about 70% of affected individuals, frequently present as multiple skin-colored, sometimes hypopigmented cutaneous nodules, symmetrically arranged on the trunk, neck, and upper limbs [
• Lipomas are benign fatty tissue tumors found anywhere that fat is located and are present in about 30% of affected individuals [
• Other skin findings include café au lait macules in 38% of affected individuals, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% [
• Meningioma was reported in 8% of 74 individuals [
• Ependymoma is present in about 1% of affected individuals.
## Morbidity and Mortality of MEN1
Improved knowledge of MEN1-associated clinical manifestations, early diagnosis of MEN1-associated tumors, presymptomatic screening of at-risk children, and treatment of metabolic complications of MEN1 have virtually eliminated ZES and/or complicated PHPT as causes of death and decreased morbidity and mortality associated with MEN1-related tumors [
## Genotype-Phenotype Correlations
No direct genotype-phenotype correlations have been identified in MEN1 [
One study reported a twofold higher risk of death in individuals with a heterozygous
Although a trend (which did not reach statistical significance) suggested that the prevalence of truncating variants in
The only specific clustering of tumors within the MEN1 phenotype was reported in those with the Burin variant
## Penetrance
The age-related penetrance for all clinical features surpasses 50% by age 20 years and 95% by age 40 years [
## Prevalence
MEN1 has a prevalence of between 1:10,000 and 1:100,000 individuals. Geographic clustering as a consequence of founder effect has been reported [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
AD = autosomal dominant; MEN1 = multiple endocrine neoplasia type 1; MOI = mode of inheritance
## Differential Diagnosis
Hereditary Cancer Syndromes in the Differential Diagnosis of MEN1
Earlier-onset pituitary tumors in
MEN2A is assoc w/medullary thyroid carcinoma & pheochromocytoma.
MEN2A-assoc PHPT is generally milder than MEN1-assoc PHPT.
Most persons w/MEN2A & biochemical PHPT do not have clinical symptoms of PHPT.
ACTH = adrenocorticotropic hormone; AD = autosomal dominant; GH = growth hormone; MEN1 = multiple endocrine neoplasia type 1; MOI = mode of inheritance; PHPT = primary hyperparathyroidism; PRL = prolactin; TSH = thyroid stimulating hormone; XL = X-linked
Between 14% and 18% of families with FIHP have identifiable
Pathogenic variants in
FIHP is characterized by parathyroid adenoma or hyperplasia without other associated endocrinopathies in two or more individuals in one family.
Differential Diagnosis of MEN1-Associated Clinical Features
If single pituitary adenoma: (1) not likely to be assoc w/MEN1 if no other findings of MEN1
If multiple pituitary adenomas: see
Sporadically occurring gastrinomas (1) more commonly pancreatic in origin
2 persons w/ZES & pathogenic variants in 2 cyclin-dependent kinase inhibitor genes (
Gastrinomas may also be present in
Affect 20%-55% of persons w/MEN1
May also be present in
Peak age at onset ~1 decade later in those w/sporadic insulinomas
Insulinomas may also be present in
When
Assoc of gastric carcinoids & hyperparathyroidism appears to constitute distinct syndrome in genetically predisposed persons; should not be regarded as "atypical" or "incomplete" expression of MEN1.
Also seen in
Age of onset in TSC: 3-4 yrs (vs in MEN1: <40 years)
MEN1 = multiple endocrine neoplasia type 1; MEN4 = multiple endocrine neoplasia type 4; NF1 = neurofibromatosis 1; TSC = tuberous sclerosis complex; VHL = von Hippel-Lindau syndrome
• Earlier-onset pituitary tumors in
• MEN2A is assoc w/medullary thyroid carcinoma & pheochromocytoma.
• MEN2A-assoc PHPT is generally milder than MEN1-assoc PHPT.
• Most persons w/MEN2A & biochemical PHPT do not have clinical symptoms of PHPT.
• If single pituitary adenoma: (1) not likely to be assoc w/MEN1 if no other findings of MEN1
• If multiple pituitary adenomas: see
• Sporadically occurring gastrinomas (1) more commonly pancreatic in origin
• 2 persons w/ZES & pathogenic variants in 2 cyclin-dependent kinase inhibitor genes (
• Gastrinomas may also be present in
• Affect 20%-55% of persons w/MEN1
• May also be present in
• Peak age at onset ~1 decade later in those w/sporadic insulinomas
• Insulinomas may also be present in
• When
• Assoc of gastric carcinoids & hyperparathyroidism appears to constitute distinct syndrome in genetically predisposed persons; should not be regarded as "atypical" or "incomplete" expression of MEN1.
• Also seen in
• Age of onset in TSC: 3-4 yrs (vs in MEN1: <40 years)
## Management
Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1) have been developed [
To establish the extent of disease and needs in an individual diagnosed with MEN1, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with MEN1
Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
Consider fasting serum concentration of intact (full-length) PTH.
Serum concentration of prolactin, IGF-1, fasting glucose, & insulin
Head MRI
Fasting serum gastrin concentration
Consider abdominal CT, MRI, or EUS exam.
Chest CT;
Chest MRI;
SRS octreotide scan.
EUS = endoscopic ultrasound; GEP = gastroenteropancreatic; MOI = mode of inheritance; PTH = parathyroid hormone; SRS = somatostatin receptor scintigraphy
Chest CT and MRI have better sesitivity than either chest x-ray or somatostatin receptor scintigraphy (SRS) scan in detecting either primary or recurrent thymic carcinoid [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Parathyroidectomy is the treatment of choice for individuals with MEN1, but it is controversial whether to perform subtotal (≤3.5 glands) or total parathyroidectomy, and whether surgery should be performed at an early or late stage of the disease. Timing of surgery and type of parathyroid intervention should be tailored to the individual's specific clinical characteristics.
Subtotal parathyroidectomy (i.e., removal of ≤3.5 glands) has resulted in persistent or recurrent hypercalcemia within ten to 12 years after surgery in 40%-60% of affected individuals with MEN1, and in hypocalcemia requiring long-term therapy with vitamin D or its active metabolite calcitriol in 10%-30% [
Total parathyroidectomy with autotransplantation in the forearm may use both fresh and cryopreserved parathyroid tissue. The procedure is dependent on the vitality of cryopreserved cells, which declines with the time interval from cryopreservation to autotransplantation.
Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
Subtotal parathyroidectomy is suggested as the initial treatment of PHPT in MEN1; total parathyroidectomy with autotransplantation may also be reserved for those with extensive disease either at first or at repeat surgery [
Parathyroidectomy may be reserved for individuals with hypercalcemia, in association with hypercalciuria, to prevent and/or reduce clinical consequences of high calcium levels.
Those with asymptomatic hypercalcemia usually can delay parathyroid surgery in favor of regular assessment for symptom onset and complications.
Parathyroidectomy is mandatory in individuals with MEN1 who have Zollinger–Ellison syndrome (ZES) to correct PHPT and hypercalcemia and, subsequently, reduce gastric acid output and the risk of peptic ulcers.
Bone antiresorptive agents administered prior to surgery help to reduce hypercalcemia and limit PTH-dependent bone resorption, thus reducing future risk of osteoporosis.
After autotransplantation of the parathyroid glands, the serum concentration of PTH should be assessed no earlier than two months postoperatively and once a year thereafter; serum concentration of PTH should be measured simultaneously in separate blood samples, one from the arm without a parathyroid autotransplant and one from the arm with the parathyroid autotransplant. This allows assessment of the function of the transplanted parathyroid tissue and monitoring for possible recurrence of hyperparathyroidism.
Individuals with PHPT who are not considered candidates for parathyroidectomy, who failed a previous intervention, or who present with postsurgical recurrence and decline to undergo any further surgical interventions can also be treated by calcimimetics (e.g., cinacalcet), a class of calcium-sensing receptor agonists that are able to restore normal calcium homeostasis and control parathyroid cell growth. Cinacalcet is a well-tolerated, safe, and effective treatment for individuals with MEN1 [
Dopamine agonists such as cabergoline, bromocriptine, pergolide, and quinagolide are the preferred treatment.
Cabergoline may be considered the current treatment of choice because of its limited side effects and greater potency [
Transsphenoidal surgery and radiotherapy are reserved for drug-resistant tumors and for macroadenomas compressing adjacent structures and generating neuroophthalmologic complications that cannot be managed through pharmacologic therapy.
Transsphenoidal surgery is the surgical treatment of choice for GH-secreting adenomas causing acromegaly and is effective in 50%-70% of individuals.
Somatostatin analogs are the medical therapy of choice for the treatment of GH-secreting adenomas. Octreotide and lanreotide normalize serum concentration of human GH and IGF-1 in more than 50% of treated individuals [
Dopamine agonists are only rarely effective in treatment of GH-secreting adenomas causing acromegaly, although they can be effective in mixed GH-PRL-secreting adenomas and 10%-20% of tumors resistant to somatostatin analogs [
In most ACTH-secreting pituitary adenomas associated with Cushing disease, the treatment is excision of the adenoma. In the series of
For those ACTH-secreting pituitary adenomas associated with Cushing disease that are not cured surgically, radiotherapy may be necessary to reduce the production of ACTH.
In nonfunctioning pituitary adenomas, surgery using a transsphenoidal approach is the treatment of choice. However, in rare instances of very large adenomas with considerable extracellular extension, the transfrontal approach is the only possibility [
In 5%-15% of individuals, medical treatment with potent dopaminergic agonists or with somatostatin analogs may shrink the adenoma before surgery [
Published data are not sufficient to compare the treatment of sporadic versus MEN1-associated pituitary adenomas. Although opinion on this issue differs,
Medications that can control some of the GEP hormone excess-dependent features of MEN1 and thus prevent severe and sometimes life-threatening morbidity in MEN1 include proton pump inhibitors or H
Surgical treatment of gastrinoma in MEN1 is controversial because these tumors are usually microscopic and scattered throughout the neuroendocrine tissue, making successful surgical outcome rare. Surgical ablation of gastrinoma is suggested only in the presence of concomitant nonfunctioning GEP tract tumors that either double their size in a six-month interval, or approach or exceed 2 cm in diameter [
Because MEN1-related gastrinomas occur most commonly in the first and second portions of the duodenum, and less commonly the third and fourth portions of the duodenum and the first jejunal loop, it is important that all these sites be examined during preoperative imaging, intraoperative exploration, and pathologic examination of surgical specimens [
Primary lymph node gastrinomas have been reported in MEN1. Long-term symptom-free follow up after the excision of a lymph node gastrinoma is the only reliable criterion for the diagnosis of a primary lymph node tumor. Thus, the findings of
Surgery is usually indicated for insulinoma and most of the other pancreatic tumors observed in MEN1. According to
The optimal therapy of gastrinoma is controversial.
In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
Unresectable tumors or advanced metastatic cancer can be treated with somatostatin analogs (SSAs), cytotoxic chemotherapy, inhibitors of tyrosine kinase receptors (sunitinib), or inhibitors of mammalian target of rapamycin (mTOR; everolimus). All these therapies have demonstrated an increase in the median progression-free survival in individuals with sporadic pancreatic neuroendocrine tumors; however, no specific trials have been performed in individuals with MEN1 who have GEP tract tumors [
Treatment for nonfunctioning pancreatic neuroendocrine tumors is controversial; some centers consider surgical resection for lesions >1 cm in size, while other centers recommend surgery only for tumors >2 cm.
Occult metastatic disease (i.e., tumors not detected by imaging investigations) may be present in a substantial proportion of affected individuals at the time of initial presentation.
Long-acting SSAs can control the secretory hyperfunction associated with carcinoid syndrome [
Thymic carcinoid recurred in all individuals with MEN1 who were followed for more than one year after resection of the tumor [
For unresectable tumors and those individuals with metastatic disease, treatment with radiotherapy or chemotherapeutic agents (e.g., cisplatin, etoposide) may be used [
Consensus guidelines for the management of MEN1-associated adrenocortical tumors do not exist, since the majority of nonfunctioning tumors of the adrenal glands are benign. The risk for malignancy is increased if the tumor has a diameter >4 cm, although adrenocortical carcinomas have been identified in tumors <4 cm [
There are no specific treatments. Skin lesions in individuals with MEN1 are treated the same way as for the general population.
The organs in MEN1 at highest risk for malignant tumor development – the duodenum, pancreas, and lungs (bronchial carcinoids) – are not suitable for ablative surgery.
The only prophylactic surgery possible in MEN1 is thymectomy to prevent thymic carcinoid [
Surveillance is recommended for individuals with MEN1, including asymptomatic individuals with a heterozygous
Recommended Minimum Surveillance for Individuals with MEN1
Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
Consider fasting serum concentration of intact (full-length) PTH.
Chest CT;
Chest MRI;
SRS octreotide scan.
EUS = endoscopic ultrasound; GEP = gastroenteropancreatic; PTH = parathyroid hormone; SRS = somatostatin receptor scintigraphy
International Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2 [
The interval depends on whether there is biochemical evidence of a neoplasia and/or signs and symptoms of a MEN1-related tumor.
CT and MRI have better sensitivity than either chest x-ray or somatostatin receptor scintigraphy (SRS) scan in detecting either primary or recurrent thymic carcinoid [
Recommended Surveillance for Individuals at 50% Risk for MEN1
Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
Fasting serum concentration of intact (full-length) PTH
Fasting serum gastrin concentration
EUS exam
EUS = endoscopic ultrasound; GEP = gastroenteropancreatic; PTH = parathyroid hormone; ZES = Zollinger-Ellison syndrome
Smoking is associated with a higher risk of developing carcinoid tumors in individuals with MEN1.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the
When molecular genetic testing for a
See
Since MEN1 is a rare condition, there are no specific guidelines regarding the clinical management and follow up of affected pregnant women.
Maternal PHPT from any cause can increase the risk of developing preeclampsia during pregnancy [
There is one report of a 29-year-old woman with molecularly confirmed MEN1 who underwent total parathyroidectomy seven years prior to conception and was maintained on calcium and vitamin D supplementation throughout pregnancy with monthly serum calcium monitoring. She also had an asymptomatic pituitary microadenoma and pancreatic islet cell tumors. Pregnancy proceeded without further complications and resulted in the delivery of a healthy infant at term. The infant did not have any neonatal complications [
Two clinical trials (PROMID and CLARINET) in individuals who did not have MEN1 demonstrated that treatment with SSAs had a significant positive effect on the prolongation of progression-free survival [
One study on octreotide long-acting release (LAR) therapy has demonstrated the same effect in individuals with MEN1. The authors suggest initiating early therapy with SSAs in those with MEN1 who had neuroendocrine tumors to reduce malignant progression and reduce morbidity [
The European Neuroendocrine Tumor Society (ENETS) is conducting a prospective randomized controlled multicenter study in ENETS Centers of Excellence to evaluate nonfunctioning pancreatic neuroendocrine tumors in MEN1:
Response rates, reported to be 15%-35%, may vary based on the type of tumor and the radionuclide used [
Search
• Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
• Consider fasting serum concentration of intact (full-length) PTH.
• Serum concentration of prolactin, IGF-1, fasting glucose, & insulin
• Head MRI
• Fasting serum gastrin concentration
• Consider abdominal CT, MRI, or EUS exam.
• Chest CT;
• Chest MRI;
• SRS octreotide scan.
• Subtotal parathyroidectomy (i.e., removal of ≤3.5 glands) has resulted in persistent or recurrent hypercalcemia within ten to 12 years after surgery in 40%-60% of affected individuals with MEN1, and in hypocalcemia requiring long-term therapy with vitamin D or its active metabolite calcitriol in 10%-30% [
• Total parathyroidectomy with autotransplantation in the forearm may use both fresh and cryopreserved parathyroid tissue. The procedure is dependent on the vitality of cryopreserved cells, which declines with the time interval from cryopreservation to autotransplantation.
• Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
• Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
• Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
• Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
• Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
• Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
• Dopamine agonists such as cabergoline, bromocriptine, pergolide, and quinagolide are the preferred treatment.
• Cabergoline may be considered the current treatment of choice because of its limited side effects and greater potency [
• Transsphenoidal surgery and radiotherapy are reserved for drug-resistant tumors and for macroadenomas compressing adjacent structures and generating neuroophthalmologic complications that cannot be managed through pharmacologic therapy.
• Transsphenoidal surgery is the surgical treatment of choice for GH-secreting adenomas causing acromegaly and is effective in 50%-70% of individuals.
• Somatostatin analogs are the medical therapy of choice for the treatment of GH-secreting adenomas. Octreotide and lanreotide normalize serum concentration of human GH and IGF-1 in more than 50% of treated individuals [
• Dopamine agonists are only rarely effective in treatment of GH-secreting adenomas causing acromegaly, although they can be effective in mixed GH-PRL-secreting adenomas and 10%-20% of tumors resistant to somatostatin analogs [
• In most ACTH-secreting pituitary adenomas associated with Cushing disease, the treatment is excision of the adenoma. In the series of
• For those ACTH-secreting pituitary adenomas associated with Cushing disease that are not cured surgically, radiotherapy may be necessary to reduce the production of ACTH.
• In nonfunctioning pituitary adenomas, surgery using a transsphenoidal approach is the treatment of choice. However, in rare instances of very large adenomas with considerable extracellular extension, the transfrontal approach is the only possibility [
• In 5%-15% of individuals, medical treatment with potent dopaminergic agonists or with somatostatin analogs may shrink the adenoma before surgery [
• Published data are not sufficient to compare the treatment of sporadic versus MEN1-associated pituitary adenomas. Although opinion on this issue differs,
• Medications that can control some of the GEP hormone excess-dependent features of MEN1 and thus prevent severe and sometimes life-threatening morbidity in MEN1 include proton pump inhibitors or H
• Surgical treatment of gastrinoma in MEN1 is controversial because these tumors are usually microscopic and scattered throughout the neuroendocrine tissue, making successful surgical outcome rare. Surgical ablation of gastrinoma is suggested only in the presence of concomitant nonfunctioning GEP tract tumors that either double their size in a six-month interval, or approach or exceed 2 cm in diameter [
• Because MEN1-related gastrinomas occur most commonly in the first and second portions of the duodenum, and less commonly the third and fourth portions of the duodenum and the first jejunal loop, it is important that all these sites be examined during preoperative imaging, intraoperative exploration, and pathologic examination of surgical specimens [
• Primary lymph node gastrinomas have been reported in MEN1. Long-term symptom-free follow up after the excision of a lymph node gastrinoma is the only reliable criterion for the diagnosis of a primary lymph node tumor. Thus, the findings of
• Surgery is usually indicated for insulinoma and most of the other pancreatic tumors observed in MEN1. According to
• The optimal therapy of gastrinoma is controversial.
• In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
• Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
• In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
• Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
• Unresectable tumors or advanced metastatic cancer can be treated with somatostatin analogs (SSAs), cytotoxic chemotherapy, inhibitors of tyrosine kinase receptors (sunitinib), or inhibitors of mammalian target of rapamycin (mTOR; everolimus). All these therapies have demonstrated an increase in the median progression-free survival in individuals with sporadic pancreatic neuroendocrine tumors; however, no specific trials have been performed in individuals with MEN1 who have GEP tract tumors [
• Treatment for nonfunctioning pancreatic neuroendocrine tumors is controversial; some centers consider surgical resection for lesions >1 cm in size, while other centers recommend surgery only for tumors >2 cm.
• Occult metastatic disease (i.e., tumors not detected by imaging investigations) may be present in a substantial proportion of affected individuals at the time of initial presentation.
• In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
• Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
• Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
• Consider fasting serum concentration of intact (full-length) PTH.
• Chest CT;
• Chest MRI;
• SRS octreotide scan.
• Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
• Fasting serum concentration of intact (full-length) PTH
• Fasting serum gastrin concentration
• EUS exam
• Two clinical trials (PROMID and CLARINET) in individuals who did not have MEN1 demonstrated that treatment with SSAs had a significant positive effect on the prolongation of progression-free survival [
• One study on octreotide long-acting release (LAR) therapy has demonstrated the same effect in individuals with MEN1. The authors suggest initiating early therapy with SSAs in those with MEN1 who had neuroendocrine tumors to reduce malignant progression and reduce morbidity [
• The European Neuroendocrine Tumor Society (ENETS) is conducting a prospective randomized controlled multicenter study in ENETS Centers of Excellence to evaluate nonfunctioning pancreatic neuroendocrine tumors in MEN1:
• Two clinical trials (PROMID and CLARINET) in individuals who did not have MEN1 demonstrated that treatment with SSAs had a significant positive effect on the prolongation of progression-free survival [
• One study on octreotide long-acting release (LAR) therapy has demonstrated the same effect in individuals with MEN1. The authors suggest initiating early therapy with SSAs in those with MEN1 who had neuroendocrine tumors to reduce malignant progression and reduce morbidity [
• The European Neuroendocrine Tumor Society (ENETS) is conducting a prospective randomized controlled multicenter study in ENETS Centers of Excellence to evaluate nonfunctioning pancreatic neuroendocrine tumors in MEN1:
• Response rates, reported to be 15%-35%, may vary based on the type of tumor and the radionuclide used [
• Two clinical trials (PROMID and CLARINET) in individuals who did not have MEN1 demonstrated that treatment with SSAs had a significant positive effect on the prolongation of progression-free survival [
• One study on octreotide long-acting release (LAR) therapy has demonstrated the same effect in individuals with MEN1. The authors suggest initiating early therapy with SSAs in those with MEN1 who had neuroendocrine tumors to reduce malignant progression and reduce morbidity [
• The European Neuroendocrine Tumor Society (ENETS) is conducting a prospective randomized controlled multicenter study in ENETS Centers of Excellence to evaluate nonfunctioning pancreatic neuroendocrine tumors in MEN1:
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MEN1, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with MEN1
Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
Consider fasting serum concentration of intact (full-length) PTH.
Serum concentration of prolactin, IGF-1, fasting glucose, & insulin
Head MRI
Fasting serum gastrin concentration
Consider abdominal CT, MRI, or EUS exam.
Chest CT;
Chest MRI;
SRS octreotide scan.
EUS = endoscopic ultrasound; GEP = gastroenteropancreatic; MOI = mode of inheritance; PTH = parathyroid hormone; SRS = somatostatin receptor scintigraphy
Chest CT and MRI have better sesitivity than either chest x-ray or somatostatin receptor scintigraphy (SRS) scan in detecting either primary or recurrent thymic carcinoid [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
• Consider fasting serum concentration of intact (full-length) PTH.
• Serum concentration of prolactin, IGF-1, fasting glucose, & insulin
• Head MRI
• Fasting serum gastrin concentration
• Consider abdominal CT, MRI, or EUS exam.
• Chest CT;
• Chest MRI;
• SRS octreotide scan.
## Treatment of Manifestations
Parathyroidectomy is the treatment of choice for individuals with MEN1, but it is controversial whether to perform subtotal (≤3.5 glands) or total parathyroidectomy, and whether surgery should be performed at an early or late stage of the disease. Timing of surgery and type of parathyroid intervention should be tailored to the individual's specific clinical characteristics.
Subtotal parathyroidectomy (i.e., removal of ≤3.5 glands) has resulted in persistent or recurrent hypercalcemia within ten to 12 years after surgery in 40%-60% of affected individuals with MEN1, and in hypocalcemia requiring long-term therapy with vitamin D or its active metabolite calcitriol in 10%-30% [
Total parathyroidectomy with autotransplantation in the forearm may use both fresh and cryopreserved parathyroid tissue. The procedure is dependent on the vitality of cryopreserved cells, which declines with the time interval from cryopreservation to autotransplantation.
Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
Subtotal parathyroidectomy is suggested as the initial treatment of PHPT in MEN1; total parathyroidectomy with autotransplantation may also be reserved for those with extensive disease either at first or at repeat surgery [
Parathyroidectomy may be reserved for individuals with hypercalcemia, in association with hypercalciuria, to prevent and/or reduce clinical consequences of high calcium levels.
Those with asymptomatic hypercalcemia usually can delay parathyroid surgery in favor of regular assessment for symptom onset and complications.
Parathyroidectomy is mandatory in individuals with MEN1 who have Zollinger–Ellison syndrome (ZES) to correct PHPT and hypercalcemia and, subsequently, reduce gastric acid output and the risk of peptic ulcers.
Bone antiresorptive agents administered prior to surgery help to reduce hypercalcemia and limit PTH-dependent bone resorption, thus reducing future risk of osteoporosis.
After autotransplantation of the parathyroid glands, the serum concentration of PTH should be assessed no earlier than two months postoperatively and once a year thereafter; serum concentration of PTH should be measured simultaneously in separate blood samples, one from the arm without a parathyroid autotransplant and one from the arm with the parathyroid autotransplant. This allows assessment of the function of the transplanted parathyroid tissue and monitoring for possible recurrence of hyperparathyroidism.
Individuals with PHPT who are not considered candidates for parathyroidectomy, who failed a previous intervention, or who present with postsurgical recurrence and decline to undergo any further surgical interventions can also be treated by calcimimetics (e.g., cinacalcet), a class of calcium-sensing receptor agonists that are able to restore normal calcium homeostasis and control parathyroid cell growth. Cinacalcet is a well-tolerated, safe, and effective treatment for individuals with MEN1 [
Dopamine agonists such as cabergoline, bromocriptine, pergolide, and quinagolide are the preferred treatment.
Cabergoline may be considered the current treatment of choice because of its limited side effects and greater potency [
Transsphenoidal surgery and radiotherapy are reserved for drug-resistant tumors and for macroadenomas compressing adjacent structures and generating neuroophthalmologic complications that cannot be managed through pharmacologic therapy.
Transsphenoidal surgery is the surgical treatment of choice for GH-secreting adenomas causing acromegaly and is effective in 50%-70% of individuals.
Somatostatin analogs are the medical therapy of choice for the treatment of GH-secreting adenomas. Octreotide and lanreotide normalize serum concentration of human GH and IGF-1 in more than 50% of treated individuals [
Dopamine agonists are only rarely effective in treatment of GH-secreting adenomas causing acromegaly, although they can be effective in mixed GH-PRL-secreting adenomas and 10%-20% of tumors resistant to somatostatin analogs [
In most ACTH-secreting pituitary adenomas associated with Cushing disease, the treatment is excision of the adenoma. In the series of
For those ACTH-secreting pituitary adenomas associated with Cushing disease that are not cured surgically, radiotherapy may be necessary to reduce the production of ACTH.
In nonfunctioning pituitary adenomas, surgery using a transsphenoidal approach is the treatment of choice. However, in rare instances of very large adenomas with considerable extracellular extension, the transfrontal approach is the only possibility [
In 5%-15% of individuals, medical treatment with potent dopaminergic agonists or with somatostatin analogs may shrink the adenoma before surgery [
Published data are not sufficient to compare the treatment of sporadic versus MEN1-associated pituitary adenomas. Although opinion on this issue differs,
Medications that can control some of the GEP hormone excess-dependent features of MEN1 and thus prevent severe and sometimes life-threatening morbidity in MEN1 include proton pump inhibitors or H
Surgical treatment of gastrinoma in MEN1 is controversial because these tumors are usually microscopic and scattered throughout the neuroendocrine tissue, making successful surgical outcome rare. Surgical ablation of gastrinoma is suggested only in the presence of concomitant nonfunctioning GEP tract tumors that either double their size in a six-month interval, or approach or exceed 2 cm in diameter [
Because MEN1-related gastrinomas occur most commonly in the first and second portions of the duodenum, and less commonly the third and fourth portions of the duodenum and the first jejunal loop, it is important that all these sites be examined during preoperative imaging, intraoperative exploration, and pathologic examination of surgical specimens [
Primary lymph node gastrinomas have been reported in MEN1. Long-term symptom-free follow up after the excision of a lymph node gastrinoma is the only reliable criterion for the diagnosis of a primary lymph node tumor. Thus, the findings of
Surgery is usually indicated for insulinoma and most of the other pancreatic tumors observed in MEN1. According to
The optimal therapy of gastrinoma is controversial.
In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
Unresectable tumors or advanced metastatic cancer can be treated with somatostatin analogs (SSAs), cytotoxic chemotherapy, inhibitors of tyrosine kinase receptors (sunitinib), or inhibitors of mammalian target of rapamycin (mTOR; everolimus). All these therapies have demonstrated an increase in the median progression-free survival in individuals with sporadic pancreatic neuroendocrine tumors; however, no specific trials have been performed in individuals with MEN1 who have GEP tract tumors [
Treatment for nonfunctioning pancreatic neuroendocrine tumors is controversial; some centers consider surgical resection for lesions >1 cm in size, while other centers recommend surgery only for tumors >2 cm.
Occult metastatic disease (i.e., tumors not detected by imaging investigations) may be present in a substantial proportion of affected individuals at the time of initial presentation.
Long-acting SSAs can control the secretory hyperfunction associated with carcinoid syndrome [
Thymic carcinoid recurred in all individuals with MEN1 who were followed for more than one year after resection of the tumor [
For unresectable tumors and those individuals with metastatic disease, treatment with radiotherapy or chemotherapeutic agents (e.g., cisplatin, etoposide) may be used [
Consensus guidelines for the management of MEN1-associated adrenocortical tumors do not exist, since the majority of nonfunctioning tumors of the adrenal glands are benign. The risk for malignancy is increased if the tumor has a diameter >4 cm, although adrenocortical carcinomas have been identified in tumors <4 cm [
There are no specific treatments. Skin lesions in individuals with MEN1 are treated the same way as for the general population.
• Subtotal parathyroidectomy (i.e., removal of ≤3.5 glands) has resulted in persistent or recurrent hypercalcemia within ten to 12 years after surgery in 40%-60% of affected individuals with MEN1, and in hypocalcemia requiring long-term therapy with vitamin D or its active metabolite calcitriol in 10%-30% [
• Total parathyroidectomy with autotransplantation in the forearm may use both fresh and cryopreserved parathyroid tissue. The procedure is dependent on the vitality of cryopreserved cells, which declines with the time interval from cryopreservation to autotransplantation.
• Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
• Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
• Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
• Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
• Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
• Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
• Dopamine agonists such as cabergoline, bromocriptine, pergolide, and quinagolide are the preferred treatment.
• Cabergoline may be considered the current treatment of choice because of its limited side effects and greater potency [
• Transsphenoidal surgery and radiotherapy are reserved for drug-resistant tumors and for macroadenomas compressing adjacent structures and generating neuroophthalmologic complications that cannot be managed through pharmacologic therapy.
• Transsphenoidal surgery is the surgical treatment of choice for GH-secreting adenomas causing acromegaly and is effective in 50%-70% of individuals.
• Somatostatin analogs are the medical therapy of choice for the treatment of GH-secreting adenomas. Octreotide and lanreotide normalize serum concentration of human GH and IGF-1 in more than 50% of treated individuals [
• Dopamine agonists are only rarely effective in treatment of GH-secreting adenomas causing acromegaly, although they can be effective in mixed GH-PRL-secreting adenomas and 10%-20% of tumors resistant to somatostatin analogs [
• In most ACTH-secreting pituitary adenomas associated with Cushing disease, the treatment is excision of the adenoma. In the series of
• For those ACTH-secreting pituitary adenomas associated with Cushing disease that are not cured surgically, radiotherapy may be necessary to reduce the production of ACTH.
• In nonfunctioning pituitary adenomas, surgery using a transsphenoidal approach is the treatment of choice. However, in rare instances of very large adenomas with considerable extracellular extension, the transfrontal approach is the only possibility [
• In 5%-15% of individuals, medical treatment with potent dopaminergic agonists or with somatostatin analogs may shrink the adenoma before surgery [
• Published data are not sufficient to compare the treatment of sporadic versus MEN1-associated pituitary adenomas. Although opinion on this issue differs,
• Medications that can control some of the GEP hormone excess-dependent features of MEN1 and thus prevent severe and sometimes life-threatening morbidity in MEN1 include proton pump inhibitors or H
• Surgical treatment of gastrinoma in MEN1 is controversial because these tumors are usually microscopic and scattered throughout the neuroendocrine tissue, making successful surgical outcome rare. Surgical ablation of gastrinoma is suggested only in the presence of concomitant nonfunctioning GEP tract tumors that either double their size in a six-month interval, or approach or exceed 2 cm in diameter [
• Because MEN1-related gastrinomas occur most commonly in the first and second portions of the duodenum, and less commonly the third and fourth portions of the duodenum and the first jejunal loop, it is important that all these sites be examined during preoperative imaging, intraoperative exploration, and pathologic examination of surgical specimens [
• Primary lymph node gastrinomas have been reported in MEN1. Long-term symptom-free follow up after the excision of a lymph node gastrinoma is the only reliable criterion for the diagnosis of a primary lymph node tumor. Thus, the findings of
• Surgery is usually indicated for insulinoma and most of the other pancreatic tumors observed in MEN1. According to
• The optimal therapy of gastrinoma is controversial.
• In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
• Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
• In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
• Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
• Unresectable tumors or advanced metastatic cancer can be treated with somatostatin analogs (SSAs), cytotoxic chemotherapy, inhibitors of tyrosine kinase receptors (sunitinib), or inhibitors of mammalian target of rapamycin (mTOR; everolimus). All these therapies have demonstrated an increase in the median progression-free survival in individuals with sporadic pancreatic neuroendocrine tumors; however, no specific trials have been performed in individuals with MEN1 who have GEP tract tumors [
• Treatment for nonfunctioning pancreatic neuroendocrine tumors is controversial; some centers consider surgical resection for lesions >1 cm in size, while other centers recommend surgery only for tumors >2 cm.
• Occult metastatic disease (i.e., tumors not detected by imaging investigations) may be present in a substantial proportion of affected individuals at the time of initial presentation.
• In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
• Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
## Primary Hyperparathyroidism (PHPT)
Parathyroidectomy is the treatment of choice for individuals with MEN1, but it is controversial whether to perform subtotal (≤3.5 glands) or total parathyroidectomy, and whether surgery should be performed at an early or late stage of the disease. Timing of surgery and type of parathyroid intervention should be tailored to the individual's specific clinical characteristics.
Subtotal parathyroidectomy (i.e., removal of ≤3.5 glands) has resulted in persistent or recurrent hypercalcemia within ten to 12 years after surgery in 40%-60% of affected individuals with MEN1, and in hypocalcemia requiring long-term therapy with vitamin D or its active metabolite calcitriol in 10%-30% [
Total parathyroidectomy with autotransplantation in the forearm may use both fresh and cryopreserved parathyroid tissue. The procedure is dependent on the vitality of cryopreserved cells, which declines with the time interval from cryopreservation to autotransplantation.
Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
Subtotal parathyroidectomy is suggested as the initial treatment of PHPT in MEN1; total parathyroidectomy with autotransplantation may also be reserved for those with extensive disease either at first or at repeat surgery [
Parathyroidectomy may be reserved for individuals with hypercalcemia, in association with hypercalciuria, to prevent and/or reduce clinical consequences of high calcium levels.
Those with asymptomatic hypercalcemia usually can delay parathyroid surgery in favor of regular assessment for symptom onset and complications.
Parathyroidectomy is mandatory in individuals with MEN1 who have Zollinger–Ellison syndrome (ZES) to correct PHPT and hypercalcemia and, subsequently, reduce gastric acid output and the risk of peptic ulcers.
Bone antiresorptive agents administered prior to surgery help to reduce hypercalcemia and limit PTH-dependent bone resorption, thus reducing future risk of osteoporosis.
After autotransplantation of the parathyroid glands, the serum concentration of PTH should be assessed no earlier than two months postoperatively and once a year thereafter; serum concentration of PTH should be measured simultaneously in separate blood samples, one from the arm without a parathyroid autotransplant and one from the arm with the parathyroid autotransplant. This allows assessment of the function of the transplanted parathyroid tissue and monitoring for possible recurrence of hyperparathyroidism.
Individuals with PHPT who are not considered candidates for parathyroidectomy, who failed a previous intervention, or who present with postsurgical recurrence and decline to undergo any further surgical interventions can also be treated by calcimimetics (e.g., cinacalcet), a class of calcium-sensing receptor agonists that are able to restore normal calcium homeostasis and control parathyroid cell growth. Cinacalcet is a well-tolerated, safe, and effective treatment for individuals with MEN1 [
• Subtotal parathyroidectomy (i.e., removal of ≤3.5 glands) has resulted in persistent or recurrent hypercalcemia within ten to 12 years after surgery in 40%-60% of affected individuals with MEN1, and in hypocalcemia requiring long-term therapy with vitamin D or its active metabolite calcitriol in 10%-30% [
• Total parathyroidectomy with autotransplantation in the forearm may use both fresh and cryopreserved parathyroid tissue. The procedure is dependent on the vitality of cryopreserved cells, which declines with the time interval from cryopreservation to autotransplantation.
• Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
• Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
• Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
• Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
• Intraoperative monitoring of parathyroid hormone (PTH) by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue and to help with the decision to implant parathyroid tissue in the forearm is recommended.
• Recurrent hypercalcemia is present in more than 50% of affected individuals with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.
## Anterior Pituitary Adenomas
Dopamine agonists such as cabergoline, bromocriptine, pergolide, and quinagolide are the preferred treatment.
Cabergoline may be considered the current treatment of choice because of its limited side effects and greater potency [
Transsphenoidal surgery and radiotherapy are reserved for drug-resistant tumors and for macroadenomas compressing adjacent structures and generating neuroophthalmologic complications that cannot be managed through pharmacologic therapy.
Transsphenoidal surgery is the surgical treatment of choice for GH-secreting adenomas causing acromegaly and is effective in 50%-70% of individuals.
Somatostatin analogs are the medical therapy of choice for the treatment of GH-secreting adenomas. Octreotide and lanreotide normalize serum concentration of human GH and IGF-1 in more than 50% of treated individuals [
Dopamine agonists are only rarely effective in treatment of GH-secreting adenomas causing acromegaly, although they can be effective in mixed GH-PRL-secreting adenomas and 10%-20% of tumors resistant to somatostatin analogs [
In most ACTH-secreting pituitary adenomas associated with Cushing disease, the treatment is excision of the adenoma. In the series of
For those ACTH-secreting pituitary adenomas associated with Cushing disease that are not cured surgically, radiotherapy may be necessary to reduce the production of ACTH.
In nonfunctioning pituitary adenomas, surgery using a transsphenoidal approach is the treatment of choice. However, in rare instances of very large adenomas with considerable extracellular extension, the transfrontal approach is the only possibility [
In 5%-15% of individuals, medical treatment with potent dopaminergic agonists or with somatostatin analogs may shrink the adenoma before surgery [
Published data are not sufficient to compare the treatment of sporadic versus MEN1-associated pituitary adenomas. Although opinion on this issue differs,
• Dopamine agonists such as cabergoline, bromocriptine, pergolide, and quinagolide are the preferred treatment.
• Cabergoline may be considered the current treatment of choice because of its limited side effects and greater potency [
• Transsphenoidal surgery and radiotherapy are reserved for drug-resistant tumors and for macroadenomas compressing adjacent structures and generating neuroophthalmologic complications that cannot be managed through pharmacologic therapy.
• Transsphenoidal surgery is the surgical treatment of choice for GH-secreting adenomas causing acromegaly and is effective in 50%-70% of individuals.
• Somatostatin analogs are the medical therapy of choice for the treatment of GH-secreting adenomas. Octreotide and lanreotide normalize serum concentration of human GH and IGF-1 in more than 50% of treated individuals [
• Dopamine agonists are only rarely effective in treatment of GH-secreting adenomas causing acromegaly, although they can be effective in mixed GH-PRL-secreting adenomas and 10%-20% of tumors resistant to somatostatin analogs [
• In most ACTH-secreting pituitary adenomas associated with Cushing disease, the treatment is excision of the adenoma. In the series of
• For those ACTH-secreting pituitary adenomas associated with Cushing disease that are not cured surgically, radiotherapy may be necessary to reduce the production of ACTH.
• In nonfunctioning pituitary adenomas, surgery using a transsphenoidal approach is the treatment of choice. However, in rare instances of very large adenomas with considerable extracellular extension, the transfrontal approach is the only possibility [
• In 5%-15% of individuals, medical treatment with potent dopaminergic agonists or with somatostatin analogs may shrink the adenoma before surgery [
• Published data are not sufficient to compare the treatment of sporadic versus MEN1-associated pituitary adenomas. Although opinion on this issue differs,
## Well-Differentiated Endocrine Tumors of the Gastroenteropancreatic (GEP) Tract
Medications that can control some of the GEP hormone excess-dependent features of MEN1 and thus prevent severe and sometimes life-threatening morbidity in MEN1 include proton pump inhibitors or H
Surgical treatment of gastrinoma in MEN1 is controversial because these tumors are usually microscopic and scattered throughout the neuroendocrine tissue, making successful surgical outcome rare. Surgical ablation of gastrinoma is suggested only in the presence of concomitant nonfunctioning GEP tract tumors that either double their size in a six-month interval, or approach or exceed 2 cm in diameter [
Because MEN1-related gastrinomas occur most commonly in the first and second portions of the duodenum, and less commonly the third and fourth portions of the duodenum and the first jejunal loop, it is important that all these sites be examined during preoperative imaging, intraoperative exploration, and pathologic examination of surgical specimens [
Primary lymph node gastrinomas have been reported in MEN1. Long-term symptom-free follow up after the excision of a lymph node gastrinoma is the only reliable criterion for the diagnosis of a primary lymph node tumor. Thus, the findings of
Surgery is usually indicated for insulinoma and most of the other pancreatic tumors observed in MEN1. According to
The optimal therapy of gastrinoma is controversial.
In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
Unresectable tumors or advanced metastatic cancer can be treated with somatostatin analogs (SSAs), cytotoxic chemotherapy, inhibitors of tyrosine kinase receptors (sunitinib), or inhibitors of mammalian target of rapamycin (mTOR; everolimus). All these therapies have demonstrated an increase in the median progression-free survival in individuals with sporadic pancreatic neuroendocrine tumors; however, no specific trials have been performed in individuals with MEN1 who have GEP tract tumors [
Treatment for nonfunctioning pancreatic neuroendocrine tumors is controversial; some centers consider surgical resection for lesions >1 cm in size, while other centers recommend surgery only for tumors >2 cm.
Occult metastatic disease (i.e., tumors not detected by imaging investigations) may be present in a substantial proportion of affected individuals at the time of initial presentation.
• Medications that can control some of the GEP hormone excess-dependent features of MEN1 and thus prevent severe and sometimes life-threatening morbidity in MEN1 include proton pump inhibitors or H
• Surgical treatment of gastrinoma in MEN1 is controversial because these tumors are usually microscopic and scattered throughout the neuroendocrine tissue, making successful surgical outcome rare. Surgical ablation of gastrinoma is suggested only in the presence of concomitant nonfunctioning GEP tract tumors that either double their size in a six-month interval, or approach or exceed 2 cm in diameter [
• Because MEN1-related gastrinomas occur most commonly in the first and second portions of the duodenum, and less commonly the third and fourth portions of the duodenum and the first jejunal loop, it is important that all these sites be examined during preoperative imaging, intraoperative exploration, and pathologic examination of surgical specimens [
• Primary lymph node gastrinomas have been reported in MEN1. Long-term symptom-free follow up after the excision of a lymph node gastrinoma is the only reliable criterion for the diagnosis of a primary lymph node tumor. Thus, the findings of
• Surgery is usually indicated for insulinoma and most of the other pancreatic tumors observed in MEN1. According to
• The optimal therapy of gastrinoma is controversial.
• In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
• Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
• In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
• Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
• Unresectable tumors or advanced metastatic cancer can be treated with somatostatin analogs (SSAs), cytotoxic chemotherapy, inhibitors of tyrosine kinase receptors (sunitinib), or inhibitors of mammalian target of rapamycin (mTOR; everolimus). All these therapies have demonstrated an increase in the median progression-free survival in individuals with sporadic pancreatic neuroendocrine tumors; however, no specific trials have been performed in individuals with MEN1 who have GEP tract tumors [
• Treatment for nonfunctioning pancreatic neuroendocrine tumors is controversial; some centers consider surgical resection for lesions >1 cm in size, while other centers recommend surgery only for tumors >2 cm.
• Occult metastatic disease (i.e., tumors not detected by imaging investigations) may be present in a substantial proportion of affected individuals at the time of initial presentation.
• In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. Individuals with MEN1 will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may also be considered together with the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomas typical of these tumors in individuals with MEN1, surgery is often not effective.
• Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1 but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
## Carcinoid Tumors
Long-acting SSAs can control the secretory hyperfunction associated with carcinoid syndrome [
Thymic carcinoid recurred in all individuals with MEN1 who were followed for more than one year after resection of the tumor [
For unresectable tumors and those individuals with metastatic disease, treatment with radiotherapy or chemotherapeutic agents (e.g., cisplatin, etoposide) may be used [
## Adrenocortical Tumors
Consensus guidelines for the management of MEN1-associated adrenocortical tumors do not exist, since the majority of nonfunctioning tumors of the adrenal glands are benign. The risk for malignancy is increased if the tumor has a diameter >4 cm, although adrenocortical carcinomas have been identified in tumors <4 cm [
## Non-Endocrine Tumors Associated with MEN1
There are no specific treatments. Skin lesions in individuals with MEN1 are treated the same way as for the general population.
## Prevention of Primary Manifestations
The organs in MEN1 at highest risk for malignant tumor development – the duodenum, pancreas, and lungs (bronchial carcinoids) – are not suitable for ablative surgery.
The only prophylactic surgery possible in MEN1 is thymectomy to prevent thymic carcinoid [
## Surveillance
Surveillance is recommended for individuals with MEN1, including asymptomatic individuals with a heterozygous
Recommended Minimum Surveillance for Individuals with MEN1
Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
Consider fasting serum concentration of intact (full-length) PTH.
Chest CT;
Chest MRI;
SRS octreotide scan.
EUS = endoscopic ultrasound; GEP = gastroenteropancreatic; PTH = parathyroid hormone; SRS = somatostatin receptor scintigraphy
International Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2 [
The interval depends on whether there is biochemical evidence of a neoplasia and/or signs and symptoms of a MEN1-related tumor.
CT and MRI have better sensitivity than either chest x-ray or somatostatin receptor scintigraphy (SRS) scan in detecting either primary or recurrent thymic carcinoid [
Recommended Surveillance for Individuals at 50% Risk for MEN1
Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
Fasting serum concentration of intact (full-length) PTH
Fasting serum gastrin concentration
EUS exam
EUS = endoscopic ultrasound; GEP = gastroenteropancreatic; PTH = parathyroid hormone; ZES = Zollinger-Ellison syndrome
• Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
• Consider fasting serum concentration of intact (full-length) PTH.
• Chest CT;
• Chest MRI;
• SRS octreotide scan.
• Fasting total serum calcium concentration (corrected for albumin) &/or ionized-serum calcium concentration
• Fasting serum concentration of intact (full-length) PTH
• Fasting serum gastrin concentration
• EUS exam
## Agents/Circumstances to Avoid
Smoking is associated with a higher risk of developing carcinoid tumors in individuals with MEN1.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the
When molecular genetic testing for a
See
## Pregnancy Management
Since MEN1 is a rare condition, there are no specific guidelines regarding the clinical management and follow up of affected pregnant women.
Maternal PHPT from any cause can increase the risk of developing preeclampsia during pregnancy [
There is one report of a 29-year-old woman with molecularly confirmed MEN1 who underwent total parathyroidectomy seven years prior to conception and was maintained on calcium and vitamin D supplementation throughout pregnancy with monthly serum calcium monitoring. She also had an asymptomatic pituitary microadenoma and pancreatic islet cell tumors. Pregnancy proceeded without further complications and resulted in the delivery of a healthy infant at term. The infant did not have any neonatal complications [
## Therapies Under Investigation
Two clinical trials (PROMID and CLARINET) in individuals who did not have MEN1 demonstrated that treatment with SSAs had a significant positive effect on the prolongation of progression-free survival [
One study on octreotide long-acting release (LAR) therapy has demonstrated the same effect in individuals with MEN1. The authors suggest initiating early therapy with SSAs in those with MEN1 who had neuroendocrine tumors to reduce malignant progression and reduce morbidity [
The European Neuroendocrine Tumor Society (ENETS) is conducting a prospective randomized controlled multicenter study in ENETS Centers of Excellence to evaluate nonfunctioning pancreatic neuroendocrine tumors in MEN1:
Response rates, reported to be 15%-35%, may vary based on the type of tumor and the radionuclide used [
Search
• Two clinical trials (PROMID and CLARINET) in individuals who did not have MEN1 demonstrated that treatment with SSAs had a significant positive effect on the prolongation of progression-free survival [
• One study on octreotide long-acting release (LAR) therapy has demonstrated the same effect in individuals with MEN1. The authors suggest initiating early therapy with SSAs in those with MEN1 who had neuroendocrine tumors to reduce malignant progression and reduce morbidity [
• The European Neuroendocrine Tumor Society (ENETS) is conducting a prospective randomized controlled multicenter study in ENETS Centers of Excellence to evaluate nonfunctioning pancreatic neuroendocrine tumors in MEN1:
• Two clinical trials (PROMID and CLARINET) in individuals who did not have MEN1 demonstrated that treatment with SSAs had a significant positive effect on the prolongation of progression-free survival [
• One study on octreotide long-acting release (LAR) therapy has demonstrated the same effect in individuals with MEN1. The authors suggest initiating early therapy with SSAs in those with MEN1 who had neuroendocrine tumors to reduce malignant progression and reduce morbidity [
• The European Neuroendocrine Tumor Society (ENETS) is conducting a prospective randomized controlled multicenter study in ENETS Centers of Excellence to evaluate nonfunctioning pancreatic neuroendocrine tumors in MEN1:
• Response rates, reported to be 15%-35%, may vary based on the type of tumor and the radionuclide used [
• Two clinical trials (PROMID and CLARINET) in individuals who did not have MEN1 demonstrated that treatment with SSAs had a significant positive effect on the prolongation of progression-free survival [
• One study on octreotide long-acting release (LAR) therapy has demonstrated the same effect in individuals with MEN1. The authors suggest initiating early therapy with SSAs in those with MEN1 who had neuroendocrine tumors to reduce malignant progression and reduce morbidity [
• The European Neuroendocrine Tumor Society (ENETS) is conducting a prospective randomized controlled multicenter study in ENETS Centers of Excellence to evaluate nonfunctioning pancreatic neuroendocrine tumors in MEN1:
## Genetic Counseling
Multiple endocrine neoplasia type 1 (MEN1) is inherited in an autosomal dominant manner.
Approximately 90% of individuals diagnosed with MEN1 have an affected parent.
Approximately 10% of individuals diagnosed with MEN1 have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see
If the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with MEN1 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to male and female sibs of inheriting the pathogenic variant is 50%. A high clinical variability has been described among affected members of the same families (bearing the same
If the proband has a known
If the parents have not been tested for the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Approximately 90% of individuals diagnosed with MEN1 have an affected parent.
• Approximately 10% of individuals diagnosed with MEN1 have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see
• If the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with MEN1 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to male and female sibs of inheriting the pathogenic variant is 50%. A high clinical variability has been described among affected members of the same families (bearing the same
• If the proband has a known
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Multiple endocrine neoplasia type 1 (MEN1) is inherited in an autosomal dominant manner.
## Risk to Family Members
Approximately 90% of individuals diagnosed with MEN1 have an affected parent.
Approximately 10% of individuals diagnosed with MEN1 have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see
If the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with MEN1 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to male and female sibs of inheriting the pathogenic variant is 50%. A high clinical variability has been described among affected members of the same families (bearing the same
If the proband has a known
If the parents have not been tested for the
• Approximately 90% of individuals diagnosed with MEN1 have an affected parent.
• Approximately 10% of individuals diagnosed with MEN1 have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see
• If the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with MEN1 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to male and female sibs of inheriting the pathogenic variant is 50%. A high clinical variability has been described among affected members of the same families (bearing the same
• If the proband has a known
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
Italy
6 Information Way
Bethesda MD 20892–3569
Association for Multiple Endocrine Neoplasia Disorders
United Kingdom
•
• United Kingdom
•
•
• Italy
•
•
•
•
•
• 6 Information Way
• Bethesda MD 20892–3569
•
•
•
•
•
•
• Association for Multiple Endocrine Neoplasia Disorders
• United Kingdom
•
## Molecular Genetics
Multiple Endocrine Neoplasia Type 1: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Multiple Endocrine Neoplasia Type 1 (
Directly interacting with transcription factors (e.g., JunD, NF-kB, PPARgamma, VDR) that induce or suppress gene transcription;
Interacting with histone-modifying enzymes and the polycomb group to influence gene transcription through modification of chromatin and the accessibility to gene promoters to transcriptional factors;
Directly interacting with gene promoters as a transcription factor;
Interfering with or regulating cell signaling pathways, such as the transforming growth factor beta (TGF-β) and the Wnt/β-catenin signaling pathways.
A physiologic role for menin has been shown in other processes, not directly related to tumorigenesis:
Regulation of early differentiation of osteoblasts (through interactions with Smad1 and Smad5 proteins) [
Inhibition of osteoblast late differentiation (by negatively regulating the BMP2-Smad1/5-Runx2 cascade, through the TGF-β/Smad3 pathway) [
Direct modulation of both SMAD1 protein and miR-26a expression during the commitment of human adipose tissue-derived mesenchymal stem cells to the osteoblast lineage [
Notable
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
• Directly interacting with transcription factors (e.g., JunD, NF-kB, PPARgamma, VDR) that induce or suppress gene transcription;
• Interacting with histone-modifying enzymes and the polycomb group to influence gene transcription through modification of chromatin and the accessibility to gene promoters to transcriptional factors;
• Directly interacting with gene promoters as a transcription factor;
• Interfering with or regulating cell signaling pathways, such as the transforming growth factor beta (TGF-β) and the Wnt/β-catenin signaling pathways.
•
• Regulation of early differentiation of osteoblasts (through interactions with Smad1 and Smad5 proteins) [
• Inhibition of osteoblast late differentiation (by negatively regulating the BMP2-Smad1/5-Runx2 cascade, through the TGF-β/Smad3 pathway) [
• Direct modulation of both SMAD1 protein and miR-26a expression during the commitment of human adipose tissue-derived mesenchymal stem cells to the osteoblast lineage [
• Regulation of early differentiation of osteoblasts (through interactions with Smad1 and Smad5 proteins) [
• Inhibition of osteoblast late differentiation (by negatively regulating the BMP2-Smad1/5-Runx2 cascade, through the TGF-β/Smad3 pathway) [
• Direct modulation of both SMAD1 protein and miR-26a expression during the commitment of human adipose tissue-derived mesenchymal stem cells to the osteoblast lineage [
• Regulation of early differentiation of osteoblasts (through interactions with Smad1 and Smad5 proteins) [
• Inhibition of osteoblast late differentiation (by negatively regulating the BMP2-Smad1/5-Runx2 cascade, through the TGF-β/Smad3 pathway) [
• Direct modulation of both SMAD1 protein and miR-26a expression during the commitment of human adipose tissue-derived mesenchymal stem cells to the osteoblast lineage [
## Molecular Pathogenesis
Directly interacting with transcription factors (e.g., JunD, NF-kB, PPARgamma, VDR) that induce or suppress gene transcription;
Interacting with histone-modifying enzymes and the polycomb group to influence gene transcription through modification of chromatin and the accessibility to gene promoters to transcriptional factors;
Directly interacting with gene promoters as a transcription factor;
Interfering with or regulating cell signaling pathways, such as the transforming growth factor beta (TGF-β) and the Wnt/β-catenin signaling pathways.
A physiologic role for menin has been shown in other processes, not directly related to tumorigenesis:
Regulation of early differentiation of osteoblasts (through interactions with Smad1 and Smad5 proteins) [
Inhibition of osteoblast late differentiation (by negatively regulating the BMP2-Smad1/5-Runx2 cascade, through the TGF-β/Smad3 pathway) [
Direct modulation of both SMAD1 protein and miR-26a expression during the commitment of human adipose tissue-derived mesenchymal stem cells to the osteoblast lineage [
Notable
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
• Directly interacting with transcription factors (e.g., JunD, NF-kB, PPARgamma, VDR) that induce or suppress gene transcription;
• Interacting with histone-modifying enzymes and the polycomb group to influence gene transcription through modification of chromatin and the accessibility to gene promoters to transcriptional factors;
• Directly interacting with gene promoters as a transcription factor;
• Interfering with or regulating cell signaling pathways, such as the transforming growth factor beta (TGF-β) and the Wnt/β-catenin signaling pathways.
•
• Regulation of early differentiation of osteoblasts (through interactions with Smad1 and Smad5 proteins) [
• Inhibition of osteoblast late differentiation (by negatively regulating the BMP2-Smad1/5-Runx2 cascade, through the TGF-β/Smad3 pathway) [
• Direct modulation of both SMAD1 protein and miR-26a expression during the commitment of human adipose tissue-derived mesenchymal stem cells to the osteoblast lineage [
• Regulation of early differentiation of osteoblasts (through interactions with Smad1 and Smad5 proteins) [
• Inhibition of osteoblast late differentiation (by negatively regulating the BMP2-Smad1/5-Runx2 cascade, through the TGF-β/Smad3 pathway) [
• Direct modulation of both SMAD1 protein and miR-26a expression during the commitment of human adipose tissue-derived mesenchymal stem cells to the osteoblast lineage [
• Regulation of early differentiation of osteoblasts (through interactions with Smad1 and Smad5 proteins) [
• Inhibition of osteoblast late differentiation (by negatively regulating the BMP2-Smad1/5-Runx2 cascade, through the TGF-β/Smad3 pathway) [
• Direct modulation of both SMAD1 protein and miR-26a expression during the commitment of human adipose tissue-derived mesenchymal stem cells to the osteoblast lineage [
## Cancer and Benign Tumors
## Chapter Notes
This chapter has been supported by Cofin MIUR 2003 (FM), by AIRC 2000 (MLB), and by the Fondazione Ente Cassa di Risparmio di Firenze (MLB).
Maria Luisa Brandi, MD, PhD (2005-present)
Alberto Falchetti, MD, PhD; University Hospital of Careggi (2005-2012)
Francesca Giusti, MD, PhD (2012-present)
Francesca Marini, PhD (2005-present)
10 March 2022 (sw) Comprehensive update posted live
14 December 2017 (ma) Comprehensive update posted live
12 February 2015 (me) Comprehensive update posted live
6 September 2012 (me) Comprehensive update posted live
2 March 2010 (me) Comprehensive update posted live
31 August 2005 (me) Review posted live
9 September 2004 (mlb) Original submission
• 10 March 2022 (sw) Comprehensive update posted live
• 14 December 2017 (ma) Comprehensive update posted live
• 12 February 2015 (me) Comprehensive update posted live
• 6 September 2012 (me) Comprehensive update posted live
• 2 March 2010 (me) Comprehensive update posted live
• 31 August 2005 (me) Review posted live
• 9 September 2004 (mlb) Original submission
## Acknowledgments
This chapter has been supported by Cofin MIUR 2003 (FM), by AIRC 2000 (MLB), and by the Fondazione Ente Cassa di Risparmio di Firenze (MLB).
## Author History
Maria Luisa Brandi, MD, PhD (2005-present)
Alberto Falchetti, MD, PhD; University Hospital of Careggi (2005-2012)
Francesca Giusti, MD, PhD (2012-present)
Francesca Marini, PhD (2005-present)
## Revision History
10 March 2022 (sw) Comprehensive update posted live
14 December 2017 (ma) Comprehensive update posted live
12 February 2015 (me) Comprehensive update posted live
6 September 2012 (me) Comprehensive update posted live
2 March 2010 (me) Comprehensive update posted live
31 August 2005 (me) Review posted live
9 September 2004 (mlb) Original submission
• 10 March 2022 (sw) Comprehensive update posted live
• 14 December 2017 (ma) Comprehensive update posted live
• 12 February 2015 (me) Comprehensive update posted live
• 6 September 2012 (me) Comprehensive update posted live
• 2 March 2010 (me) Comprehensive update posted live
• 31 August 2005 (me) Review posted live
• 9 September 2004 (mlb) Original submission
## References
Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). Available
• Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). Available
## Published Guidelines / Consensus Statements
Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). Available
• Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). Available
## Literature Cited
|
[] |
31/8/2005
|
10/3/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
men2
|
men2
|
[
"MEN2",
"MEN2 Syndrome",
"MEN2 Syndrome",
"Multiple Endocrine Neoplasia Type 2A (MEN2A)",
"Multiple Endocrine Neoplasia Type 2B (MEN2B)",
"Familial Medullary Thyroid Carcinoma (FMTC)",
"Proto-oncogene tyrosine-protein kinase receptor ret",
"RET",
"Multiple Endocrine Neoplasia Type 2"
] |
Multiple Endocrine Neoplasia Type 2
|
Charis Eng, Gilman Plitt
|
Summary Multiple endocrine neoplasia type 2 (MEN2) includes the following phenotypes: MEN2A, familial medullary thyroid carcinoma (FMTC, which may be a variant of MEN2A), and MEN2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN2A and MEN2B involve an increased risk for pheochromocytoma; MEN2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features of MEN2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a marfanoid habitus. MTC typically occurs in early childhood in MEN2B, early adulthood in MEN2A, and middle age in FMTC. The diagnosis of MEN2 is established in a proband who fulfills existing clinical diagnostic criteria or by identification of a heterozygous germline gain-of-function variant in All MEN2 phenotypes are inherited in an autosomal dominant manner. Up to 95% of individuals diagnosed with MEN2A and 50% of individuals diagnosed with MEN2B have an affected parent. (By definition, individuals with FMTC have multiple family members who are affected.) Approximately 5%-9% of individuals with MEN2A and 50% of individuals with MEN2B have the disorder as the result of a
|
Multiple endocrine neoplasia type 2A (MEN2A)
Familial medullary thyroid carcinoma (FMTC)
Multiple endocrine neoplasia type 2B (MEN2B)
For synonyms and outdated names see
• Multiple endocrine neoplasia type 2A (MEN2A)
• Familial medullary thyroid carcinoma (FMTC)
• Multiple endocrine neoplasia type 2B (MEN2B)
## Diagnosis
Clinical diagnostic criteria for multiple endocrine neoplasia type 2 (MEN2) have been published [
MEN2 includes the phenotypes MEN2A; familial medullary thyroid carcinoma (FMTC), which may itself be a variant of MEN2A; and MEN2B.
MEN2A
FMTC
MEN2B
The
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Multiple Endocrine Neoplasia Type 2
FMTC = familial medullary thyroid carcinoma; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B; NA = not applicable
See
Since MEN2 occurs through a gain-of-function mechanism, gene-targeted deletion/duplication analysis is not indicated.
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants, and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis of all
Pathogenic variants of codons 618, 620, and 634 each account for 20%-30% of pathogenic variants. Other pathogenic variants in exons 5, 8, 10, 11, and 13-16 appear to account for a small percentage of pathogenic variants in families with FMTC, with an important minority affecting codons 768 and 804 [
Approximately 95% of individuals have a pathogenic variant at codon 918 in exon 16 [
Pathogenic variants in exons 10 and 11 [
Pathogenic variants typically detected:
• For an introduction to multigene panels click
## Suggestive Findings
MEN2 includes the phenotypes MEN2A; familial medullary thyroid carcinoma (FMTC), which may itself be a variant of MEN2A; and MEN2B.
MEN2A
FMTC
MEN2B
## Establishing the Diagnosis
The
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Multiple Endocrine Neoplasia Type 2
FMTC = familial medullary thyroid carcinoma; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B; NA = not applicable
See
Since MEN2 occurs through a gain-of-function mechanism, gene-targeted deletion/duplication analysis is not indicated.
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants, and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis of all
Pathogenic variants of codons 618, 620, and 634 each account for 20%-30% of pathogenic variants. Other pathogenic variants in exons 5, 8, 10, 11, and 13-16 appear to account for a small percentage of pathogenic variants in families with FMTC, with an important minority affecting codons 768 and 804 [
Approximately 95% of individuals have a pathogenic variant at codon 918 in exon 16 [
Pathogenic variants in exons 10 and 11 [
Pathogenic variants typically detected:
• For an introduction to multigene panels click
## Clinical Diagnosis
## Molecular Diagnosis
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Multiple Endocrine Neoplasia Type 2
FMTC = familial medullary thyroid carcinoma; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B; NA = not applicable
See
Since MEN2 occurs through a gain-of-function mechanism, gene-targeted deletion/duplication analysis is not indicated.
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants, and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis of all
Pathogenic variants of codons 618, 620, and 634 each account for 20%-30% of pathogenic variants. Other pathogenic variants in exons 5, 8, 10, 11, and 13-16 appear to account for a small percentage of pathogenic variants in families with FMTC, with an important minority affecting codons 768 and 804 [
Approximately 95% of individuals have a pathogenic variant at codon 918 in exon 16 [
Pathogenic variants in exons 10 and 11 [
Pathogenic variants typically detected:
• For an introduction to multigene panels click
## Clinical Characteristics
The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN2) are:
Symptoms of MTC include neck mass or neck pain prior to age 35 years. Diarrhea (the most frequent systemic symptom) occurs in affected individuals with a plasma calcitonin concentration >10 ng/mL and implies a poor prognosis [
Up to 70% of individuals with a palpable thyroid mass or diarrhea already have cervical lymph node metastases [
About 20%-30% of all individuals with MTC have a germline
Note: All individuals with an MTC-predisposing
Approximately 50% of individuals diagnosed with MTC who have undergone total thyroidectomy and neck nodal dissections have recurrent disease [
CCH is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C cells. In MEN2, the age of transformation from CCH to MTC varies with different germline
[
MEN2 is classified into three phenotypes: MEN2A, familial medullary thyroid carcinoma (FMTC, which is now considered a variant of MEN2A), and MEN2B (see
Incidence of Select Clinical Manifestations by Multiple Endocrine Neoplasia Type 2 Phenotype
FMTC = familial medullary thyroid carcinoma; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B
Reviewed in
FMTC is not associated with an increased risk for pheochromocytoma or parathyroid disease, and risk of pheochromocytoma and parathyroid disease are similar to the general population. Individuals with presumed FMTC who develop pheochromocytoma or parathyroid disease are instead more likely to have MEN2A.
Pheochromocytomas usually present after MTC or concomitantly; however, they are the first manifestation in 13%-27% of individuals with MEN2A [
HPT in MEN2A is typically mild and may be due to a single parathyroid adenoma or due to marked parathyroid hyperplasia. Most individuals with HPT have no symptoms; however, hypercalciuria and renal calculi may occur [
A small number of families with MEN2A have pruritic cutaneous lichen amyloidosis, also known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC [
The age of onset of MTC is later in FMTC and the penetrance of MTC is lower than that observed in MEN2A and MEN2B [
Pheochromocytomas occur in 50% of individuals with MEN2B; about half are multiple and often bilateral. Individuals with an undiagnosed pheochromocytoma may die from a cardiovascular hypertensive crisis perioperatively.
MEN2B is not associated with an increased risk for clinically significant parathyroid disease.
Individuals with MEN2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. The lips become prominent (or "blubbery") over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination.
About 40% of affected individuals have diffuse ganglioneuromatosis of the gastrointestinal tract. Associated symptoms include abdominal distention, megacolon, constipation, or diarrhea. In one study of 19 individuals with MEN2B, 84% reported gastrointestinal symptoms beginning in infancy or early childhood [
About 75% of affected individuals have a marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.
A report of 12 Brazilian families indicated that
Codon 634 pathogenic variants are also associated with development of cutaneous lichen amyloidosis [
While 25% of FMTC kindreds have a pathogenic variant in codon 634,
The American Thyroid Association Guidelines Task Force has classified pathogenic variants based on their risk for aggressive MTC [
Multiple Endocrine Neoplasia Type 2: Genotype-Phenotype Correlations
+ = present; − = absent; ATA = American Thyroid Association; CLA = cutaneous lichen amyloidosis; FMTC = familial medullary thyroid carcinoma; H = high risk: HPT = hyperparathyroidism; HST = highest risk; HSCR = Hirschsprung disease; MEN2 = multiple endocrine neoplasia; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B; MOD = moderate risk; MTC = medullary thyroid carcinoma; PCC = pheochromocytoma; PTC = papillary thyroid cancer
Penetrance of some
MEN2A is also referred to as Sipple syndrome.
Mucosal neuroma syndrome is a synonym for MEN2B. MEN2B was initially called Wagenmann-Froboese syndrome [
The prevalence of MEN2 has been estimated at 1:35,000 [
• Symptoms of MTC include neck mass or neck pain prior to age 35 years. Diarrhea (the most frequent systemic symptom) occurs in affected individuals with a plasma calcitonin concentration >10 ng/mL and implies a poor prognosis [
• Up to 70% of individuals with a palpable thyroid mass or diarrhea already have cervical lymph node metastases [
• About 20%-30% of all individuals with MTC have a germline
• A report of 12 Brazilian families indicated that
• Codon 634 pathogenic variants are also associated with development of cutaneous lichen amyloidosis [
• While 25% of FMTC kindreds have a pathogenic variant in codon 634,
## Clinical Description
The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN2) are:
Symptoms of MTC include neck mass or neck pain prior to age 35 years. Diarrhea (the most frequent systemic symptom) occurs in affected individuals with a plasma calcitonin concentration >10 ng/mL and implies a poor prognosis [
Up to 70% of individuals with a palpable thyroid mass or diarrhea already have cervical lymph node metastases [
About 20%-30% of all individuals with MTC have a germline
Note: All individuals with an MTC-predisposing
Approximately 50% of individuals diagnosed with MTC who have undergone total thyroidectomy and neck nodal dissections have recurrent disease [
CCH is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C cells. In MEN2, the age of transformation from CCH to MTC varies with different germline
[
MEN2 is classified into three phenotypes: MEN2A, familial medullary thyroid carcinoma (FMTC, which is now considered a variant of MEN2A), and MEN2B (see
Incidence of Select Clinical Manifestations by Multiple Endocrine Neoplasia Type 2 Phenotype
FMTC = familial medullary thyroid carcinoma; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B
Reviewed in
FMTC is not associated with an increased risk for pheochromocytoma or parathyroid disease, and risk of pheochromocytoma and parathyroid disease are similar to the general population. Individuals with presumed FMTC who develop pheochromocytoma or parathyroid disease are instead more likely to have MEN2A.
Pheochromocytomas usually present after MTC or concomitantly; however, they are the first manifestation in 13%-27% of individuals with MEN2A [
HPT in MEN2A is typically mild and may be due to a single parathyroid adenoma or due to marked parathyroid hyperplasia. Most individuals with HPT have no symptoms; however, hypercalciuria and renal calculi may occur [
A small number of families with MEN2A have pruritic cutaneous lichen amyloidosis, also known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC [
The age of onset of MTC is later in FMTC and the penetrance of MTC is lower than that observed in MEN2A and MEN2B [
Pheochromocytomas occur in 50% of individuals with MEN2B; about half are multiple and often bilateral. Individuals with an undiagnosed pheochromocytoma may die from a cardiovascular hypertensive crisis perioperatively.
MEN2B is not associated with an increased risk for clinically significant parathyroid disease.
Individuals with MEN2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. The lips become prominent (or "blubbery") over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination.
About 40% of affected individuals have diffuse ganglioneuromatosis of the gastrointestinal tract. Associated symptoms include abdominal distention, megacolon, constipation, or diarrhea. In one study of 19 individuals with MEN2B, 84% reported gastrointestinal symptoms beginning in infancy or early childhood [
About 75% of affected individuals have a marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.
• Symptoms of MTC include neck mass or neck pain prior to age 35 years. Diarrhea (the most frequent systemic symptom) occurs in affected individuals with a plasma calcitonin concentration >10 ng/mL and implies a poor prognosis [
• Up to 70% of individuals with a palpable thyroid mass or diarrhea already have cervical lymph node metastases [
• About 20%-30% of all individuals with MTC have a germline
## MTC and CCH
Symptoms of MTC include neck mass or neck pain prior to age 35 years. Diarrhea (the most frequent systemic symptom) occurs in affected individuals with a plasma calcitonin concentration >10 ng/mL and implies a poor prognosis [
Up to 70% of individuals with a palpable thyroid mass or diarrhea already have cervical lymph node metastases [
About 20%-30% of all individuals with MTC have a germline
Note: All individuals with an MTC-predisposing
Approximately 50% of individuals diagnosed with MTC who have undergone total thyroidectomy and neck nodal dissections have recurrent disease [
CCH is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C cells. In MEN2, the age of transformation from CCH to MTC varies with different germline
• Symptoms of MTC include neck mass or neck pain prior to age 35 years. Diarrhea (the most frequent systemic symptom) occurs in affected individuals with a plasma calcitonin concentration >10 ng/mL and implies a poor prognosis [
• Up to 70% of individuals with a palpable thyroid mass or diarrhea already have cervical lymph node metastases [
• About 20%-30% of all individuals with MTC have a germline
## Pheochromocytoma
[
## Parathyroid Abnormalities
## MEN2 Phenotypes
MEN2 is classified into three phenotypes: MEN2A, familial medullary thyroid carcinoma (FMTC, which is now considered a variant of MEN2A), and MEN2B (see
Incidence of Select Clinical Manifestations by Multiple Endocrine Neoplasia Type 2 Phenotype
FMTC = familial medullary thyroid carcinoma; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B
Reviewed in
FMTC is not associated with an increased risk for pheochromocytoma or parathyroid disease, and risk of pheochromocytoma and parathyroid disease are similar to the general population. Individuals with presumed FMTC who develop pheochromocytoma or parathyroid disease are instead more likely to have MEN2A.
Pheochromocytomas usually present after MTC or concomitantly; however, they are the first manifestation in 13%-27% of individuals with MEN2A [
HPT in MEN2A is typically mild and may be due to a single parathyroid adenoma or due to marked parathyroid hyperplasia. Most individuals with HPT have no symptoms; however, hypercalciuria and renal calculi may occur [
A small number of families with MEN2A have pruritic cutaneous lichen amyloidosis, also known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC [
The age of onset of MTC is later in FMTC and the penetrance of MTC is lower than that observed in MEN2A and MEN2B [
Pheochromocytomas occur in 50% of individuals with MEN2B; about half are multiple and often bilateral. Individuals with an undiagnosed pheochromocytoma may die from a cardiovascular hypertensive crisis perioperatively.
MEN2B is not associated with an increased risk for clinically significant parathyroid disease.
Individuals with MEN2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. The lips become prominent (or "blubbery") over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination.
About 40% of affected individuals have diffuse ganglioneuromatosis of the gastrointestinal tract. Associated symptoms include abdominal distention, megacolon, constipation, or diarrhea. In one study of 19 individuals with MEN2B, 84% reported gastrointestinal symptoms beginning in infancy or early childhood [
About 75% of affected individuals have a marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.
## Genotype-Phenotype Correlations
A report of 12 Brazilian families indicated that
Codon 634 pathogenic variants are also associated with development of cutaneous lichen amyloidosis [
While 25% of FMTC kindreds have a pathogenic variant in codon 634,
The American Thyroid Association Guidelines Task Force has classified pathogenic variants based on their risk for aggressive MTC [
Multiple Endocrine Neoplasia Type 2: Genotype-Phenotype Correlations
+ = present; − = absent; ATA = American Thyroid Association; CLA = cutaneous lichen amyloidosis; FMTC = familial medullary thyroid carcinoma; H = high risk: HPT = hyperparathyroidism; HST = highest risk; HSCR = Hirschsprung disease; MEN2 = multiple endocrine neoplasia; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B; MOD = moderate risk; MTC = medullary thyroid carcinoma; PCC = pheochromocytoma; PTC = papillary thyroid cancer
• A report of 12 Brazilian families indicated that
• Codon 634 pathogenic variants are also associated with development of cutaneous lichen amyloidosis [
• While 25% of FMTC kindreds have a pathogenic variant in codon 634,
## Penetrance
Penetrance of some
## Nomenclature
MEN2A is also referred to as Sipple syndrome.
Mucosal neuroma syndrome is a synonym for MEN2B. MEN2B was initially called Wagenmann-Froboese syndrome [
## Prevalence
The prevalence of MEN2 has been estimated at 1:35,000 [
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Secondary CCH has been described occasionally in the setting of aging and hyperparathyroidism (HPT). Secondary CCH rarely transforms to MTC and is not related to MEN2.
Evaluation of biochemical features can help differentiate MEN2-associated pheochromocytoma.
Pheochromocytoma Susceptibility Genes in the Differential Diagnosis of Multiple Endocrine Neoplasia Type 2
GI = gastrointestinal; MEN2 = multiple endocrine neoplasia type 2; PCC = pheochromocytoma; PGL = paraganglioma
Listed genes represent the core genes associated with hereditary PGL-PCC syndrome.
## Management
Clinical practice guidelines for multiple endocrine neoplasia type 2 (MEN2) have been published [
To establish the extent of disease and needs in an individual diagnosed with MEN2, the evaluations summarized in
Multiple Endocrine Neoplasia Type 2: Recommended Evaluations Following Initial Diagnosis
Plasma calcitonin
Plasma CEA
Plasma free metanephrines or 24-hour urine fractionated metanephrines
Serum calcium followed by parathyroid hormone & 25-hydroxyvitamin D if calcium is ↑
CT w/contrast of chest & abdomen
MRI of liver in presence of nodal disease or calcitonin >400 pg/mL
CEA = carcinoembryonic antigen; MEN2 = multiple endocrine neoplasia type 2; MOI = mode of inheritance; MTC = medullary thyroid carcinoma
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Note: Prophylactic thyroidectomy is not routinely offered to at-risk individuals in whom the disorder has not been confirmed.
Risk of Aggressive Medullary Thyroid Carcinoma by
Adapted from
H = high risk; HST = highest risk; MOD = moderate risk; MTC = medullary thyroid carcinoma
See
Criteria: normal annual basal and or stimulated serum calcitonin; normal annual neck ultrasound examination; family history of less aggressive MTC
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in endocrinology, endocrine surgery, and medical genetics (see
Multiple Endocrine Neoplasia Type 2: Treatment of Manifestations
Measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines to evaluate for functioning PCC prior to any surgery in persons w/MEN2A, MEN2B, or FMTC
If PCC is detected, adrenalectomy before thyroidectomy to avoid intraoperative catecholamine crisis
Standard treatment for MTC is surgical removal of thyroid & lymph node dissection.
Consider external beam radiation therapy or intensity-modulated radiation therapy for incomplete tumor resection or extrathyroidal extension w/positive margins.
Consider multikinase inhibitors (first line; vandetanib & cabozantinib) & RET-selective inhibitors (second line; selpercatinib [LOXO-292] & pralsetinib [BLU-667]) in those w/metastatic MTC.
Consider anti-PD-1 antibody pembrolizumab for persons w/metastatic, tumor mutational burden-high disease (tumors with ≥10 mutations/megabase) that has progressed on first-line treatment.
Resection of visibly enlarged parathyroid gland(s)
Subtotal parathyroidectomy
Total parathyroidectomy w/forearm autograft
Preoperative localization w/excision of localized hypertrophied parathyroid gland(s) w/subtotal parathyroidectomy or total parathyroidectomy w/forearm autotransplantation in those w/4-gland disease
Consider medications to control primary HPT in persons w/high risk of surgical mortality, limited life expectancy, or persistent or recurrent primary HPT after one or more surgical attempts.
FMTC = familial medullary thyroid carcinoma; HPT = hyperparathyroidism; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B; MTC = medullary thyroid carcinoma; PCC = pheochromocytoma
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Multiple Endocrine Neoplasia Type 2: Recommended Surveillance
Plasma free metanephrines or 24-hour urine for fractionated metanephrines
MRI &/or CT if biochemical results are abnormal
ATA = American Thyroid Association; CEA = carcinoembryonic antigen; H = high risk; MOD = moderate risk; MTC = medullary thyroid carcinoma; PCC = pheochromocytoma
Caution should be used in interpreting calcitonin results for children younger than age three years, especially those younger than age six months [
Continued monitoring for residual or recurrent MTC is indicated after thyroidectomy, even if thyroidectomy is performed prior to biochemical evidence of disease.
Dopamine D
Other medications including monoamine oxidase inhibitors, sympathomimetics (e.g., ephedrine), and certain peptide and corticosteroid hormones may also cause complications; tricyclic antidepressants are inconsistent in causing adverse reactions [
It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures [
Molecular genetic testing if the
The following screening of at-risk family members if the pathogenic variant in the family is not known:
Neck ultrasound examination and basal and/or stimulated calcitonin measurements for MTC
Annual albumin-corrected calcium or ionized calcium for HPT
Annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines as appropriate [
See
Women with MEN2 should be screened for pheochromocytoma prior to a planned pregnancy, or as early as possible during an unplanned pregnancy [
Clinical trials of multikinase inhibitors such as sorafenib, sunitinib, and regorafenib are currently under way. National Comprehensive Cancer Network and American Thyroid Association guidelines recommend consideration of clinical trial participation for individuals who fail standard treatment with a tyrosine kinase inhibitor such as vandetanib or cabozantinib [
Sorafenib is FDA approved for use in renal cell and hepatocellular carcinoma. A meta-analysis including eight clinical trials and 101 individuals with metastatic MTC treated with sorafenib demonstrated a partial response of 21% and 58% stable disease [
Clinical trials of immune checkpoint inhibitors such as pembrolizumab, nivolumab, and ipilimumab are currently under way [
Several studies have investigated peptide receptor radionuclide therapy (PRRT), targeting somatostatin receptors with radionuclides such as
Search
• Plasma calcitonin
• Plasma CEA
• Plasma free metanephrines or 24-hour urine fractionated metanephrines
• Serum calcium followed by parathyroid hormone & 25-hydroxyvitamin D if calcium is ↑
• CT w/contrast of chest & abdomen
• MRI of liver in presence of nodal disease or calcitonin >400 pg/mL
• Measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines to evaluate for functioning PCC prior to any surgery in persons w/MEN2A, MEN2B, or FMTC
• If PCC is detected, adrenalectomy before thyroidectomy to avoid intraoperative catecholamine crisis
• Standard treatment for MTC is surgical removal of thyroid & lymph node dissection.
• Consider external beam radiation therapy or intensity-modulated radiation therapy for incomplete tumor resection or extrathyroidal extension w/positive margins.
• Consider multikinase inhibitors (first line; vandetanib & cabozantinib) & RET-selective inhibitors (second line; selpercatinib [LOXO-292] & pralsetinib [BLU-667]) in those w/metastatic MTC.
• Consider anti-PD-1 antibody pembrolizumab for persons w/metastatic, tumor mutational burden-high disease (tumors with ≥10 mutations/megabase) that has progressed on first-line treatment.
• Resection of visibly enlarged parathyroid gland(s)
• Subtotal parathyroidectomy
• Total parathyroidectomy w/forearm autograft
• Preoperative localization w/excision of localized hypertrophied parathyroid gland(s) w/subtotal parathyroidectomy or total parathyroidectomy w/forearm autotransplantation in those w/4-gland disease
• Consider medications to control primary HPT in persons w/high risk of surgical mortality, limited life expectancy, or persistent or recurrent primary HPT after one or more surgical attempts.
• Plasma free metanephrines or 24-hour urine for fractionated metanephrines
• MRI &/or CT if biochemical results are abnormal
• Molecular genetic testing if the
• The following screening of at-risk family members if the pathogenic variant in the family is not known:
• Neck ultrasound examination and basal and/or stimulated calcitonin measurements for MTC
• Annual albumin-corrected calcium or ionized calcium for HPT
• Annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines as appropriate [
• Neck ultrasound examination and basal and/or stimulated calcitonin measurements for MTC
• Annual albumin-corrected calcium or ionized calcium for HPT
• Annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines as appropriate [
• Neck ultrasound examination and basal and/or stimulated calcitonin measurements for MTC
• Annual albumin-corrected calcium or ionized calcium for HPT
• Annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines as appropriate [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MEN2, the evaluations summarized in
Multiple Endocrine Neoplasia Type 2: Recommended Evaluations Following Initial Diagnosis
Plasma calcitonin
Plasma CEA
Plasma free metanephrines or 24-hour urine fractionated metanephrines
Serum calcium followed by parathyroid hormone & 25-hydroxyvitamin D if calcium is ↑
CT w/contrast of chest & abdomen
MRI of liver in presence of nodal disease or calcitonin >400 pg/mL
CEA = carcinoembryonic antigen; MEN2 = multiple endocrine neoplasia type 2; MOI = mode of inheritance; MTC = medullary thyroid carcinoma
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Plasma calcitonin
• Plasma CEA
• Plasma free metanephrines or 24-hour urine fractionated metanephrines
• Serum calcium followed by parathyroid hormone & 25-hydroxyvitamin D if calcium is ↑
• CT w/contrast of chest & abdomen
• MRI of liver in presence of nodal disease or calcitonin >400 pg/mL
## Treatment of Manifestations
Note: Prophylactic thyroidectomy is not routinely offered to at-risk individuals in whom the disorder has not been confirmed.
Risk of Aggressive Medullary Thyroid Carcinoma by
Adapted from
H = high risk; HST = highest risk; MOD = moderate risk; MTC = medullary thyroid carcinoma
See
Criteria: normal annual basal and or stimulated serum calcitonin; normal annual neck ultrasound examination; family history of less aggressive MTC
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in endocrinology, endocrine surgery, and medical genetics (see
Multiple Endocrine Neoplasia Type 2: Treatment of Manifestations
Measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines to evaluate for functioning PCC prior to any surgery in persons w/MEN2A, MEN2B, or FMTC
If PCC is detected, adrenalectomy before thyroidectomy to avoid intraoperative catecholamine crisis
Standard treatment for MTC is surgical removal of thyroid & lymph node dissection.
Consider external beam radiation therapy or intensity-modulated radiation therapy for incomplete tumor resection or extrathyroidal extension w/positive margins.
Consider multikinase inhibitors (first line; vandetanib & cabozantinib) & RET-selective inhibitors (second line; selpercatinib [LOXO-292] & pralsetinib [BLU-667]) in those w/metastatic MTC.
Consider anti-PD-1 antibody pembrolizumab for persons w/metastatic, tumor mutational burden-high disease (tumors with ≥10 mutations/megabase) that has progressed on first-line treatment.
Resection of visibly enlarged parathyroid gland(s)
Subtotal parathyroidectomy
Total parathyroidectomy w/forearm autograft
Preoperative localization w/excision of localized hypertrophied parathyroid gland(s) w/subtotal parathyroidectomy or total parathyroidectomy w/forearm autotransplantation in those w/4-gland disease
Consider medications to control primary HPT in persons w/high risk of surgical mortality, limited life expectancy, or persistent or recurrent primary HPT after one or more surgical attempts.
FMTC = familial medullary thyroid carcinoma; HPT = hyperparathyroidism; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B; MTC = medullary thyroid carcinoma; PCC = pheochromocytoma
• Measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines to evaluate for functioning PCC prior to any surgery in persons w/MEN2A, MEN2B, or FMTC
• If PCC is detected, adrenalectomy before thyroidectomy to avoid intraoperative catecholamine crisis
• Standard treatment for MTC is surgical removal of thyroid & lymph node dissection.
• Consider external beam radiation therapy or intensity-modulated radiation therapy for incomplete tumor resection or extrathyroidal extension w/positive margins.
• Consider multikinase inhibitors (first line; vandetanib & cabozantinib) & RET-selective inhibitors (second line; selpercatinib [LOXO-292] & pralsetinib [BLU-667]) in those w/metastatic MTC.
• Consider anti-PD-1 antibody pembrolizumab for persons w/metastatic, tumor mutational burden-high disease (tumors with ≥10 mutations/megabase) that has progressed on first-line treatment.
• Resection of visibly enlarged parathyroid gland(s)
• Subtotal parathyroidectomy
• Total parathyroidectomy w/forearm autograft
• Preoperative localization w/excision of localized hypertrophied parathyroid gland(s) w/subtotal parathyroidectomy or total parathyroidectomy w/forearm autotransplantation in those w/4-gland disease
• Consider medications to control primary HPT in persons w/high risk of surgical mortality, limited life expectancy, or persistent or recurrent primary HPT after one or more surgical attempts.
## Targeted Therapy
Note: Prophylactic thyroidectomy is not routinely offered to at-risk individuals in whom the disorder has not been confirmed.
Risk of Aggressive Medullary Thyroid Carcinoma by
Adapted from
H = high risk; HST = highest risk; MOD = moderate risk; MTC = medullary thyroid carcinoma
See
Criteria: normal annual basal and or stimulated serum calcitonin; normal annual neck ultrasound examination; family history of less aggressive MTC
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in endocrinology, endocrine surgery, and medical genetics (see
Multiple Endocrine Neoplasia Type 2: Treatment of Manifestations
Measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines to evaluate for functioning PCC prior to any surgery in persons w/MEN2A, MEN2B, or FMTC
If PCC is detected, adrenalectomy before thyroidectomy to avoid intraoperative catecholamine crisis
Standard treatment for MTC is surgical removal of thyroid & lymph node dissection.
Consider external beam radiation therapy or intensity-modulated radiation therapy for incomplete tumor resection or extrathyroidal extension w/positive margins.
Consider multikinase inhibitors (first line; vandetanib & cabozantinib) & RET-selective inhibitors (second line; selpercatinib [LOXO-292] & pralsetinib [BLU-667]) in those w/metastatic MTC.
Consider anti-PD-1 antibody pembrolizumab for persons w/metastatic, tumor mutational burden-high disease (tumors with ≥10 mutations/megabase) that has progressed on first-line treatment.
Resection of visibly enlarged parathyroid gland(s)
Subtotal parathyroidectomy
Total parathyroidectomy w/forearm autograft
Preoperative localization w/excision of localized hypertrophied parathyroid gland(s) w/subtotal parathyroidectomy or total parathyroidectomy w/forearm autotransplantation in those w/4-gland disease
Consider medications to control primary HPT in persons w/high risk of surgical mortality, limited life expectancy, or persistent or recurrent primary HPT after one or more surgical attempts.
FMTC = familial medullary thyroid carcinoma; HPT = hyperparathyroidism; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B; MTC = medullary thyroid carcinoma; PCC = pheochromocytoma
• Measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines to evaluate for functioning PCC prior to any surgery in persons w/MEN2A, MEN2B, or FMTC
• If PCC is detected, adrenalectomy before thyroidectomy to avoid intraoperative catecholamine crisis
• Standard treatment for MTC is surgical removal of thyroid & lymph node dissection.
• Consider external beam radiation therapy or intensity-modulated radiation therapy for incomplete tumor resection or extrathyroidal extension w/positive margins.
• Consider multikinase inhibitors (first line; vandetanib & cabozantinib) & RET-selective inhibitors (second line; selpercatinib [LOXO-292] & pralsetinib [BLU-667]) in those w/metastatic MTC.
• Consider anti-PD-1 antibody pembrolizumab for persons w/metastatic, tumor mutational burden-high disease (tumors with ≥10 mutations/megabase) that has progressed on first-line treatment.
• Resection of visibly enlarged parathyroid gland(s)
• Subtotal parathyroidectomy
• Total parathyroidectomy w/forearm autograft
• Preoperative localization w/excision of localized hypertrophied parathyroid gland(s) w/subtotal parathyroidectomy or total parathyroidectomy w/forearm autotransplantation in those w/4-gland disease
• Consider medications to control primary HPT in persons w/high risk of surgical mortality, limited life expectancy, or persistent or recurrent primary HPT after one or more surgical attempts.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Multiple Endocrine Neoplasia Type 2: Recommended Surveillance
Plasma free metanephrines or 24-hour urine for fractionated metanephrines
MRI &/or CT if biochemical results are abnormal
ATA = American Thyroid Association; CEA = carcinoembryonic antigen; H = high risk; MOD = moderate risk; MTC = medullary thyroid carcinoma; PCC = pheochromocytoma
Caution should be used in interpreting calcitonin results for children younger than age three years, especially those younger than age six months [
Continued monitoring for residual or recurrent MTC is indicated after thyroidectomy, even if thyroidectomy is performed prior to biochemical evidence of disease.
• Plasma free metanephrines or 24-hour urine for fractionated metanephrines
• MRI &/or CT if biochemical results are abnormal
## Agents/Circumstances to Avoid
Dopamine D
Other medications including monoamine oxidase inhibitors, sympathomimetics (e.g., ephedrine), and certain peptide and corticosteroid hormones may also cause complications; tricyclic antidepressants are inconsistent in causing adverse reactions [
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures [
Molecular genetic testing if the
The following screening of at-risk family members if the pathogenic variant in the family is not known:
Neck ultrasound examination and basal and/or stimulated calcitonin measurements for MTC
Annual albumin-corrected calcium or ionized calcium for HPT
Annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines as appropriate [
See
• Molecular genetic testing if the
• The following screening of at-risk family members if the pathogenic variant in the family is not known:
• Neck ultrasound examination and basal and/or stimulated calcitonin measurements for MTC
• Annual albumin-corrected calcium or ionized calcium for HPT
• Annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines as appropriate [
• Neck ultrasound examination and basal and/or stimulated calcitonin measurements for MTC
• Annual albumin-corrected calcium or ionized calcium for HPT
• Annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines as appropriate [
• Neck ultrasound examination and basal and/or stimulated calcitonin measurements for MTC
• Annual albumin-corrected calcium or ionized calcium for HPT
• Annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines as appropriate [
## Pregnancy Management
Women with MEN2 should be screened for pheochromocytoma prior to a planned pregnancy, or as early as possible during an unplanned pregnancy [
## Therapies Under Investigation
Clinical trials of multikinase inhibitors such as sorafenib, sunitinib, and regorafenib are currently under way. National Comprehensive Cancer Network and American Thyroid Association guidelines recommend consideration of clinical trial participation for individuals who fail standard treatment with a tyrosine kinase inhibitor such as vandetanib or cabozantinib [
Sorafenib is FDA approved for use in renal cell and hepatocellular carcinoma. A meta-analysis including eight clinical trials and 101 individuals with metastatic MTC treated with sorafenib demonstrated a partial response of 21% and 58% stable disease [
Clinical trials of immune checkpoint inhibitors such as pembrolizumab, nivolumab, and ipilimumab are currently under way [
Several studies have investigated peptide receptor radionuclide therapy (PRRT), targeting somatostatin receptors with radionuclides such as
Search
## Genetic Counseling
All of the multiple endocrine neoplasia type 2 (MEN2) subtypes – MEN2A, familial medullary thyroid carcinoma (FMTC), and MEN2B – are inherited in an autosomal dominant manner.
The proportion of individuals with MEN2 who have an affected parent varies by subtype:
Up to 95% of individuals diagnosed with MEN2A have an affected parent.
By definition, individuals with FMTC have multiple family members who are affected.
50% of individuals diagnosed with MEN2B have an affected parent.
A proband with MEN2A or MEN2B may have the disorder as the result of a
The proportion of individuals with MEN2A caused by a
The proportion of individuals with MEN2B caused by a
It is appropriate to evaluate the parents of an individual with MEN2A or MEN2B for manifestations of the disorder and to offer molecular genetic testing if the
If the proband has a known germline
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
Recommendations for the evaluation of parents of a proband with a clinical diagnosis of MEN2 and an undetectable
The family history of some individuals diagnosed with MEN2A or MEN2B may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN2 subtype (see
If the proband has a known
If the parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for MEN2 because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
Because early detection of at-risk individuals affects medical management, testing of asymptomatic children is beneficial [
See also Management,
The optimal time for determination of genetic risk and availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The proportion of individuals with MEN2 who have an affected parent varies by subtype:
• Up to 95% of individuals diagnosed with MEN2A have an affected parent.
• By definition, individuals with FMTC have multiple family members who are affected.
• 50% of individuals diagnosed with MEN2B have an affected parent.
• Up to 95% of individuals diagnosed with MEN2A have an affected parent.
• By definition, individuals with FMTC have multiple family members who are affected.
• 50% of individuals diagnosed with MEN2B have an affected parent.
• A proband with MEN2A or MEN2B may have the disorder as the result of a
• The proportion of individuals with MEN2A caused by a
• The proportion of individuals with MEN2B caused by a
• The proportion of individuals with MEN2A caused by a
• The proportion of individuals with MEN2B caused by a
• It is appropriate to evaluate the parents of an individual with MEN2A or MEN2B for manifestations of the disorder and to offer molecular genetic testing if the
• If the proband has a known germline
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Recommendations for the evaluation of parents of a proband with a clinical diagnosis of MEN2 and an undetectable
• The family history of some individuals diagnosed with MEN2A or MEN2B may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• Up to 95% of individuals diagnosed with MEN2A have an affected parent.
• By definition, individuals with FMTC have multiple family members who are affected.
• 50% of individuals diagnosed with MEN2B have an affected parent.
• The proportion of individuals with MEN2A caused by a
• The proportion of individuals with MEN2B caused by a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN2 subtype (see
• If the proband has a known
• If the parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for MEN2 because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
• Because early detection of at-risk individuals affects medical management, testing of asymptomatic children is beneficial [
• See also Management,
• The optimal time for determination of genetic risk and availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
All of the multiple endocrine neoplasia type 2 (MEN2) subtypes – MEN2A, familial medullary thyroid carcinoma (FMTC), and MEN2B – are inherited in an autosomal dominant manner.
## Risk to Family Members
The proportion of individuals with MEN2 who have an affected parent varies by subtype:
Up to 95% of individuals diagnosed with MEN2A have an affected parent.
By definition, individuals with FMTC have multiple family members who are affected.
50% of individuals diagnosed with MEN2B have an affected parent.
A proband with MEN2A or MEN2B may have the disorder as the result of a
The proportion of individuals with MEN2A caused by a
The proportion of individuals with MEN2B caused by a
It is appropriate to evaluate the parents of an individual with MEN2A or MEN2B for manifestations of the disorder and to offer molecular genetic testing if the
If the proband has a known germline
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
Recommendations for the evaluation of parents of a proband with a clinical diagnosis of MEN2 and an undetectable
The family history of some individuals diagnosed with MEN2A or MEN2B may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN2 subtype (see
If the proband has a known
If the parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for MEN2 because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
• The proportion of individuals with MEN2 who have an affected parent varies by subtype:
• Up to 95% of individuals diagnosed with MEN2A have an affected parent.
• By definition, individuals with FMTC have multiple family members who are affected.
• 50% of individuals diagnosed with MEN2B have an affected parent.
• Up to 95% of individuals diagnosed with MEN2A have an affected parent.
• By definition, individuals with FMTC have multiple family members who are affected.
• 50% of individuals diagnosed with MEN2B have an affected parent.
• A proband with MEN2A or MEN2B may have the disorder as the result of a
• The proportion of individuals with MEN2A caused by a
• The proportion of individuals with MEN2B caused by a
• The proportion of individuals with MEN2A caused by a
• The proportion of individuals with MEN2B caused by a
• It is appropriate to evaluate the parents of an individual with MEN2A or MEN2B for manifestations of the disorder and to offer molecular genetic testing if the
• If the proband has a known germline
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Recommendations for the evaluation of parents of a proband with a clinical diagnosis of MEN2 and an undetectable
• The family history of some individuals diagnosed with MEN2A or MEN2B may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• Up to 95% of individuals diagnosed with MEN2A have an affected parent.
• By definition, individuals with FMTC have multiple family members who are affected.
• 50% of individuals diagnosed with MEN2B have an affected parent.
• The proportion of individuals with MEN2A caused by a
• The proportion of individuals with MEN2B caused by a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN2 subtype (see
• If the proband has a known
• If the parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for MEN2 because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
## Related Genetic Counseling Issues
Because early detection of at-risk individuals affects medical management, testing of asymptomatic children is beneficial [
See also Management,
The optimal time for determination of genetic risk and availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Because early detection of at-risk individuals affects medical management, testing of asymptomatic children is beneficial [
• See also Management,
• The optimal time for determination of genetic risk and availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
Italy
Association for Multiple Endocrine Neoplasia Disorders
United Kingdom
•
• United Kingdom
•
•
• Italy
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
• Association for Multiple Endocrine Neoplasia Disorders
• United Kingdom
•
## Molecular Genetics
Multiple Endocrine Neoplasia Type 2: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Multiple Endocrine Neoplasia Type 2 (
The most common pathogenic variants are non-conservative substitutions located in one of six cysteine codons in the extracellular domain of the encoded protein. They include codons 609, 611, 618, and 620 in exon 10 and codons 630 and 634 in exon 11 [
The risk for aggressive medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism can be estimated based on genotype (see
Approximately 95% of all individuals with the MEN2B phenotype have a pathogenic variant in the tyrosine kinase domain of
Two variants on the same
In addition to the pathogenic variants in the cysteine residues in exons 10 and 11 that have been found in families with MEN2A, pathogenic variants in codons 631, 768, 790, 804, 844, and 891, and others in exons 5, 8, 10, 11, and 13-16, have been identified in a small number of families [
A pathogenic variant at codon 603 was reported in one family and appeared to be associated with both MTC and papillary thyroid cancer [
Rare families with two pathogenic variants on the same allele have been reported; for example, alteration of both codons 634 and 635 in one family with MEN2A; alteration of both codons 804 and 844 in one family with FMTC [
For families in which MEN2A and Hirschsprung disease (HSCR) cosegregate, models to explain how the same pathogenic variant can cause gain of function and loss of function have been proposed [
Note: In contrast to the activating pathogenic variants in MEN2, pathogenic variants that cause HSCR result in a decrease in the transforming activity of RET because RET molecules are stuck in the endoplasmic reticulum and do not reach the cell surface [
Notable
See
ATA MOD
See
ATA H
See
ATA MOD
See
ATA H
See
ATA HST (See
See
Modifier & predisposition variants
ATA = American Thyroid Association; H = high risk; HST = highest risk; MOD = moderate risk
Variants listed in the table have been provided by the authors.
The protein sequence has not been analyzed, but no change in the amino acid is expected.
Evidence suggests that other rare allelic variants may be predisposition factors. For example,
• See
• ATA MOD
• See
• ATA H
• See
• ATA MOD
• See
• ATA H
• See
• ATA HST (See
• See
• Modifier & predisposition variants
## Molecular Pathogenesis
The most common pathogenic variants are non-conservative substitutions located in one of six cysteine codons in the extracellular domain of the encoded protein. They include codons 609, 611, 618, and 620 in exon 10 and codons 630 and 634 in exon 11 [
The risk for aggressive medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism can be estimated based on genotype (see
Approximately 95% of all individuals with the MEN2B phenotype have a pathogenic variant in the tyrosine kinase domain of
Two variants on the same
In addition to the pathogenic variants in the cysteine residues in exons 10 and 11 that have been found in families with MEN2A, pathogenic variants in codons 631, 768, 790, 804, 844, and 891, and others in exons 5, 8, 10, 11, and 13-16, have been identified in a small number of families [
A pathogenic variant at codon 603 was reported in one family and appeared to be associated with both MTC and papillary thyroid cancer [
Rare families with two pathogenic variants on the same allele have been reported; for example, alteration of both codons 634 and 635 in one family with MEN2A; alteration of both codons 804 and 844 in one family with FMTC [
For families in which MEN2A and Hirschsprung disease (HSCR) cosegregate, models to explain how the same pathogenic variant can cause gain of function and loss of function have been proposed [
Note: In contrast to the activating pathogenic variants in MEN2, pathogenic variants that cause HSCR result in a decrease in the transforming activity of RET because RET molecules are stuck in the endoplasmic reticulum and do not reach the cell surface [
Notable
See
ATA MOD
See
ATA H
See
ATA MOD
See
ATA H
See
ATA HST (See
See
Modifier & predisposition variants
ATA = American Thyroid Association; H = high risk; HST = highest risk; MOD = moderate risk
Variants listed in the table have been provided by the authors.
The protein sequence has not been analyzed, but no change in the amino acid is expected.
Evidence suggests that other rare allelic variants may be predisposition factors. For example,
• See
• ATA MOD
• See
• ATA H
• See
• ATA MOD
• See
• ATA H
• See
• ATA HST (See
• See
• Modifier & predisposition variants
## Chapter Notes
Charis Eng, MD, PhD, FACP (2010-present)Jessica Marquard, MS, LGC; Cleveland Clinic (2010-2019)Gilman Pitt, MD (2023-present)Karen Snow-Bailey, PhD, FACMG, FHGSA; Auckland City Hospital (1999-2006*)Georgia L Wiesner, MD, MS, FACMG; Case Western Reserve University School of Medicine (1999-2010)
* Karen Snow-Bailey died on September 10, 2006. The following is excerpted from a tribute by Stephen N Thibodeau, PhD, of the Mayo Clinic, Rochester, MN:
"Karen was well known to so many of us, as she was an active member of the Association for Molecular Pathology (AMP)....In 1993, Karen joined the medical staff at the Mayo Clinic, where she was responsible for codirecting the Molecular Genetics Laboratory in the Department of Laboratory Medicine and Pathology....In 2002, Karen returned to New Zealand to be closer to family and became an international presence. Importantly, she began to have a tremendous influence in the development of diagnostic genetics services both in New Zealand and Australia....Karen was a scientist, an educator, and an artist....We will all miss Karen as a colleague, as a mentor to many, as an individual who had a vision for the future, but most importantly, as a warm and compassionate friend who cared for others."
[Reprinted from
10 August 2023 (sw) Comprehensive update posted live
15 August 2019 (ma) Comprehensive update posted live
25 June 2015 (me) Comprehensive update posted live
10 January 2013 (me) Comprehensive update posted live
4 May 2010 (me) Comprehensive update posted live
7 March 2005 (me) Comprehensive update posted live
21 January 2003 (me) Comprehensive update posted live
27 September 1999 (me) Review posted live
October 1998 (gw) Original submission
• 10 August 2023 (sw) Comprehensive update posted live
• 15 August 2019 (ma) Comprehensive update posted live
• 25 June 2015 (me) Comprehensive update posted live
• 10 January 2013 (me) Comprehensive update posted live
• 4 May 2010 (me) Comprehensive update posted live
• 7 March 2005 (me) Comprehensive update posted live
• 21 January 2003 (me) Comprehensive update posted live
• 27 September 1999 (me) Review posted live
• October 1998 (gw) Original submission
## Author History
Charis Eng, MD, PhD, FACP (2010-present)Jessica Marquard, MS, LGC; Cleveland Clinic (2010-2019)Gilman Pitt, MD (2023-present)Karen Snow-Bailey, PhD, FACMG, FHGSA; Auckland City Hospital (1999-2006*)Georgia L Wiesner, MD, MS, FACMG; Case Western Reserve University School of Medicine (1999-2010)
* Karen Snow-Bailey died on September 10, 2006. The following is excerpted from a tribute by Stephen N Thibodeau, PhD, of the Mayo Clinic, Rochester, MN:
"Karen was well known to so many of us, as she was an active member of the Association for Molecular Pathology (AMP)....In 1993, Karen joined the medical staff at the Mayo Clinic, where she was responsible for codirecting the Molecular Genetics Laboratory in the Department of Laboratory Medicine and Pathology....In 2002, Karen returned to New Zealand to be closer to family and became an international presence. Importantly, she began to have a tremendous influence in the development of diagnostic genetics services both in New Zealand and Australia....Karen was a scientist, an educator, and an artist....We will all miss Karen as a colleague, as a mentor to many, as an individual who had a vision for the future, but most importantly, as a warm and compassionate friend who cared for others."
[Reprinted from
## Revision History
10 August 2023 (sw) Comprehensive update posted live
15 August 2019 (ma) Comprehensive update posted live
25 June 2015 (me) Comprehensive update posted live
10 January 2013 (me) Comprehensive update posted live
4 May 2010 (me) Comprehensive update posted live
7 March 2005 (me) Comprehensive update posted live
21 January 2003 (me) Comprehensive update posted live
27 September 1999 (me) Review posted live
October 1998 (gw) Original submission
• 10 August 2023 (sw) Comprehensive update posted live
• 15 August 2019 (ma) Comprehensive update posted live
• 25 June 2015 (me) Comprehensive update posted live
• 10 January 2013 (me) Comprehensive update posted live
• 4 May 2010 (me) Comprehensive update posted live
• 7 March 2005 (me) Comprehensive update posted live
• 21 January 2003 (me) Comprehensive update posted live
• 27 September 1999 (me) Review posted live
• October 1998 (gw) Original submission
## Key Sections in this
## References
National Comprehensive Cancer Network. NCCN Guidelines: Neuroendocrine and Adrenal Tumors. NCCN website. Available
Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, Lipkin SM, Syngal S, Wollins DS, Lindor NM. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33:3660-7. [
Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567-610. [
• National Comprehensive Cancer Network. NCCN Guidelines: Neuroendocrine and Adrenal Tumors. NCCN website. Available
• Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, Lipkin SM, Syngal S, Wollins DS, Lindor NM. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33:3660-7. [
• Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567-610. [
## Published Guidelines / Consensus Statements
National Comprehensive Cancer Network. NCCN Guidelines: Neuroendocrine and Adrenal Tumors. NCCN website. Available
Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, Lipkin SM, Syngal S, Wollins DS, Lindor NM. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33:3660-7. [
Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567-610. [
• National Comprehensive Cancer Network. NCCN Guidelines: Neuroendocrine and Adrenal Tumors. NCCN website. Available
• Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, Lipkin SM, Syngal S, Wollins DS, Lindor NM. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33:3660-7. [
• Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567-610. [
## Literature Cited
|
[] |
27/9/1999
|
10/8/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
men4
|
men4
|
[
"MEN4",
"CDKN1B-Related Multiple Endocrine Neoplasia",
"MEN4",
"CDKN1B-Related Multiple Endocrine Neoplasia",
"Cyclin-dependent kinase inhibitor 1B",
"CDKN1B",
"Multiple Endocrine Neoplasia Type 4"
] |
Multiple Endocrine Neoplasia Type 4
|
Pamela Brock, Lawrence Kirschner
|
Summary Multiple endocrine neoplasia type 4 (MEN4) is characterized by the development of endocrine tumors, especially those involving the parathyroid and/or pituitary gland. Parathyroid adenomas and parathyroid hyperplasia manifest as hypercalcemia (primary hyperparathyroidism) as a result of the overproduction of parathyroid hormone. Anterior pituitary adenomas can secrete adrenocorticotrophic hormone (ACTH), growth hormone (GH), prolactin, or are nonfunctional (nonsecreting) adenomas. Well-differentiated endocrine tumors of the gastroenteropancreatic tract, carcinoid tumors, and adrenocortical tumors can also occur. The diagnosis of MEN4 is established in a proband with a germline heterozygous pathogenic variant in MEN4 is inherited in an autosomal dominant manner. Most individuals diagnosed with MEN4 have an affected parent; some individuals diagnosed with MEN4 may have the disorder as the result of a
|
## Diagnosis
Multiple endocrine neoplasia type 4 (MEN4)
Adrenocorticotrophic hormone-secreting anterior pituitary adenomas are mostly associated with Cushing disease.
Growth hormone-secreting anterior pituitary adenomas cause gigantism in children and signs and symptoms of acromegaly in adults.
Prolactinomas (prolactin-secreting anterior pituitary adenomas) manifest as oligomenorrhea/amenorrhea and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
Nonfunctioning (nonsecreting) anterior pituitary adenomas manifest as enlarging tumors, compressing adjacent structures such as the optic chiasm and causing visual disturbances, headaches, and/or hypopituitarism.
Note: The imaging test of choice for all types of pituitary tumors is MRI.
Nonfunctioning pancreatic endocrine tumors are the most frequently seen tumors in MEN4. They are not found during biochemical testing but may be detected on abdominal imaging studies (CT, MRI, ultrasound) performed for other specific indications.
Zollinger-Ellison syndrome (ZES; peptic ulcer with or without chronic diarrhea) resulting from a gastrin-secreting duodenal mucosal tumor (gastrinoma)
Note: Endoscopic ultrasound examination is the most sensitive imaging procedure for the detection of small (≤10 mm) pancreatic endocrine tumors in asymptomatic individuals with multiple endocrine neoplasia type 1 (MEN1) [
No clinical diagnostic criteria can accurately distinguish MEN4 from multiple MEN1 or coincidental tumor co-occurrence. Therefore, the diagnosis of MEN4
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include single-gene testing and a multigene panel depending on the phenotype.
For an introduction to multigene panels click
Molecular Genetic Testing Used in Multiple Endocrine Neoplasia Type 4
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Adrenocorticotrophic hormone-secreting anterior pituitary adenomas are mostly associated with Cushing disease.
• Growth hormone-secreting anterior pituitary adenomas cause gigantism in children and signs and symptoms of acromegaly in adults.
• Prolactinomas (prolactin-secreting anterior pituitary adenomas) manifest as oligomenorrhea/amenorrhea and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
• Nonfunctioning (nonsecreting) anterior pituitary adenomas manifest as enlarging tumors, compressing adjacent structures such as the optic chiasm and causing visual disturbances, headaches, and/or hypopituitarism.
• Nonfunctioning pancreatic endocrine tumors are the most frequently seen tumors in MEN4. They are not found during biochemical testing but may be detected on abdominal imaging studies (CT, MRI, ultrasound) performed for other specific indications.
• Zollinger-Ellison syndrome (ZES; peptic ulcer with or without chronic diarrhea) resulting from a gastrin-secreting duodenal mucosal tumor (gastrinoma)
• For an introduction to multigene panels click
## Suggestive Findings
Multiple endocrine neoplasia type 4 (MEN4)
Adrenocorticotrophic hormone-secreting anterior pituitary adenomas are mostly associated with Cushing disease.
Growth hormone-secreting anterior pituitary adenomas cause gigantism in children and signs and symptoms of acromegaly in adults.
Prolactinomas (prolactin-secreting anterior pituitary adenomas) manifest as oligomenorrhea/amenorrhea and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
Nonfunctioning (nonsecreting) anterior pituitary adenomas manifest as enlarging tumors, compressing adjacent structures such as the optic chiasm and causing visual disturbances, headaches, and/or hypopituitarism.
Note: The imaging test of choice for all types of pituitary tumors is MRI.
Nonfunctioning pancreatic endocrine tumors are the most frequently seen tumors in MEN4. They are not found during biochemical testing but may be detected on abdominal imaging studies (CT, MRI, ultrasound) performed for other specific indications.
Zollinger-Ellison syndrome (ZES; peptic ulcer with or without chronic diarrhea) resulting from a gastrin-secreting duodenal mucosal tumor (gastrinoma)
Note: Endoscopic ultrasound examination is the most sensitive imaging procedure for the detection of small (≤10 mm) pancreatic endocrine tumors in asymptomatic individuals with multiple endocrine neoplasia type 1 (MEN1) [
• Adrenocorticotrophic hormone-secreting anterior pituitary adenomas are mostly associated with Cushing disease.
• Growth hormone-secreting anterior pituitary adenomas cause gigantism in children and signs and symptoms of acromegaly in adults.
• Prolactinomas (prolactin-secreting anterior pituitary adenomas) manifest as oligomenorrhea/amenorrhea and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
• Nonfunctioning (nonsecreting) anterior pituitary adenomas manifest as enlarging tumors, compressing adjacent structures such as the optic chiasm and causing visual disturbances, headaches, and/or hypopituitarism.
• Nonfunctioning pancreatic endocrine tumors are the most frequently seen tumors in MEN4. They are not found during biochemical testing but may be detected on abdominal imaging studies (CT, MRI, ultrasound) performed for other specific indications.
• Zollinger-Ellison syndrome (ZES; peptic ulcer with or without chronic diarrhea) resulting from a gastrin-secreting duodenal mucosal tumor (gastrinoma)
## Establishing the Diagnosis
No clinical diagnostic criteria can accurately distinguish MEN4 from multiple MEN1 or coincidental tumor co-occurrence. Therefore, the diagnosis of MEN4
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include single-gene testing and a multigene panel depending on the phenotype.
For an introduction to multigene panels click
Molecular Genetic Testing Used in Multiple Endocrine Neoplasia Type 4
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Clinical Characteristics
Multiple endocrine neoplasia type 4 (MEN4) is characterized by the development of endocrine tumors, especially those involving the parathyroid and/or pituitary gland. The clinical presentation has significant overlap with multiple endocrine neoplasia type 1 (MEN1). While there are some conflicting reports, most indicate that, by comparison, MEN4 is more attenuated, with lower penetrance and later ages of diagnosis [
To date, 65 individuals have been identified with a disease-causing variant in
Endocrine Tumor Types in Multiple Endocrine Neoplasia Type 4
Based on
ACTH = adrenocorticotrophic hormone; GEP-NET = gastroenteropancreatic neuroendocrine tumor; GH = growth hormone; NA = not applicable; NFA = nonfunctioning adenoma; PHPT = primary hyperparathyroidism; PRL = prolactin
A study of mostly children with Cushing disease identified
Individuals with MEN4 have been found to have breast cancer, colon cancer, testicular cancer, prostate cancer, cervical neuroendocrine carcinoma, meningioma, and renal angiomyolipoma. Further research is needed to determine if these tumors are part of the phenotype or occurred by coincidence in an individual with MEN4.
Cutaneous manifestations associated with MEN1 have not been reported in individuals with MEN4. Further research is needed to determine if cutaneous tumors are absent from the MEN4 phenotype versus underassessed in clinical reports.
A recent report suggested that individuals with
Penetrance is reduced and age related.
MEN4 is likely both rare and underdiagnosed. To date, 65 individuals have been reported with a disease-causing variant in
Disease-causing variants in
## Clinical Description
Multiple endocrine neoplasia type 4 (MEN4) is characterized by the development of endocrine tumors, especially those involving the parathyroid and/or pituitary gland. The clinical presentation has significant overlap with multiple endocrine neoplasia type 1 (MEN1). While there are some conflicting reports, most indicate that, by comparison, MEN4 is more attenuated, with lower penetrance and later ages of diagnosis [
To date, 65 individuals have been identified with a disease-causing variant in
Endocrine Tumor Types in Multiple Endocrine Neoplasia Type 4
Based on
ACTH = adrenocorticotrophic hormone; GEP-NET = gastroenteropancreatic neuroendocrine tumor; GH = growth hormone; NA = not applicable; NFA = nonfunctioning adenoma; PHPT = primary hyperparathyroidism; PRL = prolactin
A study of mostly children with Cushing disease identified
Individuals with MEN4 have been found to have breast cancer, colon cancer, testicular cancer, prostate cancer, cervical neuroendocrine carcinoma, meningioma, and renal angiomyolipoma. Further research is needed to determine if these tumors are part of the phenotype or occurred by coincidence in an individual with MEN4.
Cutaneous manifestations associated with MEN1 have not been reported in individuals with MEN4. Further research is needed to determine if cutaneous tumors are absent from the MEN4 phenotype versus underassessed in clinical reports.
## Genotype-Phenotype Correlations
A recent report suggested that individuals with
## Penetrance
Penetrance is reduced and age related.
## Prevalence
MEN4 is likely both rare and underdiagnosed. To date, 65 individuals have been reported with a disease-causing variant in
Disease-causing variants in
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Hereditary Cancer Syndromes in the Differential Diagnosis of Multiple Endocrine Neoplasia Type 4
Earlier onset pituitary tumors in
Not assoc w/other endocrinopathies typical of MEN4
Not assoc w/GEP-NETs
Not assoc w/other endocrinopathies typical of MEN4
Not assoc w/GEP-NETs
Not assoc w/other endocrinopathies typical of MEN4
Not assoc w/pituitary tumors or GEP-NETs
MEN2A is assoc w/medullary thyroid carcinoma & pheochromocytoma.
MEN2A-assoc PHPT is less penetrant than MEN4-assoc PHPT.
ACTH = adrenocorticotropic hormone; AD = autosomal dominant; GEP-NET = gastroenteropancreatic neuroendocrine tumor; GH = growth hormone; MEN4 = multiple endocrine neoplasia type 4; MOI = mode of inheritance; PHPT = primary hyperparathyroidism; PRL = prolactin; TSH = thyroid-stimulating hormone; XL = X-linked
Between 14% and 18% of families with FIHP have identifiable
Pathogenic variants in
FIHP is characterized by parathyroid adenoma or hyperplasia without other associated endocrinopathies in two or more individuals in one family.
Differential Diagnosis of Multiple Endocrine Neoplasia Type 4-Associated Clinical Features
MEN1 = multiple endocrine neoplasia type 1; MEN4 = multiple endocrine neoplasia type 4; NF1 = neurofibromatosis 1; TSC = tuberous sclerosis complex; VHL = von Hippel-Lindau syndrome
• Earlier onset pituitary tumors in
• Not assoc w/other endocrinopathies typical of MEN4
• Not assoc w/GEP-NETs
• Not assoc w/other endocrinopathies typical of MEN4
• Not assoc w/GEP-NETs
• Not assoc w/other endocrinopathies typical of MEN4
• Not assoc w/pituitary tumors or GEP-NETs
• MEN2A is assoc w/medullary thyroid carcinoma & pheochromocytoma.
• MEN2A-assoc PHPT is less penetrant than MEN4-assoc PHPT.
## Management
No consensus clinical practice guidelines for multiple endocrine neoplasia type 4 (MEN4) have been established. Given the clinical overlap with multiple endocrine neoplasia type 1 (MEN1), MEN1-related screening can be used as a guide, keeping in mind that MEN4 is more attenuated, with lower penetrance and later age at tumor diagnosis.
To establish the extent of disease and needs in an individual diagnosed with MEN4, the evaluations summarized in
Multiple Endocrine Neoplasia Type 4: Recommended Evaluations Following Initial Diagnosis
Referral to endocrinologist w/experience in MEN
Assess for clinical manifestations of endocrine tumors (e.g., kidney stones, signs of cortisol, GH, or prolactin excess, excessive nausea, vomiting, or diarrhea)
Pituitary MRI
Serum hormone testing (ACTH, cortisol, IGF-1, prolactin) guided by clinical suspicion
Abdominal imaging (e.g., contrast-enhanced CT or MRI)
Note: Endoscopic ultrasound is more sensitive but more invasive.
ACTH = adrenocorticotrophic hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; MEN = multiple endocrine neoplasia; MEN4 = multiple endocrine neoplasia type 4; MOI = mode of inheritance; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Multiple Endocrine Neoplasia Type 4: Treatment of Manifestations
Pituitary surgery for ACTH- or GH-secreting tumors
Cabergoline for PRL-secreting tumors
Surgical resection if possible
Consider referral to medical oncologist.
Some persons may be treated w/somatostatin analogs.
Persons w/gastrin-secreting tumors can be treated w/proton pump inhibitors.
ACTH = adrenocorticotrophic hormone; GH = growth hormone; PHPT = primary hyperparathyroidism; PRL = prolactin
For further treatment details see Multiple Endocrine Neoplasia Type 1, Treatment of Manifestations,
Multiple Endocrine Neoplasia Type 4: Recommended Surveillance
Serum calcium
PTH & vitamin D measurement may also be considered to ensure sufficiency.
IGF-1 = insulin-like growth factor 1; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone
Abnormal findings would indicate the need for more frequent follow up (current
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the
When molecular genetic testing for a
See
Search
• Referral to endocrinologist w/experience in MEN
• Assess for clinical manifestations of endocrine tumors (e.g., kidney stones, signs of cortisol, GH, or prolactin excess, excessive nausea, vomiting, or diarrhea)
• Pituitary MRI
• Serum hormone testing (ACTH, cortisol, IGF-1, prolactin) guided by clinical suspicion
• Abdominal imaging (e.g., contrast-enhanced CT or MRI)
• Note: Endoscopic ultrasound is more sensitive but more invasive.
• Pituitary surgery for ACTH- or GH-secreting tumors
• Cabergoline for PRL-secreting tumors
• Surgical resection if possible
• Consider referral to medical oncologist.
• Some persons may be treated w/somatostatin analogs.
• Persons w/gastrin-secreting tumors can be treated w/proton pump inhibitors.
• Serum calcium
• PTH & vitamin D measurement may also be considered to ensure sufficiency.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MEN4, the evaluations summarized in
Multiple Endocrine Neoplasia Type 4: Recommended Evaluations Following Initial Diagnosis
Referral to endocrinologist w/experience in MEN
Assess for clinical manifestations of endocrine tumors (e.g., kidney stones, signs of cortisol, GH, or prolactin excess, excessive nausea, vomiting, or diarrhea)
Pituitary MRI
Serum hormone testing (ACTH, cortisol, IGF-1, prolactin) guided by clinical suspicion
Abdominal imaging (e.g., contrast-enhanced CT or MRI)
Note: Endoscopic ultrasound is more sensitive but more invasive.
ACTH = adrenocorticotrophic hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; MEN = multiple endocrine neoplasia; MEN4 = multiple endocrine neoplasia type 4; MOI = mode of inheritance; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Referral to endocrinologist w/experience in MEN
• Assess for clinical manifestations of endocrine tumors (e.g., kidney stones, signs of cortisol, GH, or prolactin excess, excessive nausea, vomiting, or diarrhea)
• Pituitary MRI
• Serum hormone testing (ACTH, cortisol, IGF-1, prolactin) guided by clinical suspicion
• Abdominal imaging (e.g., contrast-enhanced CT or MRI)
• Note: Endoscopic ultrasound is more sensitive but more invasive.
## Treatment of Manifestations
Multiple Endocrine Neoplasia Type 4: Treatment of Manifestations
Pituitary surgery for ACTH- or GH-secreting tumors
Cabergoline for PRL-secreting tumors
Surgical resection if possible
Consider referral to medical oncologist.
Some persons may be treated w/somatostatin analogs.
Persons w/gastrin-secreting tumors can be treated w/proton pump inhibitors.
ACTH = adrenocorticotrophic hormone; GH = growth hormone; PHPT = primary hyperparathyroidism; PRL = prolactin
For further treatment details see Multiple Endocrine Neoplasia Type 1, Treatment of Manifestations,
• Pituitary surgery for ACTH- or GH-secreting tumors
• Cabergoline for PRL-secreting tumors
• Surgical resection if possible
• Consider referral to medical oncologist.
• Some persons may be treated w/somatostatin analogs.
• Persons w/gastrin-secreting tumors can be treated w/proton pump inhibitors.
## Surveillance
Multiple Endocrine Neoplasia Type 4: Recommended Surveillance
Serum calcium
PTH & vitamin D measurement may also be considered to ensure sufficiency.
IGF-1 = insulin-like growth factor 1; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone
Abnormal findings would indicate the need for more frequent follow up (current
• Serum calcium
• PTH & vitamin D measurement may also be considered to ensure sufficiency.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the
When molecular genetic testing for a
See
## Therapies Under Investigation
Search
## Genetic Counseling
Multiple endocrine neoplasia type 4 (MEN4) is inherited in an autosomal dominant manner.
Most individuals diagnosed with MEN4 have an affected parent.
Some individuals diagnosed with MEN4 may have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with MEN4 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. However, penetrance appears to be reduced (see
If the
If the parents have not been tested for the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with MEN4 have an affected parent.
• Some individuals diagnosed with MEN4 may have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with MEN4 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. However, penetrance appears to be reduced (see
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Multiple endocrine neoplasia type 4 (MEN4) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with MEN4 have an affected parent.
Some individuals diagnosed with MEN4 may have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with MEN4 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. However, penetrance appears to be reduced (see
If the
If the parents have not been tested for the
• Most individuals diagnosed with MEN4 have an affected parent.
• Some individuals diagnosed with MEN4 may have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with MEN4 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. However, penetrance appears to be reduced (see
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
Association for Multiple Endocrine Neoplasia Disorders
United Kingdom
•
• United Kingdom
•
•
•
•
•
•
• Association for Multiple Endocrine Neoplasia Disorders
• United Kingdom
•
## Molecular Genetics
Multiple Endocrine Neoplasia Type 4: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Multiple Endocrine Neoplasia Type 4 (
## Molecular Pathogenesis
## Chapter Notes
21 September 2023 (sw) Review posted live
3 March 2023 (pb) Original submission
• 21 September 2023 (sw) Review posted live
• 3 March 2023 (pb) Original submission
## Revision History
21 September 2023 (sw) Review posted live
3 March 2023 (pb) Original submission
• 21 September 2023 (sw) Review posted live
• 3 March 2023 (pb) Original submission
## References
## Literature Cited
|
[] |
21/9/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
menkes
|
menkes
|
[
"Classic Menkes Disease",
"Occipital Horn Syndrome",
"ATP7A-Related Distal Motor Neuropathy",
"Copper-transporting ATPase 1",
"ATP7A",
"ATP7A-Related Copper Transport Disorders"
] |
Stephen G Kaler, Andrew T DiStasio
|
Summary Menkes disease, occipital horn syndrome (OHS), and While nonspecific temperature instability and hypoglycemia in the neonatal period may be noted retrospectively, infants with Menkes disease and OHS are characterized by low concentrations of copper in some tissues as a result of impaired intestinal copper absorption, accumulation of copper in other tissues, and reduced activity of copper-dependent enzymes such as dopamine-beta-hydroxylase (DBH) and lysyl oxidase. While serum copper concentration and serum ceruloplasmin concentration are low in Menkes disease and OHS, they are normal in The diagnosis of Classic Menkes disease. Seizure management per neurologist; early intervention and individualized education plan per developmental pediatrician, feeding therapy and gastrostomy tube placement to enhance caloric intake; antibiotic prophylaxis to prevent bladder infection and surgery for bladder diverticula; RSV, influenza and COVID vaccinations due to risk of recurrent pneumonia; social work support. Occipital horn syndrome. Possible droxidopa treatment for dysautonomia; early academic support and individualized education plan as indicated per developmental pediatrician; surgical treatment of bladder diverticula and antibiotic prophylaxis as necessary; physical therapy; joint splints per orthopedist or rheumatologist for joint laxity. Menkes disease. At each visit assess seizures, developmental progress, educational needs, growth and nutrition, therapy needs, mobility, self-help skills, frequency of pulmonary infections, and family needs. Occipital horn syndrome. At each visit assess orthostatic blood pressures, development, and educational needs. Annual pelvic ultrasound for bladder diverticula. The
|
Classic Menkes disease
Occipital horn syndrome
For synonyms and outdated names see
• Classic Menkes disease
• Occipital horn syndrome
## Diagnosis
An
Shortly thereafter, hair changes become manifest: the scalp and (usually) eyebrow hair is short, sparse, coarse, twisted, and often lightly pigmented (white, silver, or gray). The hair is shorter and thinner on the sides and back of the head. The hair can be reminiscent of steel wool cleaning pads. Light microscopic hair analysis reveals
Specific clinical features include:
Hypotonia and neurodevelopmental delays typically manifest by age three to six months
Distinctive facial features: jowly appearance with sagging cheeks
Pectus excavatum
Skin laxity, particularly on the nape of the neck, axillae, and trunk
Bladder diverticula that can result in bladder outlet obstruction
Umbilical or inguinal hernias
Autonomic dysfunction: dizziness, syncope (if ambulatory), chronic diarrhea
Neck masses, usually representing internal jugular vein phlebectasia [
Occipital horns (distinctive wedge-shaped calcifications at the site of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone). These calcifications may be clinically palpable or observed on skull radiographs.
Lax skin and joints
Bladder diverticula
Inguinal hernias
Vascular tortuosity
Dysautonomia (chronic diarrhea, orthostatic hypotension)
Mild cognitive deficits
Progressive DMN with minimal or no sensory symptoms
Distal muscle weakness and atrophy in the feet and hands with
Deep tendon reflexes varying from normal to diminished, with frequently absent ankle reflexes
Reduced compound motor amplitudes on nerve conduction tests with generally normal conduction velocities with positive waves and fibrillations on EMG
Approximate Serum Copper and Ceruloplasmin Concentrations in Males with Menkes Disease, Occipital Horn Syndrome, and
OHS = occipital horn syndrome; DMN = distal motor neuropathy
Diagnosis of Menkes disease using serum copper and ceruloplasmin in males under eight weeks of age is problematic given the normally low serum concentration in healthy infants at this age. These levels rise steadily in early infancy for the latter group, in contrast to Menkes disease where the levels remain low if copper replacement therapy is not initiated.
The diagnosis of
Note: (1) The clinical/laboratory findings necessary to establish this diagnosis in a female proband are the same as for males (see
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Targeted next-generation sequencing of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
In individuals with a compelling presentation for whom molecular genetic testing fails to identify a pathogenic variant in
Note: This method is reserved for research situations or urgent prenatal testing when a family’s
• Hypotonia and neurodevelopmental delays typically manifest by age three to six months
• Distinctive facial features: jowly appearance with sagging cheeks
• Pectus excavatum
• Skin laxity, particularly on the nape of the neck, axillae, and trunk
• Bladder diverticula that can result in bladder outlet obstruction
• Umbilical or inguinal hernias
• Autonomic dysfunction: dizziness, syncope (if ambulatory), chronic diarrhea
• Neck masses, usually representing internal jugular vein phlebectasia [
• Occipital horns (distinctive wedge-shaped calcifications at the site of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone). These calcifications may be clinically palpable or observed on skull radiographs.
• Lax skin and joints
• Bladder diverticula
• Inguinal hernias
• Vascular tortuosity
• Dysautonomia (chronic diarrhea, orthostatic hypotension)
• Mild cognitive deficits
• Progressive DMN with minimal or no sensory symptoms
• Distal muscle weakness and atrophy in the feet and hands with
• Deep tendon reflexes varying from normal to diminished, with frequently absent ankle reflexes
• Reduced compound motor amplitudes on nerve conduction tests with generally normal conduction velocities with positive waves and fibrillations on EMG
• For an introduction to multigene panels click
• Note: This method is reserved for research situations or urgent prenatal testing when a family’s
## Suggestive Findings
An
Shortly thereafter, hair changes become manifest: the scalp and (usually) eyebrow hair is short, sparse, coarse, twisted, and often lightly pigmented (white, silver, or gray). The hair is shorter and thinner on the sides and back of the head. The hair can be reminiscent of steel wool cleaning pads. Light microscopic hair analysis reveals
Specific clinical features include:
Hypotonia and neurodevelopmental delays typically manifest by age three to six months
Distinctive facial features: jowly appearance with sagging cheeks
Pectus excavatum
Skin laxity, particularly on the nape of the neck, axillae, and trunk
Bladder diverticula that can result in bladder outlet obstruction
Umbilical or inguinal hernias
Autonomic dysfunction: dizziness, syncope (if ambulatory), chronic diarrhea
Neck masses, usually representing internal jugular vein phlebectasia [
Occipital horns (distinctive wedge-shaped calcifications at the site of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone). These calcifications may be clinically palpable or observed on skull radiographs.
Lax skin and joints
Bladder diverticula
Inguinal hernias
Vascular tortuosity
Dysautonomia (chronic diarrhea, orthostatic hypotension)
Mild cognitive deficits
Progressive DMN with minimal or no sensory symptoms
Distal muscle weakness and atrophy in the feet and hands with
Deep tendon reflexes varying from normal to diminished, with frequently absent ankle reflexes
Reduced compound motor amplitudes on nerve conduction tests with generally normal conduction velocities with positive waves and fibrillations on EMG
Approximate Serum Copper and Ceruloplasmin Concentrations in Males with Menkes Disease, Occipital Horn Syndrome, and
OHS = occipital horn syndrome; DMN = distal motor neuropathy
Diagnosis of Menkes disease using serum copper and ceruloplasmin in males under eight weeks of age is problematic given the normally low serum concentration in healthy infants at this age. These levels rise steadily in early infancy for the latter group, in contrast to Menkes disease where the levels remain low if copper replacement therapy is not initiated.
• Hypotonia and neurodevelopmental delays typically manifest by age three to six months
• Distinctive facial features: jowly appearance with sagging cheeks
• Pectus excavatum
• Skin laxity, particularly on the nape of the neck, axillae, and trunk
• Bladder diverticula that can result in bladder outlet obstruction
• Umbilical or inguinal hernias
• Autonomic dysfunction: dizziness, syncope (if ambulatory), chronic diarrhea
• Neck masses, usually representing internal jugular vein phlebectasia [
• Occipital horns (distinctive wedge-shaped calcifications at the site of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone). These calcifications may be clinically palpable or observed on skull radiographs.
• Lax skin and joints
• Bladder diverticula
• Inguinal hernias
• Vascular tortuosity
• Dysautonomia (chronic diarrhea, orthostatic hypotension)
• Mild cognitive deficits
• Progressive DMN with minimal or no sensory symptoms
• Distal muscle weakness and atrophy in the feet and hands with
• Deep tendon reflexes varying from normal to diminished, with frequently absent ankle reflexes
• Reduced compound motor amplitudes on nerve conduction tests with generally normal conduction velocities with positive waves and fibrillations on EMG
## Clinical Findings
Shortly thereafter, hair changes become manifest: the scalp and (usually) eyebrow hair is short, sparse, coarse, twisted, and often lightly pigmented (white, silver, or gray). The hair is shorter and thinner on the sides and back of the head. The hair can be reminiscent of steel wool cleaning pads. Light microscopic hair analysis reveals
Specific clinical features include:
Hypotonia and neurodevelopmental delays typically manifest by age three to six months
Distinctive facial features: jowly appearance with sagging cheeks
Pectus excavatum
Skin laxity, particularly on the nape of the neck, axillae, and trunk
Bladder diverticula that can result in bladder outlet obstruction
Umbilical or inguinal hernias
Autonomic dysfunction: dizziness, syncope (if ambulatory), chronic diarrhea
Neck masses, usually representing internal jugular vein phlebectasia [
Occipital horns (distinctive wedge-shaped calcifications at the site of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone). These calcifications may be clinically palpable or observed on skull radiographs.
Lax skin and joints
Bladder diverticula
Inguinal hernias
Vascular tortuosity
Dysautonomia (chronic diarrhea, orthostatic hypotension)
Mild cognitive deficits
Progressive DMN with minimal or no sensory symptoms
Distal muscle weakness and atrophy in the feet and hands with
Deep tendon reflexes varying from normal to diminished, with frequently absent ankle reflexes
Reduced compound motor amplitudes on nerve conduction tests with generally normal conduction velocities with positive waves and fibrillations on EMG
• Hypotonia and neurodevelopmental delays typically manifest by age three to six months
• Distinctive facial features: jowly appearance with sagging cheeks
• Pectus excavatum
• Skin laxity, particularly on the nape of the neck, axillae, and trunk
• Bladder diverticula that can result in bladder outlet obstruction
• Umbilical or inguinal hernias
• Autonomic dysfunction: dizziness, syncope (if ambulatory), chronic diarrhea
• Neck masses, usually representing internal jugular vein phlebectasia [
• Occipital horns (distinctive wedge-shaped calcifications at the site of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone). These calcifications may be clinically palpable or observed on skull radiographs.
• Lax skin and joints
• Bladder diverticula
• Inguinal hernias
• Vascular tortuosity
• Dysautonomia (chronic diarrhea, orthostatic hypotension)
• Mild cognitive deficits
• Progressive DMN with minimal or no sensory symptoms
• Distal muscle weakness and atrophy in the feet and hands with
• Deep tendon reflexes varying from normal to diminished, with frequently absent ankle reflexes
• Reduced compound motor amplitudes on nerve conduction tests with generally normal conduction velocities with positive waves and fibrillations on EMG
## Laboratory Findings
Approximate Serum Copper and Ceruloplasmin Concentrations in Males with Menkes Disease, Occipital Horn Syndrome, and
OHS = occipital horn syndrome; DMN = distal motor neuropathy
Diagnosis of Menkes disease using serum copper and ceruloplasmin in males under eight weeks of age is problematic given the normally low serum concentration in healthy infants at this age. These levels rise steadily in early infancy for the latter group, in contrast to Menkes disease where the levels remain low if copper replacement therapy is not initiated.
## Establishing the Diagnosis
The diagnosis of
Note: (1) The clinical/laboratory findings necessary to establish this diagnosis in a female proband are the same as for males (see
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Targeted next-generation sequencing of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
In individuals with a compelling presentation for whom molecular genetic testing fails to identify a pathogenic variant in
Note: This method is reserved for research situations or urgent prenatal testing when a family’s
• For an introduction to multigene panels click
• Note: This method is reserved for research situations or urgent prenatal testing when a family’s
## Molecular Genetic Testing
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Targeted next-generation sequencing of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Additional Biochemical Studies
In individuals with a compelling presentation for whom molecular genetic testing fails to identify a pathogenic variant in
Note: This method is reserved for research situations or urgent prenatal testing when a family’s
• Note: This method is reserved for research situations or urgent prenatal testing when a family’s
## Clinical Characteristics
The clinical spectrum of
Infants appear healthy until age two to three months, when loss of early developmental milestones, hypotonia, seizures, and failure to thrive occur. Classic Menkes disease is usually first suspected when infants exhibit typical neurologic changes and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, often lightly pigmented) and jowly appearance of the face.
Transient hypoglycemia, prolonged physiologic jaundice, and persistent temperature instability are nonspecific signs that may be noted in the neonatal period.
Vascular tortuosity, neck masses (due to internal jugular vein dilatation), bladder diverticula that can result in bladder outlet obstruction, and gastric polyps are not uncommon. Subdural hematomas and cerebrovascular accidents are also not uncommon.
Without early treatment with daily subcutaneous copper injections (and sometimes despite treatment), classic Menkes disease progresses to severe neurodegeneration and death, typically between ages seven months and 3.5 years. Cardiorespiratory failure, often precipitated by pneumonia, is a common cause of death.
Brain MRI shows cerebral and cerebellar atrophy with ventriculomegaly, delayed myelination, and vascular tortuosity.
MR angiography reveals a "corkscrew" appearance of cerebral vessels.
Plain radiographs of the skull often reveal wormian bones. Metaphyseal spurring of long bones and rib fractures are also typical and may trigger concern regarding non-accidental trauma. In these instances, it is crucial to convey to social workers and other child protective services staff that these skeletal findings are consistent with the difficult natural history of this illness [
A few affected individuals in whom motor and cognitive development are better than in classic Menkes disease have been described. Individuals with mild Menkes disease may walk independently and acquire formal language. Weakness, ataxia, tremor, and head-bobbing are characteristic neurologic findings. Seizures, if present, commence in mid- to late childhood; intellectual disability is mild. Connective tissue problems may be more prominent than in classic Menkes disease.
Cognitive ability is within the normal range or slightly reduced. The predominant neurologic abnormalities in individuals with OHS are dysautonomia (e.g., orthostatic hypotension, chronic diarrhea) and subtle neurocognitive deficits. Lax skin and joints and bladder diverticula are common manifestations of lysyl oxidase (copper-dependent enzyme) deficiency. Elbow dislocations are not uncommon [Author, personal observation]. Inguinal hernias do not appear to occur at increased frequency in individuals with OHS. Scoliosis may occur with advancing age.
Little information exists on the full natural history of OHS or the fertility of affected individuals. An essentially normal life span appears likely.
The age of onset ranges from as young as five years up to 60 years; most typically, the presenting features occur in the second or third decade of life [
Females who are heterozygous for an
About 50% of females who are obligate heterozygotes for an
Evaluation of females who are obligate heterozygotes for an
The amount of residual ATPase enzyme activity correlates with the phenotype in Menkes disease, OHS, and
Milder variants of Menkes disease and OHS are often associated with splice junction pathogenic variants that alter but do not eliminate proper RNA splicing (i.e., "leaky" splice junction defects).
The pathogenic variants associated with
Intrafamilial phenotypic variability is occasionally observed in Menkes disease [
Menkes disease is also known as Menkes kinky hair syndrome, or trichopoliodystrophy.
Occipital horn syndrome was formerly known as X-linked cutis laxa.
Previous estimates of the prevalence of Menkes disease were based on confirmed clinical cases ascertained from specific populations and varied from 1:40,000 to 1:354,507.
However, recent analyses based on genomic ascertainment of pathogenic alleles and assuming Hardy-Weinberg equilibrium predict a birth prevalence of
• Brain MRI shows cerebral and cerebellar atrophy with ventriculomegaly, delayed myelination, and vascular tortuosity.
• MR angiography reveals a "corkscrew" appearance of cerebral vessels.
• Plain radiographs of the skull often reveal wormian bones. Metaphyseal spurring of long bones and rib fractures are also typical and may trigger concern regarding non-accidental trauma. In these instances, it is crucial to convey to social workers and other child protective services staff that these skeletal findings are consistent with the difficult natural history of this illness [
## Clinical Description
The clinical spectrum of
Infants appear healthy until age two to three months, when loss of early developmental milestones, hypotonia, seizures, and failure to thrive occur. Classic Menkes disease is usually first suspected when infants exhibit typical neurologic changes and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, often lightly pigmented) and jowly appearance of the face.
Transient hypoglycemia, prolonged physiologic jaundice, and persistent temperature instability are nonspecific signs that may be noted in the neonatal period.
Vascular tortuosity, neck masses (due to internal jugular vein dilatation), bladder diverticula that can result in bladder outlet obstruction, and gastric polyps are not uncommon. Subdural hematomas and cerebrovascular accidents are also not uncommon.
Without early treatment with daily subcutaneous copper injections (and sometimes despite treatment), classic Menkes disease progresses to severe neurodegeneration and death, typically between ages seven months and 3.5 years. Cardiorespiratory failure, often precipitated by pneumonia, is a common cause of death.
Brain MRI shows cerebral and cerebellar atrophy with ventriculomegaly, delayed myelination, and vascular tortuosity.
MR angiography reveals a "corkscrew" appearance of cerebral vessels.
Plain radiographs of the skull often reveal wormian bones. Metaphyseal spurring of long bones and rib fractures are also typical and may trigger concern regarding non-accidental trauma. In these instances, it is crucial to convey to social workers and other child protective services staff that these skeletal findings are consistent with the difficult natural history of this illness [
A few affected individuals in whom motor and cognitive development are better than in classic Menkes disease have been described. Individuals with mild Menkes disease may walk independently and acquire formal language. Weakness, ataxia, tremor, and head-bobbing are characteristic neurologic findings. Seizures, if present, commence in mid- to late childhood; intellectual disability is mild. Connective tissue problems may be more prominent than in classic Menkes disease.
Cognitive ability is within the normal range or slightly reduced. The predominant neurologic abnormalities in individuals with OHS are dysautonomia (e.g., orthostatic hypotension, chronic diarrhea) and subtle neurocognitive deficits. Lax skin and joints and bladder diverticula are common manifestations of lysyl oxidase (copper-dependent enzyme) deficiency. Elbow dislocations are not uncommon [Author, personal observation]. Inguinal hernias do not appear to occur at increased frequency in individuals with OHS. Scoliosis may occur with advancing age.
Little information exists on the full natural history of OHS or the fertility of affected individuals. An essentially normal life span appears likely.
The age of onset ranges from as young as five years up to 60 years; most typically, the presenting features occur in the second or third decade of life [
Females who are heterozygous for an
About 50% of females who are obligate heterozygotes for an
Evaluation of females who are obligate heterozygotes for an
• Brain MRI shows cerebral and cerebellar atrophy with ventriculomegaly, delayed myelination, and vascular tortuosity.
• MR angiography reveals a "corkscrew" appearance of cerebral vessels.
• Plain radiographs of the skull often reveal wormian bones. Metaphyseal spurring of long bones and rib fractures are also typical and may trigger concern regarding non-accidental trauma. In these instances, it is crucial to convey to social workers and other child protective services staff that these skeletal findings are consistent with the difficult natural history of this illness [
## Classic Menkes Disease
Infants appear healthy until age two to three months, when loss of early developmental milestones, hypotonia, seizures, and failure to thrive occur. Classic Menkes disease is usually first suspected when infants exhibit typical neurologic changes and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, often lightly pigmented) and jowly appearance of the face.
Transient hypoglycemia, prolonged physiologic jaundice, and persistent temperature instability are nonspecific signs that may be noted in the neonatal period.
Vascular tortuosity, neck masses (due to internal jugular vein dilatation), bladder diverticula that can result in bladder outlet obstruction, and gastric polyps are not uncommon. Subdural hematomas and cerebrovascular accidents are also not uncommon.
Without early treatment with daily subcutaneous copper injections (and sometimes despite treatment), classic Menkes disease progresses to severe neurodegeneration and death, typically between ages seven months and 3.5 years. Cardiorespiratory failure, often precipitated by pneumonia, is a common cause of death.
Brain MRI shows cerebral and cerebellar atrophy with ventriculomegaly, delayed myelination, and vascular tortuosity.
MR angiography reveals a "corkscrew" appearance of cerebral vessels.
Plain radiographs of the skull often reveal wormian bones. Metaphyseal spurring of long bones and rib fractures are also typical and may trigger concern regarding non-accidental trauma. In these instances, it is crucial to convey to social workers and other child protective services staff that these skeletal findings are consistent with the difficult natural history of this illness [
• Brain MRI shows cerebral and cerebellar atrophy with ventriculomegaly, delayed myelination, and vascular tortuosity.
• MR angiography reveals a "corkscrew" appearance of cerebral vessels.
• Plain radiographs of the skull often reveal wormian bones. Metaphyseal spurring of long bones and rib fractures are also typical and may trigger concern regarding non-accidental trauma. In these instances, it is crucial to convey to social workers and other child protective services staff that these skeletal findings are consistent with the difficult natural history of this illness [
## Mild Menkes Disease
A few affected individuals in whom motor and cognitive development are better than in classic Menkes disease have been described. Individuals with mild Menkes disease may walk independently and acquire formal language. Weakness, ataxia, tremor, and head-bobbing are characteristic neurologic findings. Seizures, if present, commence in mid- to late childhood; intellectual disability is mild. Connective tissue problems may be more prominent than in classic Menkes disease.
## Occipital Horn Syndrome (OHS; X-Linked Cutis Laxa)
Cognitive ability is within the normal range or slightly reduced. The predominant neurologic abnormalities in individuals with OHS are dysautonomia (e.g., orthostatic hypotension, chronic diarrhea) and subtle neurocognitive deficits. Lax skin and joints and bladder diverticula are common manifestations of lysyl oxidase (copper-dependent enzyme) deficiency. Elbow dislocations are not uncommon [Author, personal observation]. Inguinal hernias do not appear to occur at increased frequency in individuals with OHS. Scoliosis may occur with advancing age.
Little information exists on the full natural history of OHS or the fertility of affected individuals. An essentially normal life span appears likely.
The age of onset ranges from as young as five years up to 60 years; most typically, the presenting features occur in the second or third decade of life [
## Heterozygous Females
Females who are heterozygous for an
About 50% of females who are obligate heterozygotes for an
Evaluation of females who are obligate heterozygotes for an
## Genotype-Phenotype Correlations
The amount of residual ATPase enzyme activity correlates with the phenotype in Menkes disease, OHS, and
Milder variants of Menkes disease and OHS are often associated with splice junction pathogenic variants that alter but do not eliminate proper RNA splicing (i.e., "leaky" splice junction defects).
The pathogenic variants associated with
Intrafamilial phenotypic variability is occasionally observed in Menkes disease [
## Nomenclature
Menkes disease is also known as Menkes kinky hair syndrome, or trichopoliodystrophy.
Occipital horn syndrome was formerly known as X-linked cutis laxa.
## Prevalence
Previous estimates of the prevalence of Menkes disease were based on confirmed clinical cases ascertained from specific populations and varied from 1:40,000 to 1:354,507.
However, recent analyses based on genomic ascertainment of pathogenic alleles and assuming Hardy-Weinberg equilibrium predict a birth prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Organic acidurias
Aminoacidurias
Mitochondrial myopathies (See
•
• Organic acidurias
• Aminoacidurias
• Mitochondrial myopathies (See
## Management
No formal clinical practice guidelines for
To establish the extent of disease and needs in a male diagnosed with an
Recommended Evaluations Following Initial Diagnosis in Individuals with Classic Menkes Disease Phenotype
Incl brain imaging (MRI/MRA) to assess degree of cerebral/cerebellar atrophy.
Consider EEG if seizures present.
Assess for signs/symptoms of autonomic dysfunction (dizziness, syncope, chronic diarrhea).
To incl gross motor, fine motor, personal-social, & language development
Eval for early intervention / special education &/or PT, OT, & speech therapy
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Evaluate for umbilical &/or inguinal hernias.
Evaluate for gastric polyps.
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; OT = occupational therapy; PA = posteroanterior; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in a Male with Occipital Horn Syndrome
To incl brain MRI/MRA for vascular tortuosity
Assess for signs/symptoms of autonomic dysfunction (orthostatic hypotension, chronic diarrhea).
To incl adaptive, cognitive, & speech-language eval
Evaluate need for additional educational support.
MOI = mode of inheritance; OHS = occipital horn syndrome
Some medical centers have clinical autonomic testing laboratories.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in a Male with
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Feet for evidence of
Mobility, activities of daily living, & need for adaptive devices
Need for handicapped parking
To inform affected persons & their families re nature, MOI, & implications of
Clinical screening of at-risk relatives based on X-linked inheritance
AFOs = ankle-foot orthoses; DMN = distal motor neuropathy; EMG = Electromyography; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Classic Menkes Disease
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Early intervention incl OT, PT, & speech therapy as indicated
IEP
Management by developmental pediatrician
Antibiotic prophylaxis regimen advised to prevent bladder infection
Surgical resection if severe
Gastrostomy tube feeds to ↓ risk of aspiration pneumonia
Vaccination against RSV, influenza, & COVID
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASM = anti-seizure medication; IEP = individualized education plan; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in a Male with Occipital Horn Syndrome
Early academic support / IEP as indicated
Management by developmental pediatrician
Surgical treatment
Antibiotic prophylaxis may be necessary to prevent bladder infection.
Physical therapy
Joint splints if recommended by orthopedic or rheumatology expert.
IEP = individualized education plan
Treatment of Manifestations in a Male with
Special shoes, incl those w/good ankle support
AFOs to correct foot drop & aid walking
PT (strength & stretching exercises)
OT
Orthopedic surgery to correct severe
Forearm crutches, canes/walkers for gait stability, & wheelchairs
Exercise w/in person's capability (Many remain physically active.)
AFOs = ankle-foot orthoses; OT = occupational therapy; PT = physical therapy
To maintain serum copper concentration in the normal range (75-150 µg/dL), the suggested dose of copper histidinate (CuHis) is:
For infants age <1 year: 250 µg administered subcutaneously (0.5 mL) 2x/day
For infants age ≥1 year: 250 µg administered subcutaneously (0.5 mL) 1x/day
Cupric chloride (CuCl
Any role for subcutaneous CuCl
For infants being treated with CuHis (or temporarily with CuCl
Recommended Surveillance for a Male with Menkes Disease
Measurement of growth parameters (weight, length, head circumference)
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
Recommended Surveillance for a Male with Occipital Horn Syndrome
Recommended Surveillance for a Male with
Neurologic exam
Electroneurography of peripheral nerves
EMG/ENG
PT assessment (gross motor skills incl gait & strength)
OT assessment (fine motor skills)
EMG = electromyography; ENG = electroneurography; OT = occupational therapy; PT = physical therapy
It is appropriate to test male relatives at risk for Menkes disease for the
See
CuHis received FDA FastTrack (2018) and Breakthrough (2020) designations from the US Food and Drug Administration and the European Medicines Agency Committee for Orphan Medicinal Products issued a positive opinion for Orphan Drug Designation in 2020. An expanded access clinical trial that provides CuHis for individuals with Menkes disease in the US (NCT04074512) is currently in progress.
For updated preliminary results on subcutaneous CuHis treatment for Menkes disease, click
Adeno-associated viral (AAV) gene therapy in combination with copper has also been investigated in Menkes disease mouse models, with promising results [
Newborn screening is not currently available for Menkes disease because biochemical strategies may not be compatible with or practical for current newborn screening platforms. A pilot study to evaluate the potential of sequence analysis of
A Phase I/II clinical trial of droxidopa (Northera
Search
Therapies proven to be ineffective include vitamin C.
• Incl brain imaging (MRI/MRA) to assess degree of cerebral/cerebellar atrophy.
• Consider EEG if seizures present.
• Assess for signs/symptoms of autonomic dysfunction (dizziness, syncope, chronic diarrhea).
• To incl gross motor, fine motor, personal-social, & language development
• Eval for early intervention / special education &/or PT, OT, & speech therapy
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Evaluate for umbilical &/or inguinal hernias.
• Evaluate for gastric polyps.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• To incl brain MRI/MRA for vascular tortuosity
• Assess for signs/symptoms of autonomic dysfunction (orthostatic hypotension, chronic diarrhea).
• To incl adaptive, cognitive, & speech-language eval
• Evaluate need for additional educational support.
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Feet for evidence of
• Mobility, activities of daily living, & need for adaptive devices
• Need for handicapped parking
• To inform affected persons & their families re nature, MOI, & implications of
• Clinical screening of at-risk relatives based on X-linked inheritance
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Early intervention incl OT, PT, & speech therapy as indicated
• IEP
• Management by developmental pediatrician
• Antibiotic prophylaxis regimen advised to prevent bladder infection
• Surgical resection if severe
• Gastrostomy tube feeds to ↓ risk of aspiration pneumonia
• Vaccination against RSV, influenza, & COVID
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Early academic support / IEP as indicated
• Management by developmental pediatrician
• Surgical treatment
• Antibiotic prophylaxis may be necessary to prevent bladder infection.
• Physical therapy
• Joint splints if recommended by orthopedic or rheumatology expert.
• Special shoes, incl those w/good ankle support
• AFOs to correct foot drop & aid walking
• PT (strength & stretching exercises)
• OT
• Orthopedic surgery to correct severe
• Forearm crutches, canes/walkers for gait stability, & wheelchairs
• Exercise w/in person's capability (Many remain physically active.)
• For infants age <1 year: 250 µg administered subcutaneously (0.5 mL) 2x/day
• For infants age ≥1 year: 250 µg administered subcutaneously (0.5 mL) 1x/day
• Measurement of growth parameters (weight, length, head circumference)
• Eval of nutritional status & safety of oral intake
• Neurologic exam
• Electroneurography of peripheral nerves
• EMG/ENG
• PT assessment (gross motor skills incl gait & strength)
• OT assessment (fine motor skills)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in a male diagnosed with an
Recommended Evaluations Following Initial Diagnosis in Individuals with Classic Menkes Disease Phenotype
Incl brain imaging (MRI/MRA) to assess degree of cerebral/cerebellar atrophy.
Consider EEG if seizures present.
Assess for signs/symptoms of autonomic dysfunction (dizziness, syncope, chronic diarrhea).
To incl gross motor, fine motor, personal-social, & language development
Eval for early intervention / special education &/or PT, OT, & speech therapy
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Evaluate for umbilical &/or inguinal hernias.
Evaluate for gastric polyps.
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; OT = occupational therapy; PA = posteroanterior; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in a Male with Occipital Horn Syndrome
To incl brain MRI/MRA for vascular tortuosity
Assess for signs/symptoms of autonomic dysfunction (orthostatic hypotension, chronic diarrhea).
To incl adaptive, cognitive, & speech-language eval
Evaluate need for additional educational support.
MOI = mode of inheritance; OHS = occipital horn syndrome
Some medical centers have clinical autonomic testing laboratories.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in a Male with
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Feet for evidence of
Mobility, activities of daily living, & need for adaptive devices
Need for handicapped parking
To inform affected persons & their families re nature, MOI, & implications of
Clinical screening of at-risk relatives based on X-linked inheritance
AFOs = ankle-foot orthoses; DMN = distal motor neuropathy; EMG = Electromyography; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Incl brain imaging (MRI/MRA) to assess degree of cerebral/cerebellar atrophy.
• Consider EEG if seizures present.
• Assess for signs/symptoms of autonomic dysfunction (dizziness, syncope, chronic diarrhea).
• To incl gross motor, fine motor, personal-social, & language development
• Eval for early intervention / special education &/or PT, OT, & speech therapy
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Evaluate for umbilical &/or inguinal hernias.
• Evaluate for gastric polyps.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• To incl brain MRI/MRA for vascular tortuosity
• Assess for signs/symptoms of autonomic dysfunction (orthostatic hypotension, chronic diarrhea).
• To incl adaptive, cognitive, & speech-language eval
• Evaluate need for additional educational support.
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Feet for evidence of
• Mobility, activities of daily living, & need for adaptive devices
• Need for handicapped parking
• To inform affected persons & their families re nature, MOI, & implications of
• Clinical screening of at-risk relatives based on X-linked inheritance
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Classic Menkes Disease
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Early intervention incl OT, PT, & speech therapy as indicated
IEP
Management by developmental pediatrician
Antibiotic prophylaxis regimen advised to prevent bladder infection
Surgical resection if severe
Gastrostomy tube feeds to ↓ risk of aspiration pneumonia
Vaccination against RSV, influenza, & COVID
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASM = anti-seizure medication; IEP = individualized education plan; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in a Male with Occipital Horn Syndrome
Early academic support / IEP as indicated
Management by developmental pediatrician
Surgical treatment
Antibiotic prophylaxis may be necessary to prevent bladder infection.
Physical therapy
Joint splints if recommended by orthopedic or rheumatology expert.
IEP = individualized education plan
Treatment of Manifestations in a Male with
Special shoes, incl those w/good ankle support
AFOs to correct foot drop & aid walking
PT (strength & stretching exercises)
OT
Orthopedic surgery to correct severe
Forearm crutches, canes/walkers for gait stability, & wheelchairs
Exercise w/in person's capability (Many remain physically active.)
AFOs = ankle-foot orthoses; OT = occupational therapy; PT = physical therapy
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Early intervention incl OT, PT, & speech therapy as indicated
• IEP
• Management by developmental pediatrician
• Antibiotic prophylaxis regimen advised to prevent bladder infection
• Surgical resection if severe
• Gastrostomy tube feeds to ↓ risk of aspiration pneumonia
• Vaccination against RSV, influenza, & COVID
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Early academic support / IEP as indicated
• Management by developmental pediatrician
• Surgical treatment
• Antibiotic prophylaxis may be necessary to prevent bladder infection.
• Physical therapy
• Joint splints if recommended by orthopedic or rheumatology expert.
• Special shoes, incl those w/good ankle support
• AFOs to correct foot drop & aid walking
• PT (strength & stretching exercises)
• OT
• Orthopedic surgery to correct severe
• Forearm crutches, canes/walkers for gait stability, & wheelchairs
• Exercise w/in person's capability (Many remain physically active.)
## Prevention of Primary Manifestations
To maintain serum copper concentration in the normal range (75-150 µg/dL), the suggested dose of copper histidinate (CuHis) is:
For infants age <1 year: 250 µg administered subcutaneously (0.5 mL) 2x/day
For infants age ≥1 year: 250 µg administered subcutaneously (0.5 mL) 1x/day
Cupric chloride (CuCl
Any role for subcutaneous CuCl
• For infants age <1 year: 250 µg administered subcutaneously (0.5 mL) 2x/day
• For infants age ≥1 year: 250 µg administered subcutaneously (0.5 mL) 1x/day
## Surveillance
For infants being treated with CuHis (or temporarily with CuCl
Recommended Surveillance for a Male with Menkes Disease
Measurement of growth parameters (weight, length, head circumference)
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
Recommended Surveillance for a Male with Occipital Horn Syndrome
Recommended Surveillance for a Male with
Neurologic exam
Electroneurography of peripheral nerves
EMG/ENG
PT assessment (gross motor skills incl gait & strength)
OT assessment (fine motor skills)
EMG = electromyography; ENG = electroneurography; OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters (weight, length, head circumference)
• Eval of nutritional status & safety of oral intake
• Neurologic exam
• Electroneurography of peripheral nerves
• EMG/ENG
• PT assessment (gross motor skills incl gait & strength)
• OT assessment (fine motor skills)
## Evaluation of Relatives at Risk
It is appropriate to test male relatives at risk for Menkes disease for the
See
## Therapies Under Investigation
CuHis received FDA FastTrack (2018) and Breakthrough (2020) designations from the US Food and Drug Administration and the European Medicines Agency Committee for Orphan Medicinal Products issued a positive opinion for Orphan Drug Designation in 2020. An expanded access clinical trial that provides CuHis for individuals with Menkes disease in the US (NCT04074512) is currently in progress.
For updated preliminary results on subcutaneous CuHis treatment for Menkes disease, click
Adeno-associated viral (AAV) gene therapy in combination with copper has also been investigated in Menkes disease mouse models, with promising results [
Newborn screening is not currently available for Menkes disease because biochemical strategies may not be compatible with or practical for current newborn screening platforms. A pilot study to evaluate the potential of sequence analysis of
A Phase I/II clinical trial of droxidopa (Northera
Search
## Other
Therapies proven to be ineffective include vitamin C.
## Genetic Counseling
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
About one third of affected males represent simplex cases.
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected. Intrafamilial phenotypic variability is occasionally observed in Menkes disease and may also be observed in
Females who inherit the pathogenic variant will be heterozygotes. About 50% of females who are obligate heterozygotes for an
If the proband represents a simplex case and if the
Male Menkes disease survivors, and males with OHS, or
Males with classic Menkes disease are not known to reproduce.
About 50% of females who are obligate heterozygotes for an
Note: Biochemical testing is generally unreliable for carrier detection because of overlap with normal ranges.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being heterozygous or affected.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• About one third of affected males represent simplex cases.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected. Intrafamilial phenotypic variability is occasionally observed in Menkes disease and may also be observed in
• Females who inherit the pathogenic variant will be heterozygotes. About 50% of females who are obligate heterozygotes for an
• Males who inherit the pathogenic variant will be affected. Intrafamilial phenotypic variability is occasionally observed in Menkes disease and may also be observed in
• Females who inherit the pathogenic variant will be heterozygotes. About 50% of females who are obligate heterozygotes for an
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected. Intrafamilial phenotypic variability is occasionally observed in Menkes disease and may also be observed in
• Females who inherit the pathogenic variant will be heterozygotes. About 50% of females who are obligate heterozygotes for an
• Male Menkes disease survivors, and males with OHS, or
• Males with classic Menkes disease are not known to reproduce.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being heterozygous or affected.
## Mode of Inheritance
## Risk to Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
About one third of affected males represent simplex cases.
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected. Intrafamilial phenotypic variability is occasionally observed in Menkes disease and may also be observed in
Females who inherit the pathogenic variant will be heterozygotes. About 50% of females who are obligate heterozygotes for an
If the proband represents a simplex case and if the
Male Menkes disease survivors, and males with OHS, or
Males with classic Menkes disease are not known to reproduce.
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• About one third of affected males represent simplex cases.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected. Intrafamilial phenotypic variability is occasionally observed in Menkes disease and may also be observed in
• Females who inherit the pathogenic variant will be heterozygotes. About 50% of females who are obligate heterozygotes for an
• Males who inherit the pathogenic variant will be affected. Intrafamilial phenotypic variability is occasionally observed in Menkes disease and may also be observed in
• Females who inherit the pathogenic variant will be heterozygotes. About 50% of females who are obligate heterozygotes for an
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected. Intrafamilial phenotypic variability is occasionally observed in Menkes disease and may also be observed in
• Females who inherit the pathogenic variant will be heterozygotes. About 50% of females who are obligate heterozygotes for an
• Male Menkes disease survivors, and males with OHS, or
• Males with classic Menkes disease are not known to reproduce.
## Heterozygote Detection
About 50% of females who are obligate heterozygotes for an
Note: Biochemical testing is generally unreliable for carrier detection because of overlap with normal ranges.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being heterozygous or affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being heterozygous or affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
France
Italy
PO Box 5801
Bethesda MD 20824
•
• France
•
•
• Italy
•
•
•
•
• PO Box 5801
• Bethesda MD 20824
•
•
•
## Molecular Genetics
ATP7A-Related Copper Transport Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for ATP7A-Related Copper Transport Disorders (
The protein encoded by
Most
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The protein encoded by
Most
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
We thank the following organizations for research support: NICHD, Cyprium Therapeutics, Inc, NINDS, NIH Clinical Center, NIH Pharmaceutical Development Section, Office of Rare Diseases/NCATS, NIH Bench-to-Bedside Program, NIH Office of Dietary Supplements, UK Menkes Foundation, The Menkes Foundation (USA), Nos Enfants Menkes, Angeli per la Vita; the many patients, living and deceased, and their devoted families, who participated in the clinical research described; and colleagues in the copper research, viral gene therapy, and newborn screening communities, as well as regulatory experts at FDA and EMA, for their collective wisdom and invaluable guidance.
15 April 2021 (sw) Comprehensive update posted live
18 August 2016 (bp) Comprehensive update posted live
14 October 2010 (me) Comprehensive update posted live
13 July 2005 (me) Comprehensive update posted live
9 May 2003 (me) Review posted live
27 November 2002 (sk) Original submission
• 15 April 2021 (sw) Comprehensive update posted live
• 18 August 2016 (bp) Comprehensive update posted live
• 14 October 2010 (me) Comprehensive update posted live
• 13 July 2005 (me) Comprehensive update posted live
• 9 May 2003 (me) Review posted live
• 27 November 2002 (sk) Original submission
## Author Notes
## Acknowledgments
We thank the following organizations for research support: NICHD, Cyprium Therapeutics, Inc, NINDS, NIH Clinical Center, NIH Pharmaceutical Development Section, Office of Rare Diseases/NCATS, NIH Bench-to-Bedside Program, NIH Office of Dietary Supplements, UK Menkes Foundation, The Menkes Foundation (USA), Nos Enfants Menkes, Angeli per la Vita; the many patients, living and deceased, and their devoted families, who participated in the clinical research described; and colleagues in the copper research, viral gene therapy, and newborn screening communities, as well as regulatory experts at FDA and EMA, for their collective wisdom and invaluable guidance.
## Revision History
15 April 2021 (sw) Comprehensive update posted live
18 August 2016 (bp) Comprehensive update posted live
14 October 2010 (me) Comprehensive update posted live
13 July 2005 (me) Comprehensive update posted live
9 May 2003 (me) Review posted live
27 November 2002 (sk) Original submission
• 15 April 2021 (sw) Comprehensive update posted live
• 18 August 2016 (bp) Comprehensive update posted live
• 14 October 2010 (me) Comprehensive update posted live
• 13 July 2005 (me) Comprehensive update posted live
• 9 May 2003 (me) Review posted live
• 27 November 2002 (sk) Original submission
## References
## Literature Cited
|
[
"B Borm, LB Moller, I Hausser, M Emeis, K Baerlocher, N Horn, R Rossi. Variable clinical expression of an identical mutation in the ATP7A gene for Menkes disease/occipital horn syndrome in three affected males in a single family.. J Pediatr 2004;145:119-21",
"V Desai, A Donsante, KJ Swoboda, M Martensen, J Thompson, SG Kaler. Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease.. Clin Genet. 2011;79:176-82",
"A Donsante, JR Tang, SC Godwin, CS Holmes, DS Goldstein, A Bassuk, SG Kaler. Differences in ATP7A gene expression underlie intra-familial variability in Menkes disease/occipital horn syndrome.. J Med Genet 2007;44:492-7",
"A Donsante, L Yi, P Zerfas, L Brinster, P Sullivan, DS Goldstein, J Prohaska, JA Centeno, SG Kaler. ATP7A gene addition to the choroid plexus results in long-term rescue of the lethal copper transport defect in a Menkes disease mouse model.. Mol Ther 2011;19:2114-23",
"MR Haddad, EY Choi, PM Zerfas, L Yi, D Martinelli, P Sullivan, DS Goldstein, J Centeno, L Brinster, M Ralle, SG Kaler. Cerebrospinal fluid-directed rAAV9-rsATP7A plus subcutaneous copper histidinate advance survival and outcomes in a Menkes disease mouse model.. Mol Ther Methods Clin Dev. 2018;10:165-78",
"SC Hill, AJ Dwyer, SG Kaler. Cervical spine anomalies in Menkes disease: a radiologic finding potentially confused with child abuse.. Pediatr Radiol 2012;42:1301-4",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"SG Kaler. The neurology of ATP7A copper transporter disease: emerging concepts and future trends.. Nat Rev Neurol 2011;7:15-29",
"SG Kaler, NR Buist, CS Holmes, DS Goldstein, RC Miller, WA Gahl. Early copper therapy in classic Menkes disease patients with a novel splicing mutation.. Ann Neurol 1995;38:921-8",
"SG Kaler, CR Ferreira, LS Yam. Estimated genetic prevalence of Menkes disease based on the Genome Aggregation Database (gnomAD).. Mol Genet Metab Rep 2020;24",
"SG Kaler, LK Gallo, VK Proud, AK Percy, Y Mark, NA Segal, DS Goldstein, CS Holmes, WA Gahl. Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus.. Nat Genet 1994;8:195-202",
"SG Kaler, CS Holmes, DS Goldstein, JR Tang, SC Godwin, A Donsante, CJ Liew, S Sato, N Patronas. Neonatal diagnosis and treatment of Menkes disease.. N Engl J Med 2008;358:605-14",
"SG Kaler, CJ Liew, A Donsante, JD Hicks, S Sato, JC Greenfield. Molecular correlates of epilepsy in early diagnosed and treated Menkes disease.. J Inher Metab Dis. 2010;33:583-9",
"M Kennerson, G Nicholson, B Kowalski, K Krajewski, D El-Khechen, S Feely, S Chu, M Shy, J Garbern. X-linked distal hereditary motor neuropathy maps to the DSMAX locus on chromosome Xq13.1-q21.. Neurology. 2009;72:246-52",
"ML Kennerson, GA Nicholson, SG Kaler, B Kowalski, JF Mercer, J Tang, RM Llanos, S Chu, RI Takata, CE Speck-Martins, J Baets, L Almeida-Souza, D Fischer, V Timmerman, PE Taylor, SS Scherer, TA Ferguson, TD Bird, P De Jonghe, SM Feely, ME Shy, JY Garbern. Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy.. Am J Hum Genet 2010;86:343-52",
"CM Moore, RR Howell. Ectodermal manifestations in Menkes disease.. Clin Genet 1985;28:532-40",
"RB Parad, SG Kaler, E Mauceli, T Sokolsky, L Yi, A Bhattacharjee. Targeted next generation sequencing for newborn screening of Menkes disease.. Mol Genet Metab Rep. 2020;24",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"KE Stevens, JE Price, J Marko, SG Kaler. Neck masses due to internal jugular vein phlebectasia: frequency in Menkes disease and literature review of 85 pediatric cases.. Am J Med Genet Part A 2020;182:1364-77",
"L Yi, A Donsante, ML Kennerson, JFB Mercer, JY Garbern, SG Kaler. Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related distal motor neuropathy.. Hum Mol Genet. 2012;21:1794-807",
"L Yi, SG Kaler. Interaction between the AAA ATPase p97/VCP and a concealed UBX domain in the copper transporter ATP7A is associated with motor neuron degeneration.. J Biol Chem 2018;293:7606-17"
] |
9/5/2003
|
15/4/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
merrf
|
merrf
|
[
"Myoclonic Epilepsy Associated with Ragged Red Fibers",
"Myoclonic Epilepsy Associated with Ragged-Red Fibers",
"Not applicable",
"MT-TF",
"MT-TH",
"MT-TI",
"MT-TK",
"MT-TL1",
"MT-TP",
"MT-TS1",
"MT-TS2",
"MERRF"
] |
MERRF
|
Frances Velez-Bartolomei, Chung Lee, Gregory Enns
|
Summary MERRF ( A clinical diagnosis of MERRF can be established in a proband with the following four "canonic" features: myoclonus, generalized epilepsy, ataxia, and ragged red fibers (RRF) in the muscle biopsy. A molecular diagnosis is established in a proband with suggestive findings and a pathogenic variant in one of the genes associated with MERRF. The m.8344A>G pathogenic variant in the mitochondrial gene MERRF is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance. The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. A male with a mtDNA pathogenic variant cannot transmit the pathogenic variant to any of his offspring. A female with a mtDNA pathogenic variant (whether symptomatic or asymptomatic) transmits the pathogenic variant to all of her offspring. Prenatal testing and preimplantation genetic testing for MERRF are possible if a mtDNA pathogenic variant has been detected in the mother. However, because the mutational load in embryonic and fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of all fetal tissues and because the mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation, prediction of the phenotype from prenatal studies is not possible.
|
## Diagnosis
Clinical diagnostic criteria for MERRF (
MERRF (
Myoclonus
Generalized epilepsy
Ataxia
Myopathy
Exercise intolerance
Dementia
Ptosis
Sensorineural hearing loss
Short stature
Optic atrophy
Peripheral neuropathy
Less common clinical signs (seen in <50% of affected individuals) include the following:
Cardiomyopathy
Pigmentary retinopathy
Pyramidal signs
Ophthalmoparesis
Multiple lipomas
Note: Other situations (unrelated to the diagnosis of MERRF or other mitochondrial diseases) in which lactate and pyruvate can be elevated are acute neurologic events such as seizure or stroke.
The clinical diagnosis of MERRF (
Myoclonus
Generalized epilepsy
Ataxia
Ragged red fibers (RRF) in the muscle biopsy
Note: Pathogenic variants can usually be detected in mtDNA from leukocytes in individuals with typical MERRF; however, the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected only in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and weakness,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in MERRF
Genes are listed from most frequent to least frequent genetic cause of MERRF.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Four
One child with MERRF was found to have two mtDNA deletions in a buccal swab, suggesting an autosomal disorder with multiple mtDNA deletions; however, the causative nuclear gene was not identified [
• Myoclonus
• Generalized epilepsy
• Ataxia
• Myopathy
• Exercise intolerance
• Dementia
• Ptosis
• Sensorineural hearing loss
• Short stature
• Optic atrophy
• Peripheral neuropathy
• Cardiomyopathy
• Pigmentary retinopathy
• Pyramidal signs
• Ophthalmoparesis
• Multiple lipomas
• Note: Other situations (unrelated to the diagnosis of MERRF or other mitochondrial diseases) in which lactate and pyruvate can be elevated are acute neurologic events such as seizure or stroke.
• Myoclonus
• Generalized epilepsy
• Ataxia
• Ragged red fibers (RRF) in the muscle biopsy
## Suggestive Findings
MERRF (
Myoclonus
Generalized epilepsy
Ataxia
Myopathy
Exercise intolerance
Dementia
Ptosis
Sensorineural hearing loss
Short stature
Optic atrophy
Peripheral neuropathy
Less common clinical signs (seen in <50% of affected individuals) include the following:
Cardiomyopathy
Pigmentary retinopathy
Pyramidal signs
Ophthalmoparesis
Multiple lipomas
Note: Other situations (unrelated to the diagnosis of MERRF or other mitochondrial diseases) in which lactate and pyruvate can be elevated are acute neurologic events such as seizure or stroke.
• Myoclonus
• Generalized epilepsy
• Ataxia
• Myopathy
• Exercise intolerance
• Dementia
• Ptosis
• Sensorineural hearing loss
• Short stature
• Optic atrophy
• Peripheral neuropathy
• Cardiomyopathy
• Pigmentary retinopathy
• Pyramidal signs
• Ophthalmoparesis
• Multiple lipomas
• Note: Other situations (unrelated to the diagnosis of MERRF or other mitochondrial diseases) in which lactate and pyruvate can be elevated are acute neurologic events such as seizure or stroke.
## Establishing the Diagnosis
The clinical diagnosis of MERRF (
Myoclonus
Generalized epilepsy
Ataxia
Ragged red fibers (RRF) in the muscle biopsy
Note: Pathogenic variants can usually be detected in mtDNA from leukocytes in individuals with typical MERRF; however, the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected only in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and weakness,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in MERRF
Genes are listed from most frequent to least frequent genetic cause of MERRF.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Four
One child with MERRF was found to have two mtDNA deletions in a buccal swab, suggesting an autosomal disorder with multiple mtDNA deletions; however, the causative nuclear gene was not identified [
• Myoclonus
• Generalized epilepsy
• Ataxia
• Ragged red fibers (RRF) in the muscle biopsy
## Option 1
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and weakness,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in MERRF
Genes are listed from most frequent to least frequent genetic cause of MERRF.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Four
One child with MERRF was found to have two mtDNA deletions in a buccal swab, suggesting an autosomal disorder with multiple mtDNA deletions; however, the causative nuclear gene was not identified [
## Clinical Characteristics
MERRF (
MERRF: Frequency of Select Features
Reviewed from the literature by
No phenotype correlations by gene have been identified.
No genotype-phenotype correlations have been identified.
For all mtDNA pathogenic variants, clinical expression depends on three factors:
The tissue vulnerability threshold probably does not vary substantially among individuals, but variable mutational load and tissue distribution may account for the clinical diversity of individuals with MERRF.
See
Ramsay
Four epidemiologic studies of mtDNA-related diseases in northern Europe gave concordantly low estimates for the prevalence of the
0-1.5:100,000 in the adult population of northern Finland [
0.39:100,000 in the adult population of northern England [
0-0.25:100,000 in a pediatric population of western Sweden [
0.7:100,000 in a large population-based study in northeast England [
See
• 0-1.5:100,000 in the adult population of northern Finland [
• 0.39:100,000 in the adult population of northern England [
• 0-0.25:100,000 in a pediatric population of western Sweden [
• 0.7:100,000 in a large population-based study in northeast England [
## Clinical Description
MERRF (
MERRF: Frequency of Select Features
Reviewed from the literature by
## Phenotype Correlations by Gene
No phenotype correlations by gene have been identified.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
For all mtDNA pathogenic variants, clinical expression depends on three factors:
The tissue vulnerability threshold probably does not vary substantially among individuals, but variable mutational load and tissue distribution may account for the clinical diversity of individuals with MERRF.
## Penetrance
See
## Nomenclature
Ramsay
## Prevalence
Four epidemiologic studies of mtDNA-related diseases in northern Europe gave concordantly low estimates for the prevalence of the
0-1.5:100,000 in the adult population of northern Finland [
0.39:100,000 in the adult population of northern England [
0-0.25:100,000 in a pediatric population of western Sweden [
0.7:100,000 in a large population-based study in northeast England [
See
• 0-1.5:100,000 in the adult population of northern Finland [
• 0.39:100,000 in the adult population of northern England [
• 0-0.25:100,000 in a pediatric population of western Sweden [
• 0.7:100,000 in a large population-based study in northeast England [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Selected Allelic Disorders
Cardiomyopathy (OMIM
Pigmentary retinopathy (OMIM
Neonatal weakness, lactic acidosis, hypoglycemia, cardiopulmonary arrest, & early fatality in one individual
Multiple symmetric lipomatosis [
MERRF/
Cardiomyopathy (OMIM
Maternally inherited diabetes mellitus w/ or w/o deafness (OMIM
MERRF/
MERRF/Kearns-Sayre syndrome (See
Progressive external ophthalmoplegia (See
Cerebellar ataxia, cataract, and diabetes mellitus (OMIM
In three families with the
One affected individual with MERRF/MELAS overlap syndrome had two pathogenic variants: the
A MERRF/Kearns-Sayre syndrome overlap syndrome has been reported to be caused by the pathogenic variant m.3255G>A in
No phenotypes other than those discussed in this
• Cardiomyopathy (OMIM
• Pigmentary retinopathy (OMIM
• Neonatal weakness, lactic acidosis, hypoglycemia, cardiopulmonary arrest, & early fatality in one individual
• Multiple symmetric lipomatosis [
• MERRF/
• Cardiomyopathy (OMIM
• Maternally inherited diabetes mellitus w/ or w/o deafness (OMIM
• MERRF/
• MERRF/Kearns-Sayre syndrome (See
• Progressive external ophthalmoplegia (See
• Cerebellar ataxia, cataract, and diabetes mellitus (OMIM
## Differential Diagnosis
The multisystem involvement, lactic acidosis, evidence of maternal inheritance, and muscle biopsy with RRF (ragged red fibers) distinguish MERRF (
Genes of Interest in the Differential Diagnosis of MERRF
AR = autosomal recessive; DiffDx = differential diagnosis; Mat = maternal; MOI = mode of inheritance; NARP = neuropathy-ataxia-retinitis pigmentosa; RRF = ragged red fibers
## Management
To establish the extent of disease and needs in an individual diagnosed with MERRF (
Recommended Evaluations Following Initial Diagnosis in Individuals with MERRF
Fasting serum glucose
Glucose tolerance test
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations in Individuals with MERRF
PT
Aerobic exercise
PT = physical therapy
The administration of coenzyme Q
The Mitochondrial Medicine Society published a consensus statement which recommends that CoQ
Affected individuals and their at-risk relatives should be followed at regular intervals (e.g., every 6-12 months initially) to monitor progression of disease and the appearance of new symptoms.
Recommended Surveillance for Individuals with MERRF
Annually
If normal for 3 yrs, less frequent evals can be considered.
Electrocardiogram
Echocardiogram
Fasting blood sugar
TSH
TSH = thyroid stimulating hormone
Individuals with MERRF should avoid mitochondrial toxins such as aminoglycoside antibiotics, linezolid, cigarettes, and alcohol. Valproic acid should be avoided in the treatment of seizures.
It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known;
Complete neurologic evaluation, ophthalmologic and audiology evaluations, EKG, echocardiogram, and blood lactate if the pathogenic variant in the family is not known.
See
During pregnancy, affected or at-risk women should be monitored for diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions.
Mitochondrial replacement therapy (MRT) – replacement of a woman's abnormal mitochondrial DNA with healthy mitochondrial DNA from a donor [
Genetic therapy through the delivery of mitochondrially targeted zinc finger nucleases delivered by an adeno-associated virus has been studied in mouse models with mitochondrial disorders. The mutational load decreased by 20% in treated animals, and biochemical phenotypes were reversed [
Search
• Fasting serum glucose
• Glucose tolerance test
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
• PT
• Aerobic exercise
• Annually
• If normal for 3 yrs, less frequent evals can be considered.
• Electrocardiogram
• Echocardiogram
• Fasting blood sugar
• TSH
• Molecular genetic testing if the pathogenic variant in the family is known;
• Complete neurologic evaluation, ophthalmologic and audiology evaluations, EKG, echocardiogram, and blood lactate if the pathogenic variant in the family is not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MERRF (
Recommended Evaluations Following Initial Diagnosis in Individuals with MERRF
Fasting serum glucose
Glucose tolerance test
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Fasting serum glucose
• Glucose tolerance test
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with MERRF
PT
Aerobic exercise
PT = physical therapy
• PT
• Aerobic exercise
## Prevention of Primary Manifestations
The administration of coenzyme Q
The Mitochondrial Medicine Society published a consensus statement which recommends that CoQ
## Surveillance
Affected individuals and their at-risk relatives should be followed at regular intervals (e.g., every 6-12 months initially) to monitor progression of disease and the appearance of new symptoms.
Recommended Surveillance for Individuals with MERRF
Annually
If normal for 3 yrs, less frequent evals can be considered.
Electrocardiogram
Echocardiogram
Fasting blood sugar
TSH
TSH = thyroid stimulating hormone
• Annually
• If normal for 3 yrs, less frequent evals can be considered.
• Electrocardiogram
• Echocardiogram
• Fasting blood sugar
• TSH
## Agents/Circumstances to Avoid
Individuals with MERRF should avoid mitochondrial toxins such as aminoglycoside antibiotics, linezolid, cigarettes, and alcohol. Valproic acid should be avoided in the treatment of seizures.
## Evaluation of Relatives at Risk
It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known;
Complete neurologic evaluation, ophthalmologic and audiology evaluations, EKG, echocardiogram, and blood lactate if the pathogenic variant in the family is not known.
See
• Molecular genetic testing if the pathogenic variant in the family is known;
• Complete neurologic evaluation, ophthalmologic and audiology evaluations, EKG, echocardiogram, and blood lactate if the pathogenic variant in the family is not known.
## Pregnancy Management
During pregnancy, affected or at-risk women should be monitored for diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions.
## Therapies Under Investigation
Mitochondrial replacement therapy (MRT) – replacement of a woman's abnormal mitochondrial DNA with healthy mitochondrial DNA from a donor [
Genetic therapy through the delivery of mitochondrially targeted zinc finger nucleases delivered by an adeno-associated virus has been studied in mouse models with mitochondrial disorders. The mutational load decreased by 20% in treated animals, and biochemical phenotypes were reversed [
Search
## Genetic Counseling
MERRF (
The father of a proband is not at risk of having the mtDNA pathogenic variant.
The mother of a proband usually has the mtDNA pathogenic variant and may or may not have clinical manifestations of the disorder. In some mothers, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
Some individuals diagnosed with MERRF have no known family history of the disorder. The explanation for apparently simplex cases may be the absence of a comprehensive and/or reliable family history or, in rare cases, a
The risk to the sibs depends on the genetic status of the mother. If the mother has the mtDNA pathogenic variant, all the sibs of a proband will inherit the mtDNA pathogenic variant. Women with higher levels of mutated mtDNA in their blood may have a greater likelihood of having affected offspring [
Clinical expression in sibs depends on the percentage of mutated mitochondria (mutational load) and the organs and tissues in which they are found (tissue distribution and threshold effect). Sibs often inherit different percentages of mutated mtDNA and have a wide range of clinical manifestations (see
All offspring of females with a mtDNA pathogenic variant will inherit the pathogenic variant.
Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the mtDNA pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MERRF are technically possible. However, prenatal testing for mtDNA pathogenic variants causing MERRF is of uncertain utility for the following reasons:
The mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues.
The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.
Prediction of phenotype, age of onset, severity, or rate of progression is not possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of a proband is not at risk of having the mtDNA pathogenic variant.
• The mother of a proband usually has the mtDNA pathogenic variant and may or may not have clinical manifestations of the disorder. In some mothers, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
• Some individuals diagnosed with MERRF have no known family history of the disorder. The explanation for apparently simplex cases may be the absence of a comprehensive and/or reliable family history or, in rare cases, a
• The risk to the sibs depends on the genetic status of the mother. If the mother has the mtDNA pathogenic variant, all the sibs of a proband will inherit the mtDNA pathogenic variant. Women with higher levels of mutated mtDNA in their blood may have a greater likelihood of having affected offspring [
• Clinical expression in sibs depends on the percentage of mutated mitochondria (mutational load) and the organs and tissues in which they are found (tissue distribution and threshold effect). Sibs often inherit different percentages of mutated mtDNA and have a wide range of clinical manifestations (see
• All offspring of females with a mtDNA pathogenic variant will inherit the pathogenic variant.
• Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues.
• The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.
• Prediction of phenotype, age of onset, severity, or rate of progression is not possible.
## Mode of Inheritance
MERRF (
## Risk to Family Members
The father of a proband is not at risk of having the mtDNA pathogenic variant.
The mother of a proband usually has the mtDNA pathogenic variant and may or may not have clinical manifestations of the disorder. In some mothers, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
Some individuals diagnosed with MERRF have no known family history of the disorder. The explanation for apparently simplex cases may be the absence of a comprehensive and/or reliable family history or, in rare cases, a
The risk to the sibs depends on the genetic status of the mother. If the mother has the mtDNA pathogenic variant, all the sibs of a proband will inherit the mtDNA pathogenic variant. Women with higher levels of mutated mtDNA in their blood may have a greater likelihood of having affected offspring [
Clinical expression in sibs depends on the percentage of mutated mitochondria (mutational load) and the organs and tissues in which they are found (tissue distribution and threshold effect). Sibs often inherit different percentages of mutated mtDNA and have a wide range of clinical manifestations (see
All offspring of females with a mtDNA pathogenic variant will inherit the pathogenic variant.
Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant.
• The father of a proband is not at risk of having the mtDNA pathogenic variant.
• The mother of a proband usually has the mtDNA pathogenic variant and may or may not have clinical manifestations of the disorder. In some mothers, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
• Some individuals diagnosed with MERRF have no known family history of the disorder. The explanation for apparently simplex cases may be the absence of a comprehensive and/or reliable family history or, in rare cases, a
• The risk to the sibs depends on the genetic status of the mother. If the mother has the mtDNA pathogenic variant, all the sibs of a proband will inherit the mtDNA pathogenic variant. Women with higher levels of mutated mtDNA in their blood may have a greater likelihood of having affected offspring [
• Clinical expression in sibs depends on the percentage of mutated mitochondria (mutational load) and the organs and tissues in which they are found (tissue distribution and threshold effect). Sibs often inherit different percentages of mutated mtDNA and have a wide range of clinical manifestations (see
• All offspring of females with a mtDNA pathogenic variant will inherit the pathogenic variant.
• Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the mtDNA pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MERRF are technically possible. However, prenatal testing for mtDNA pathogenic variants causing MERRF is of uncertain utility for the following reasons:
The mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues.
The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.
Prediction of phenotype, age of onset, severity, or rate of progression is not possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues.
• The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.
• Prediction of phenotype, age of onset, severity, or rate of progression is not possible.
## Resources
Australia
Mitochondrial Care Network
United Kingdom
•
•
•
•
•
• Australia
•
•
•
•
• Mitochondrial Care Network
•
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
MERRF: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MERRF (
The origin of mtDNA pathogenic variants is uncertain. It is also unclear how the mtDNA single-nucleotide variants cause MERRF. Using rho
MERRF: Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
The origin of mtDNA pathogenic variants is uncertain. It is also unclear how the mtDNA single-nucleotide variants cause MERRF. Using rho
MERRF: Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Chapter Notes
Salvatore DiMauro, MD; Columbia University Medical Center (2003-2021)Gregory Enns, MB, ChB (2021-present)Michio Hirano, MD; Columbia University Medical Center (2003-2021)Chung Lee, MD (2021-present)Frances Velez-Bartolomei, MD (2021-present)
7 January 2021 (sw) Comprehensive update posted live
29 January 2015 (me) Comprehensive update posted live
18 August 2009 (me) Comprehensive update posted live
27 September 2005 (me) Comprehensive update posted live
3 June 2003 (ca) Review posted live
8 May 2003 (sdm) Original submission
• 7 January 2021 (sw) Comprehensive update posted live
• 29 January 2015 (me) Comprehensive update posted live
• 18 August 2009 (me) Comprehensive update posted live
• 27 September 2005 (me) Comprehensive update posted live
• 3 June 2003 (ca) Review posted live
• 8 May 2003 (sdm) Original submission
## Author History
Salvatore DiMauro, MD; Columbia University Medical Center (2003-2021)Gregory Enns, MB, ChB (2021-present)Michio Hirano, MD; Columbia University Medical Center (2003-2021)Chung Lee, MD (2021-present)Frances Velez-Bartolomei, MD (2021-present)
## Revision History
7 January 2021 (sw) Comprehensive update posted live
29 January 2015 (me) Comprehensive update posted live
18 August 2009 (me) Comprehensive update posted live
27 September 2005 (me) Comprehensive update posted live
3 June 2003 (ca) Review posted live
8 May 2003 (sdm) Original submission
• 7 January 2021 (sw) Comprehensive update posted live
• 29 January 2015 (me) Comprehensive update posted live
• 18 August 2009 (me) Comprehensive update posted live
• 27 September 2005 (me) Comprehensive update posted live
• 3 June 2003 (ca) Review posted live
• 8 May 2003 (sdm) Original submission
## References
## Literature Cited
|
[
"PF Chinnery, N Howell, RN Lightowlers, DM Turnbull. MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring.. Brain. 1998;121:1889-94",
"A Chomyn, G Meola, N Bresolin, ST Lai, G Scarlato, G Attardi. In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria.. Mol Cell Biol 1991;11:2236-44",
"PS Chong, S Vucic, ET Hedley-Whyte, M Dreyer, D Cros. Multiple symmetric lipomatosis (Madelung's disease) caused by the MERRF (A8344G) mutation: a report of two cases and review of the literature.. J Clin Neuromuscul Dis. 2003;5:1-7",
"C Crest, S Dupont, E Leguern, C Adam, M Baulac. Levetiracetam in progressive myoclonic epilepsy: an exploratory study in 9 patients.. Neurology 2004;62:640-3",
"M Crimi, S Galbiati, I Moroni, A Bordoni, MP Perini, E Lamantea, M Sciacco, M Zeviani, I Biunno, M Moggio, G Scarlato, GP Comi. A missense mutation in the mitochondrial ND5 gene associated with a Leigh-MELAS overlap syndrome.. Neurology 2003;60:1857-61",
"N Darin, A Oldfors, AR Moslemi, E Holme, M Tulinius. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities.. Ann Neurol 2001;49:377-83",
"S DiMauro, G. Davidzon. Mitochondrial DNA and disease.. Ann Med. 2005;37:222-32",
"V Emmanuele, DS Silvers, E Sotiriou, K Tanji, S DiMauro, M Hirano. MERRF and Kearns-Sayre overlap syndrome due to the mitochondrial DNA m.3291T>C mutation.. Muscle Nerve 2011;44:448-51",
"J Finsterer, S Zarrouk-Mahjoub, J Shoffner. MERRF Classification: Implications for diagnosis and clinical trials.. Pediatr Neurol 2018;80:8-23",
"J Finsterer, S Zarrouk-Mahjoubb. Management of epilepsy in MERRF syndrome.. Seizure 2017;50:166-170",
"H Fujioka, B Tandler, M Rosca, SE McCandless, B Katirji, ML Cohen, S Rapisuwon, CL Hoppel. Multiple muscle cell alterations in a case of encephalomyopathy.. Ultrastruct Pathol 2014;38:13-25",
"PA Gammage, C Viscomi, M Simard, ASH Costa, E Gaude, CA Powell, L Van Haute, BJ McCann, P Rebelo-Guiomar, R Cerutti, L Zhang, EJ Rebar, M Zeviani, C Frezza, JB Stewart, M Minczuk. Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.. Nat Med. 2018;24:1691-5",
"RC Gilson, S Osswald. Madelung lipomatosis presenting as a manifestation of myoclonic epilepsy with ragged red fibers (MERRF) syndrome.. JAAD Case Rep. 2018;4:822-3",
"GS Gorman, AM Schaefer, Y Ng, N Gomez, EL Blakely, CL Alston, C Feeney, R Horvath, P Yu-Wai-Man, PF Chinnery, RW Taylor, DM Turnbull, R McFarland. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease.. Ann Neurol 2015;77:753-9",
"MD Herrero-Martín, T Ayuso, MT Tuñón, MA Martín, E Ruiz-Pesini, J. A Montoya. MELAS/MERRF phenotype associated with the mitochondrial DNA 5521G>A mutation.. J Neurol Neurosurg Psychiatry. 2010;81:471-2",
"JR Hunt. Dyssynergia cerebellaris myoclonia-primary atrophy of the dentate system: a contribution to the pathology and symptomatology of the cerebellum.. Brain 1921;44:490-538",
"S Ito, W Shirai, M Asahina, T Hattori. Clinical and brain MR imaging features focusing on the brain stem and cerebellum in patients with myoclonic epilepsy with ragged-red fibers due to mitochondrial A8344G mutation.. AJNR Am J Neuroradiol 2008;29:392-5",
"R Kälviäinen. Progressive myoclonus epilepsies.. Semin Neurol. 2015;35:293-9",
"M Mancuso, D Orsucci, C Angelini, E Bertini, V Carelli, GP Comi, C Minetti, M Moggio, T Mongini, S Servidei, P Tonin, A Toscano, G Uziel, C Bruno, E Caldarazzo Ienco, M Filosto, C Lamperti, D Martinelli, I Moroni, O Musumeci, E Pegoraro, D Ronchi, FM Santorelli, D Sauchelli, M Scarpelli, M Sciacco, M Spinazzi, ML Valentino, L Vercelli, M Zeviani, G Siciliano. Phenotypic heterogeneity of the 8344A>G mtDNA \"MERRF\" mutation.. Neurology 2013;80:2049-54",
"M Mancuso, L Petrozzi, M Filosto, C Nesti, A Rocchi, A Choub, S Pistolesi, R Massentani, G Fontanini, G Siciliano. MERRF syndrome without ragged-red fibers: the need for molecular diagnosis.. Biochem Biophys Res Commun 2007;354:1058-60",
"R Martín-Jiménez, E Martin-Hernandez, A Cabello, MT Garcia-Silva, J Arenas, Y Campos. Clinical and cellular consequences of the mutation m.12300G>A in the mitochondrial tRNA(Leu(CUN)) gene.. Mitochondrion 2012;12:288-93",
"JP Masucci, M Davidson, Y Koga, EA Schon, MP King. In vitro analysis of mutations causing myoclonus epilepsy with ragged-red fibers in the mitochondrial tRNA(Lys)gene: two genotypes produce similar phenotypes.. Mol Cell Biol 1995;15:2872-81",
"AB Naini, J Lu, P Kaufmann, RA Bernstein, M Mancuso, E Bonilla, M Hirano, S DiMauro. Novel mitochondrial DNA ND5 mutation in a patient with clinical features of MELAS and MERRF.. Arch Neurol 2005;62:473-6",
"M Nakamura, I Yabe, A Sudo, K Hosoki, H Yaguchi, S Saitoh, H Sasaki. MERRF/MELAS overlap syndrome: a double pathogenic mutation in mitochondrial tRNA genes.. J Med Genet 2010;47:659-64",
"Y Nishigaki, S Tadesse, E Bonilla, D Shungu, S Hersh, BJ Keats, CI Berlin, MF Goldberg, J Vockley, S DiMauro, M Hirano. A novel mitochondrial tRNA(Leu(UUR)) mutation in a patient with features of MERRF and Kearns-Sayre syndrome.. Neuromuscul Disord 2003;13:334-40",
"S Orcesi, K Gorni, C Termine, C Uggetti, P Veggiotti, F Carrara, M Zeviani, A Berardinelli, G Lanzi. Bilateral putaminal necrosis associated with the mitochondrial DNA A8344G myoclonus epilepsy with ragged red fibers (MERRF) mutation: an infantile case.. J Child Neurol 2006;21:79-82",
"S Parikh, A Goldstein, M Koenig, F Scaglia, GM Enns, R Saneto, I Anselm, BH Cohen, MJ Falk, C Greene, AL Gropman, R Haas, M Hirano, P Morgan, K Sims, M Tarnopolsky, JL Van Hove, L Wolfe, S DiMauro. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society.. Genet Med 2015;17:689-701",
"U Perera, BA Kennedy, RA Hegele. Multiple symmetric lipomatosis (Madelung disease) in a large Canadian family with the mitochondrial MTTK c.8344A>G Variant.. J Investig Med High Impact Case Rep. 2018:6",
"AM Remes, K Majamaa-Voltti, M Karppa, JS Moilanen, S Uimonen, H Helander, H Rusanen, PI Salmela, M Sorri, IE Hassinen, K Majamaa. Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population.. Neurology 2005;64:976-81",
"MC Rodriguez, JR MacDonald, DJ Mahoney, G Parise, MF Beal, MA Tarnopolsky. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders.. Muscle Nerve 2007;35:235-42",
"AM Schaefer, R McFarland, EL Blakely, L He, RG Whittaker, RW Taylor, PF Chinnery, DM Turnbull. Prevalence of mitochondrial DNA disease in adults.. Ann Neurol 2008;63:35-9",
"H Sharma, D Singh, A Mahant, SK Sohal, AK Kesavan. Samiksha. Development of mitochondrial replacement therapy: a review.. Heliyon. 2020;6",
"M Sissler, M Helm, M Frugier, R Giege, C Florentz. Aminoacylation properties of pathology-related human mitochondrial tRNA(Lys) variants.. RNA 2004;10:841-53",
"T Taivassalo, RG Haller. Implications of exercise training in mtDNA defects--use it or lose it?. Biochim Biophys Acta 2004;1659:221-31",
"C Vollono, G Primiano, G Della Marca, A Losurdo, S Servidei. Migraine in mitochondrial disorders: Prevalence and characteristics.. Cephalalgia. 2018;38:1093-106",
"KL Yoon, SG Ernst, C Rasmussen, EC Dooling, JR Aprille. Mitochondrial disorder associated with newborn cardiopulmonary arrest.. Pediatr Res 1993;33:433-40",
"WR Yorns, I Valencia, A Jayaraman, S Sheth, A Legido, MJ Goldenthal. Buccal swab analysis of mitochondrial enzyme deficiency and DNA defects in a child with suspected myoclonic epilepsy and ragged red fibers (MERRF).. J Child Neurol 2012;27:398-401"
] |
3/6/2003
|
7/1/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mf-dys-mic
|
mf-dys-mic
|
[
"Mandibulofacial Dysostosis, Guion-Almeida Type (MFDGA), EFTUD2-Related Mandibulofacial Dysostosis with Microcephaly (Guion-Almeida Type)",
"Mandibulofacial Dysostosis, Guion-Almeida Type (MFDGA)",
"EFTUD2-Related Mandibulofacial Dysostosis with Microcephaly (Guion-Almeida Type)",
"116 kDa U5 small nuclear ribonucleoprotein component",
"EFTUD2",
"Mandibulofacial Dysostosis with Microcephaly"
] |
Mandibulofacial Dysostosis with Microcephaly
|
Matthew Lines, Taila Hartley, Stella K MacDonald, Kym M Boycott
|
Summary Mandibulofacial dysostosis with microcephaly (MFDM) is characterized by malar and mandibular hypoplasia, microcephaly (congenital or postnatal onset), intellectual disability (mild, moderate, or severe), malformations of the external ear, and hearing loss that is typically conductive. Associated craniofacial malformations may include cleft palate, choanal atresia, zygomatic arch cleft (identified on cranial CT scan), and facial asymmetry. Other relatively common findings (present in 25%-35% of individuals) can include cardiac anomalies, thumb anomalies, esophageal atresia/tracheoesophageal fistula, short stature, spine anomalies, and epilepsy. The diagnosis of MFDM is confirmed in a proband with typical clinical findings and a heterozygous pathogenic variant in MFDM is an autosomal dominant disorder. Most individuals diagnosed with MFDM to date are presumed to have the disorder as the result of a
|
## Diagnosis
Mandibulofacial dysostosis with microcephaly (MFDM)
The diagnosis of MFDM
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the clinical phenotype of MFDM varies, individuals with highly characteristic clinical findings are likely to be diagnosed using gene-targeted testing (see
When the phenotypic and laboratory findings suggest the diagnosis of MFDM, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders with similar craniofacial features or is not considered because an individual has atypical phenotypic features,
If exome sequencing is not diagnostic, other techniques (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis (see
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mandibulofacial Dysostosis with Microcephaly
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Suggestive Findings
Mandibulofacial dysostosis with microcephaly (MFDM)
## Establishing the Diagnosis
The diagnosis of MFDM
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the clinical phenotype of MFDM varies, individuals with highly characteristic clinical findings are likely to be diagnosed using gene-targeted testing (see
When the phenotypic and laboratory findings suggest the diagnosis of MFDM, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders with similar craniofacial features or is not considered because an individual has atypical phenotypic features,
If exome sequencing is not diagnostic, other techniques (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis (see
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mandibulofacial Dysostosis with Microcephaly
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of MFDM, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders with similar craniofacial features or is not considered because an individual has atypical phenotypic features,
If exome sequencing is not diagnostic, other techniques (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis (see
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mandibulofacial Dysostosis with Microcephaly
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising craniofacial skeletal anomalies, microcephaly, developmental delay / intellectual disability, abnormalities of the ears and hearing, and, in some instances, extracranial malformations (esophageal atresia, congenital heart defects, thumb anomalies), and/or short stature.
To date, 126 individuals have been identified with a pathogenic variant in
Mandibulofacial Dysostosis with Microcephaly: Frequency of Select Features
Accompanying findings in MFDM include micrognathia/mandibular hypoplasia, cleft palate, and/or choanal abnormality.
Cleft palate in MFDM occurs as a Pierre Robin sequence, characterized by a midline bony defect without accompanying cleft lip. Submucous cleft has also been described. Choanal atresia is generally osseous, being either unilateral or bilateral; choanal stenosis is also frequent.
Zygomatic arch cleft has been identified in ten of 19 individuals assessed (best done with cranial CT with 3-D reconstruction).
Affected children are ambulatory but show delayed motor development, taking first steps at a median age of 26 months (n=38; range 13-60 months) [
Among those who are verbal, the median reported age at first words is 27 months (n=32; range 12 months to 5.6 years); some affected persons remain nonverbal into adult life [
To date there have been no detailed or cross-sectional studies of long-term neuropsychological outcomes in MFDM. Developmental data in the few affected adults identified to date suggest a broad range of outcomes, with some affected persons achieving semi-independent living with paid employment [
No genotype-phenotype correlations for
Individuals with microdeletions encompassing
MFDM is highly penetrant but variably expressive. Features may be subclinical in some affected individuals, as in the case of two non-mosaic, intellectually normal mothers – each with two affected children – in whom the only reported clinical findings were unilateral zygomatic cleft and facial asymmetry [
The descriptive term "mandibulofacial dysostosis with microcephaly" is synonymous with the eponym "mandibulofacial dysostosis, Guion-Almeida type" [
Some have suggested that MFDM be classified as an acrofacial dysostosis rather than a mandibulofacial dysostosis [
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
The prevalence of MFDM has not been established. At least 126 cases caused by mutation of
## Clinical Description
Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising craniofacial skeletal anomalies, microcephaly, developmental delay / intellectual disability, abnormalities of the ears and hearing, and, in some instances, extracranial malformations (esophageal atresia, congenital heart defects, thumb anomalies), and/or short stature.
To date, 126 individuals have been identified with a pathogenic variant in
Mandibulofacial Dysostosis with Microcephaly: Frequency of Select Features
Accompanying findings in MFDM include micrognathia/mandibular hypoplasia, cleft palate, and/or choanal abnormality.
Cleft palate in MFDM occurs as a Pierre Robin sequence, characterized by a midline bony defect without accompanying cleft lip. Submucous cleft has also been described. Choanal atresia is generally osseous, being either unilateral or bilateral; choanal stenosis is also frequent.
Zygomatic arch cleft has been identified in ten of 19 individuals assessed (best done with cranial CT with 3-D reconstruction).
Affected children are ambulatory but show delayed motor development, taking first steps at a median age of 26 months (n=38; range 13-60 months) [
Among those who are verbal, the median reported age at first words is 27 months (n=32; range 12 months to 5.6 years); some affected persons remain nonverbal into adult life [
To date there have been no detailed or cross-sectional studies of long-term neuropsychological outcomes in MFDM. Developmental data in the few affected adults identified to date suggest a broad range of outcomes, with some affected persons achieving semi-independent living with paid employment [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for
Individuals with microdeletions encompassing
## Penetrance
MFDM is highly penetrant but variably expressive. Features may be subclinical in some affected individuals, as in the case of two non-mosaic, intellectually normal mothers – each with two affected children – in whom the only reported clinical findings were unilateral zygomatic cleft and facial asymmetry [
## Nomenclature
The descriptive term "mandibulofacial dysostosis with microcephaly" is synonymous with the eponym "mandibulofacial dysostosis, Guion-Almeida type" [
Some have suggested that MFDM be classified as an acrofacial dysostosis rather than a mandibulofacial dysostosis [
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
The prevalence of MFDM has not been established. At least 126 cases caused by mutation of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Mandibulofacial Dysostosis with Microcephaly
MFD (may resemble MFD in MFDM)
Malformations occur in 1st & 2nd branchial arch-derived structures.
ID (w/o microcephaly) is not common but may be present in some persons.
Lower lid clefts, absent eyelashes, & lacrimal system anomalies may be present.
Cardiac & esophageal malformations are not assoc w/TCS.
Intellect & OFC are usually in average range in TCS.
Unlike TCS, palpebral fissures are not consistently downslanting in MFDM.
AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart defect; DiffDx = differential diagnosis; ID = intellectual disability; MFD = mandibulofacial dysostosis; MFDM = mandibulofacial dysostosis with microcephaly; MOI = mode of inheritance; OFC = occipitofrontal circumference; TEF = tracheoesophageal fistula; XL = X-linked
The finding of a
Intellectual disability (without microcephaly) may be present in individuals with either (a) a history of neonatal airway compromise or (b) microdeletions encompassing
Listed genes represent the most common genetic causes of Diamond-Blackfan anemia (DBA); more than 20 genes are known to be associated with DBA (see
DBA is most often inherited in an autosomal dominant manner;
Craniofacial microsomia (CFM) is a first- and second-arch malformation spectrum encompassing several phenotypes, including oculo-auriculo-vertebral (OAV) syndrome and Goldenhar syndrome (OMIM
CFM shares several major features with mandibulofacial dysostosis with microcephaly (MFDM), including preauricular tags, microtia, aural atresia, hearing loss, and – notably – facial asymmetry, present in approximately 65% of persons with CFM and also a frequent finding in MFDM (58%).
The spectrum of orofacial clefting differs between the two conditions: midline cleft palate is typical of MFDM, while CFM can be associated with any type of orofacial cleft, including lateral oral clefts. Although various extracranial anomalies may occur in either condition, vertebral anomalies in particular should suggest CFM.
At least two persons with an
Tracheoesophageal fistula is a feature of several other recognized conditions, including
• MFD (may resemble MFD in MFDM)
• Malformations occur in 1st & 2nd branchial arch-derived structures.
• ID (w/o microcephaly) is not common but may be present in some persons.
• Lower lid clefts, absent eyelashes, & lacrimal system anomalies may be present.
• Cardiac & esophageal malformations are not assoc w/TCS.
• Intellect & OFC are usually in average range in TCS.
• Unlike TCS, palpebral fissures are not consistently downslanting in MFDM.
## Mandibulofacial Dysostosis
Genes of Interest in the Differential Diagnosis of Mandibulofacial Dysostosis with Microcephaly
MFD (may resemble MFD in MFDM)
Malformations occur in 1st & 2nd branchial arch-derived structures.
ID (w/o microcephaly) is not common but may be present in some persons.
Lower lid clefts, absent eyelashes, & lacrimal system anomalies may be present.
Cardiac & esophageal malformations are not assoc w/TCS.
Intellect & OFC are usually in average range in TCS.
Unlike TCS, palpebral fissures are not consistently downslanting in MFDM.
AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart defect; DiffDx = differential diagnosis; ID = intellectual disability; MFD = mandibulofacial dysostosis; MFDM = mandibulofacial dysostosis with microcephaly; MOI = mode of inheritance; OFC = occipitofrontal circumference; TEF = tracheoesophageal fistula; XL = X-linked
The finding of a
Intellectual disability (without microcephaly) may be present in individuals with either (a) a history of neonatal airway compromise or (b) microdeletions encompassing
Listed genes represent the most common genetic causes of Diamond-Blackfan anemia (DBA); more than 20 genes are known to be associated with DBA (see
DBA is most often inherited in an autosomal dominant manner;
• MFD (may resemble MFD in MFDM)
• Malformations occur in 1st & 2nd branchial arch-derived structures.
• ID (w/o microcephaly) is not common but may be present in some persons.
• Lower lid clefts, absent eyelashes, & lacrimal system anomalies may be present.
• Cardiac & esophageal malformations are not assoc w/TCS.
• Intellect & OFC are usually in average range in TCS.
• Unlike TCS, palpebral fissures are not consistently downslanting in MFDM.
## Craniofacial Microsomia
Craniofacial microsomia (CFM) is a first- and second-arch malformation spectrum encompassing several phenotypes, including oculo-auriculo-vertebral (OAV) syndrome and Goldenhar syndrome (OMIM
CFM shares several major features with mandibulofacial dysostosis with microcephaly (MFDM), including preauricular tags, microtia, aural atresia, hearing loss, and – notably – facial asymmetry, present in approximately 65% of persons with CFM and also a frequent finding in MFDM (58%).
The spectrum of orofacial clefting differs between the two conditions: midline cleft palate is typical of MFDM, while CFM can be associated with any type of orofacial cleft, including lateral oral clefts. Although various extracranial anomalies may occur in either condition, vertebral anomalies in particular should suggest CFM.
At least two persons with an
## Tracheoesophageal Fistula
Tracheoesophageal fistula is a feature of several other recognized conditions, including
## Management
To establish the extent of disease and needs in an individual diagnosed with mandibulofacial dysostosis with microcephaly (MFDM), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mandibulofacial Dysostosis with Microcephaly
Airway assessment for evidence of upper-airway obstruction w/or w/o choanal atresia
Exam for midline cleft palate & referral to multidisciplinary cleft palate team as required
Community or
Social work involvement for parental support;
Home nursing referral.
DD/ID = developmental delay / intellectual disability; EA/TF = esophageal atresia / tracheoesophageal fistula; MFD = mandibulofacial dysostosis; MFDM = mandibulofacial dysostosis with microcephaly; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
There are no published management guidelines to date for MFDM.
Esophageal atresia / tracheoesophageal fistula, cardiac defects, renal anomalies, and thumb anomalies are treated in a routine manner. Short stature is managed expectantly. Of note, the response to human growth hormone has not been specifically reported.
Treatment of Manifestations in Individuals with MFDM
Neonates w/airway compromise at delivery may require intubation &/or tracheostomy for initial stabilization.
Treatment of craniofacial manifestations is individualized & managed by a multidisciplinary team incl oromaxillofacial surgery, plastic surgery, otolaryngology, dentistry/orthodontics, & occupational & speech-language therapy.
DD/ID = developmental delay / intellectual disability
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with MFDM
See
Search
• Airway assessment for evidence of upper-airway obstruction w/or w/o choanal atresia
• Exam for midline cleft palate & referral to multidisciplinary cleft palate team as required
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Neonates w/airway compromise at delivery may require intubation &/or tracheostomy for initial stabilization.
• Treatment of craniofacial manifestations is individualized & managed by a multidisciplinary team incl oromaxillofacial surgery, plastic surgery, otolaryngology, dentistry/orthodontics, & occupational & speech-language therapy.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with mandibulofacial dysostosis with microcephaly (MFDM), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mandibulofacial Dysostosis with Microcephaly
Airway assessment for evidence of upper-airway obstruction w/or w/o choanal atresia
Exam for midline cleft palate & referral to multidisciplinary cleft palate team as required
Community or
Social work involvement for parental support;
Home nursing referral.
DD/ID = developmental delay / intellectual disability; EA/TF = esophageal atresia / tracheoesophageal fistula; MFD = mandibulofacial dysostosis; MFDM = mandibulofacial dysostosis with microcephaly; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Airway assessment for evidence of upper-airway obstruction w/or w/o choanal atresia
• Exam for midline cleft palate & referral to multidisciplinary cleft palate team as required
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There are no published management guidelines to date for MFDM.
Esophageal atresia / tracheoesophageal fistula, cardiac defects, renal anomalies, and thumb anomalies are treated in a routine manner. Short stature is managed expectantly. Of note, the response to human growth hormone has not been specifically reported.
Treatment of Manifestations in Individuals with MFDM
Neonates w/airway compromise at delivery may require intubation &/or tracheostomy for initial stabilization.
Treatment of craniofacial manifestations is individualized & managed by a multidisciplinary team incl oromaxillofacial surgery, plastic surgery, otolaryngology, dentistry/orthodontics, & occupational & speech-language therapy.
DD/ID = developmental delay / intellectual disability
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Neonates w/airway compromise at delivery may require intubation &/or tracheostomy for initial stabilization.
• Treatment of craniofacial manifestations is individualized & managed by a multidisciplinary team incl oromaxillofacial surgery, plastic surgery, otolaryngology, dentistry/orthodontics, & occupational & speech-language therapy.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with MFDM
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Mandibulofacial dysostosis with microcephaly (MFDM) is an autosomal dominant disorder often caused by a
More than 80% of individuals diagnosed with MFDM to date are presumed to have the disorder as the result of a
In 12 of 64 individuals diagnosed with MFDM, the causative pathogenic variant was inherited from a parent with a milder phenotypic presentation [
Molecular genetic testing and clinical evaluation are recommended for the parents of a proband with an apparent
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The incidence of parental germline mosaicism in MFDM is 6% [
The family history of some individuals diagnosed with MFDM may appear to be negative because of a failure to recognize the disorder in family members because of milder manifestations of the disorder in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of the proband (at conception) is 50%. Although MFDM is thought to be highly penetrant, intrafamilial clinical variability is observed, and a sib who inherits an
If the proband has a known MFDM-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism.
If the parents have not been tested for the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals, as well as to young adults who are affected or at risk.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• More than 80% of individuals diagnosed with MFDM to date are presumed to have the disorder as the result of a
• In 12 of 64 individuals diagnosed with MFDM, the causative pathogenic variant was inherited from a parent with a milder phenotypic presentation [
• Molecular genetic testing and clinical evaluation are recommended for the parents of a proband with an apparent
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The incidence of parental germline mosaicism in MFDM is 6% [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The incidence of parental germline mosaicism in MFDM is 6% [
• The family history of some individuals diagnosed with MFDM may appear to be negative because of a failure to recognize the disorder in family members because of milder manifestations of the disorder in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The incidence of parental germline mosaicism in MFDM is 6% [
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of the proband (at conception) is 50%. Although MFDM is thought to be highly penetrant, intrafamilial clinical variability is observed, and a sib who inherits an
• If the proband has a known MFDM-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism.
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals, as well as to young adults who are affected or at risk.
## Mode of Inheritance
Mandibulofacial dysostosis with microcephaly (MFDM) is an autosomal dominant disorder often caused by a
## Risk to Family Members
More than 80% of individuals diagnosed with MFDM to date are presumed to have the disorder as the result of a
In 12 of 64 individuals diagnosed with MFDM, the causative pathogenic variant was inherited from a parent with a milder phenotypic presentation [
Molecular genetic testing and clinical evaluation are recommended for the parents of a proband with an apparent
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The incidence of parental germline mosaicism in MFDM is 6% [
The family history of some individuals diagnosed with MFDM may appear to be negative because of a failure to recognize the disorder in family members because of milder manifestations of the disorder in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of the proband (at conception) is 50%. Although MFDM is thought to be highly penetrant, intrafamilial clinical variability is observed, and a sib who inherits an
If the proband has a known MFDM-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism.
If the parents have not been tested for the
• More than 80% of individuals diagnosed with MFDM to date are presumed to have the disorder as the result of a
• In 12 of 64 individuals diagnosed with MFDM, the causative pathogenic variant was inherited from a parent with a milder phenotypic presentation [
• Molecular genetic testing and clinical evaluation are recommended for the parents of a proband with an apparent
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The incidence of parental germline mosaicism in MFDM is 6% [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The incidence of parental germline mosaicism in MFDM is 6% [
• The family history of some individuals diagnosed with MFDM may appear to be negative because of a failure to recognize the disorder in family members because of milder manifestations of the disorder in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The incidence of parental germline mosaicism in MFDM is 6% [
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of the proband (at conception) is 50%. Although MFDM is thought to be highly penetrant, intrafamilial clinical variability is observed, and a sib who inherits an
• If the proband has a known MFDM-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism.
• If the parents have not been tested for the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals, as well as to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals, as well as to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Bethesda MD 20892-2190
•
•
•
•
•
• Bethesda MD 20892-2190
•
•
•
## Molecular Genetics
Mandibulofacial Dysostosis with Microcephaly: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Mandibulofacial Dysostosis with Microcephaly (
## Molecular Pathogenesis
## Chapter Notes
Matthew Lines, MD; [email protected]
Taila Hartley, MSc; [email protected]
Stella K MacDonald, BSc; [email protected]
Kym M Boycott, PhD, MD; [email protected]
The authors wish to gratefully acknowledge the patients and their families from around the world who have contributed to the understanding of this condition. Our knowledge of MFDM has been facilitated by research support from the Care4Rare Canada Consortium.
6 April 2023 (sw) Revision: "
12 November 2020 (ha) Comprehensive update posted live
3 July 2014 (me) Review posted live
21 January 2014 (ml) Original submission
• 6 April 2023 (sw) Revision: "
• 12 November 2020 (ha) Comprehensive update posted live
• 3 July 2014 (me) Review posted live
• 21 January 2014 (ml) Original submission
## Author Notes
Matthew Lines, MD; [email protected]
Taila Hartley, MSc; [email protected]
Stella K MacDonald, BSc; [email protected]
Kym M Boycott, PhD, MD; [email protected]
## Acknowledgments
The authors wish to gratefully acknowledge the patients and their families from around the world who have contributed to the understanding of this condition. Our knowledge of MFDM has been facilitated by research support from the Care4Rare Canada Consortium.
## Revision History
6 April 2023 (sw) Revision: "
12 November 2020 (ha) Comprehensive update posted live
3 July 2014 (me) Review posted live
21 January 2014 (ml) Original submission
• 6 April 2023 (sw) Revision: "
• 12 November 2020 (ha) Comprehensive update posted live
• 3 July 2014 (me) Review posted live
• 21 January 2014 (ml) Original submission
## References
## Literature Cited
Range of external ear findings in MFDM. Microtia may be of any degree, and is frequently accompanied by preauricular tag(s) and/or auditory canal atresia/stenosis. The superior helix is relatively deficient. The posterior-inferior rim of the lobule may adopt a square configuration (e.g., see bottom right), which, if present, is suggestive.
Typical craniofacial features of MFDM. These include micrognathia, malar hypoplasia, a relatively high nasal root with prominent ridge, everted lower lip, and (frequently) facial asymmetry. Characteristic ear malformations, present in essentially all individuals, are depicted in more detail in
|
[
"C Bartels, C Klatt, R Lührmann, P Fabrizio. The ribosomal translocase homologue Snu114p is involved in unwinding U4/U6 RNA during activation of the spliceosome.. EMBO Rep. 2002;3:875-80",
"D Bick, P Fraser, M Gutzeit, J Harris, T Hambuch, D Helbling, H Jacob, JN Kersten, SR Leuthner, T May, PE North, SZ Prisco, BA Schuler, M Shimoyama, KA Strong, SK Van Why, R Veith, J Verbsky, AM Weborg, BM Wilk, RE Willoughby, EA Worthey, DP Dimmock. Successful application of whole genome sequencing in a medical genetics clinic.. J Pediatr Genet. 2017;6:61-76",
"B Deml, LM Reis, S Muheisen, D Bick, EV Semina. EFTUD2 deficiency in vertebrates: identification of a novel human mutation and generation of a zebrafish model.. Birth Defects Res A Clin Mol Teratol. 2015;103:630-40",
"P Fabrizio, B Laggerbauer, J Lauber, WS Lane, R Lührmann. An evolutionarily conserved U5 snRNP-specific protein is a GTP-binding factor closely related to the ribosomal translocase EF-2.. EMBO J. 1997;16:4092-106",
"SK Gandomi, M Parra, D Reeves, V Yap, CL Gau. Array-CGH is an effective first-tier diagnostic test for EFTUD2-associated congenital mandibulofacial dysostosis with microcephaly.. Clin Genet. 2015;87:80-4",
"CT Gordon, F Petit, M Oufadem, C Decaestecker, AS Jourdain, J Andrieux, V Malan, JL Alessandri, G Baujat, C Baumann, O Boute-Benejean, R Caumes, B Delobel, K Dieterich, D Gaillard, M Gonzales, D Lacombe, F Escande, S Manouvrier-Hanu, S Marlin, M Mathieu-Dramard, SG Mehta, I Simonic, A Munnich, M Vekemans, N Porchet, L de Pontual, S Sarnacki, T Attie-Bitach, S Lyonnet, M Holder-Espinasse, J Amiel. EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia.. J Med Genet. 2012;49:737-46",
"ML Guion-Almeida, S Vendramini-Pittoli, MR Passos-Bueno, RM Zechi-Ceide. Mandibulofacial syndrome with growth and mental retardation, microcephaly, ear anomalies with skin tags, and cleft palate in a mother and her son: autosomal dominant or X-linked syndrome?. Am J Med Genet A. 2009;149A:2762-4",
"L Huang, MR Vanstone, T Hartley, M Osmond, N Barrowman, J Allanson, L Baker, TA Dabir, KM Dipple, WB Dobyns, J Estrella, H Faghfoury, FP Favaro, H Goel, PA Gregersen, KW Gripp, A Grix, ML Guion-Almeida, MH Harr, C Hudson, AG Hunter, J Johnson, SK Joss, A Kimball, U Kini, AD Kline, J Lauzon, DL Lildballe, V López-González, J Martinezmoles, C Meldrum, GM Mirzaa, CF Morel, JE Morton, LC Pyle, F Quintero-Rivera, J Richer, AE Scheuerle, B Schönewolf-Greulich, DJ Shears, J Silver, AC Smith, IK Temple, JM van de Kamp, FS van Dijk, AM Vandersteen, SM White, EH Zackai, R Zou, DE Bulman, KM Boycott, MA Lines. Mandibulofacial dysostosis with microcephaly: mutation and database update.. Hum Mutat. 2016;37:148-54",
"JC Lacour, L McBride, H St Hilaire, GS Mundinger, M Moses, J Koon, JI Torres, Y Lacassie. Novel de novo EFTUD2 mutations in 2 cases with MFDM, initially suspected to have alternative craniofacial diagnoses.. Cleft Palate Craniofac J. 2019;56:674-8",
"D Lehalle, CT Gordon, M Oufadem, G Goudefroye, L Boutaud, JL Alessandri, N Baena, G Baujat, C Baumann, O Boute-Benejean, R Caumes, C Decaestecker, D Gaillard, A Goldenberg, M Gonzales, M Holder-Espinasse, ML Jacquemont, D Lacombe, S Manouvrier-Hanu, S Marlin, M Mathieu-Dramard, G Morin, L Pasquier, F Petit, M Rio, R Smigiel, C Thauvin-Robinet, A Vasiljevic, A Verloes, V Malan, A Munnich, L de Pontual, M Vekemans, S Lyonnet, T Attié-Bitach, J Amiel. Delineation of EFTUD2 haploinsufficiency-related phenotypes through a series of 36 patients.. Hum Mutat. 2014;35:478-85",
"L Lei, SY Yan, R Yang, JY Chen, Y Li, Y Bu, N Chang, Q Zhou, X Zhu, CY Li, JW Xiong. Spliceosomal protein EFTUD2 mutation leads to p53-dependent apoptosis in zebrafish neural progenitors.. Nucleic Acids Res. 2017;45:3422-36",
"MA Lines, L Huang, J Schwartzentruber, SL Douglas, DC Lynch, C Beaulieu, ML Guion-Almeida, RM Zechi-Ceide, B Gener, G Gillessen-Kaesbach, C Nava, G Baujat, D Horn, U Kini, A Caliebe, Y Alanay, GE Utine, D Lev, J Kohlhase, AW Grix, DR Lohmann, U Hehr, D Böhm, J Majewski, DE Bulman, D Wieczorek, KM Boycott. Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly.. Am J Hum Genet. 2012;90:369-77",
"DV Luquetti, AV Hing, MJ Rieder, DA Nickerson, EH Turner, J Smith, S Park, ML Cunningham. Mandibulofacial dysostosis with microcephaly\" caused by EFTUD2 mutations: expanding the phenotype.. Am J Med Genet A. 2013;161A:108-13",
"M Matsuo, A Yamauchi, Y Ito, M Sakauchi, T Yamamoto, N Okamoto, Y Tsurusaki, N Miyake, N Matsumoto, K Saito. Mandibulofacial dysostosis with microcephaly: a case presenting with seizures.. Brain Dev. 2017;39:177-81",
"JH McDermott, DDD Study, J Clayton-Smith. Sibling recurrence of total anomalous pulmonary venous drainage.. Eur J Med Genet. 2017;60:265-67",
"AC Need, V Shashi, Y Hitomi, K Schoch, KV Shianna, MT McDonald, MH Meisler, DB Goldstein. Clinical application of exome sequencing in undiagnosed genetic conditions.. J Med Genet. 2012;49:353-61",
"J Paderova, J Drabova, A Holubova, M Vlckova, M Havlovicova, A Gregorova, R Pourova, V Romankovaa, V Moslerovaa, J Geryka, P Norambuenaa, V Krulisovaa, A Krepelovaa, M Macek, M. Macek. Under the mask of kabuki syndrome: elucidation of genetic-and phenotypic heterogeneity in patients with kabuki-like phenotype.. Eur J Med Genet. 2018;61:315-21",
"S Rengasamy Venugopalan, SEG Farrow, M Lypka. Whole-exome sequencing identified a variant in EFTUD2 gene in establishing a genetic diagnosis.. Orthod Craniofac Res. 2017;20:50-6",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"A Sarkar, LT Emrick, EM Smith, EG Austin, Y Yang, JV Hunter, F Scaglia, SR Lalani. Novel de novo mutations in EFTUD2 detected by exome sequencing in mandibulofacial dysostosis with microcephaly syndrome.. Am J Med Genet A. 2015;167A:914-8",
"JB Silva, D Soares, M Leão, H Santos. Mandibulofacial dysostosis with microcephaly: a syndrome to remember.. BMJ Case Rep. 2019;12",
"EC Small, SR Leggett, AA Winans, JP Staley. The EF-G-like GTPase Snu114p regulates spliceosome dynamics mediated by Brr2p, a DExD/H box ATPase.. Mol Cell. 2006;23:389-99",
"R Smigiel, N Bezniakow, A Jakubiak, M Błoch, D Patkowski, E Obersztyn, MM Sasiadek. Phenotype analysis of polish patients with mandibulofacial dysostosis type guion-almeida associated with esophageal atresia and choanal atresia caused by EFTUD2 gene mutations.. J Appl Genet. 2015;56:199-204",
"S Unger, CR Ferreira, GR Mortier, H Ali, DR Bertola, A Calder, DH Cohn, V Cormier-Daire, KM Girisha, C Hall, D Krakow, O Makitie, S Mundlos, G Nishimura, SP Robertson, R Savarirayan, D Sillence, M Simon, VR Sutton, ML Warman, A Superti-Furga. Nosology of genetic skeletal disorders: 2023 revision.. Am J Med Genet A. 2023",
"M Vincent, D Geneviève, A Ostertag, S Marlin, D Lacombe, D Martin-Coignard, C Coubes, A David, S Lyonnet, C Vilain, A Dieux-Coeslier, S Manouvrier, B Isidor, ML Jacquemont, S Julia, V Layet, S Naudion, S Odent, L Pasquier, S Pelras, N Philip, G Pierquin, F Prieur, N Aboussair, T Attie-Bitach, G Baujat, P Blanchet, C Blanchet, H Dollfus, B Doray, E Schaefer, P Edery, F Giuliano, A Goldenberg, C Goizet, A Guichet, C Herlin, L Lambert, B Leheup, J Martinovic, S Mercier, C Mignot, ML Moutard, MJ Perez, L Pinson, J Puechberty, M Willems, H Randrianaivo, K Szakszon, A Toutain, A Verloes, J Vigneron, E Sanchez, P Sarda, JL Laplanche, C Collet. Treacher collins syndrome: a clinical and molecular study based on a large series of patients.. Genet Med. 2016;18:49-56",
"C Voigt, A Mégarbané, K Neveling, JC Czeschik, B Albrecht, B Callewaert, F von Deimling, A Hehr, M Falkenberg Smeland, R König, A Kuechler, C Marcelis, M Puiu, W Reardon, HM Riise Stensland, B Schweiger, M Steehouwer, C Teller, M Martin, S Rahmann, U Hehr, HG Brunner, HJ Lüdecke, D Wieczorek. Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations.. Orphanet J Rare Dis. 2013;8:110",
"MC Wahl, CL Will, R Lührmann. The spliceosome: design principles of a dynamic RNP machine.. Cell. 2009;136:701-18",
"LA Williams, SC Quinonez, WR Uhlmann. The genetics journey: a case report of a genetic diagnosis made 30 years later.. J Genet Couns. 2017;26:894-901",
"J Wu, Y Yang, Y He, Q Li, X Wang, C Sun, L Wang, Y An, F. Luo. EFTUD2 gene deficiency disrupts osteoblast maturation and inhibits chondrocyte differentiation via activation of the p53 signaling pathway.. Hum Genomics. 2019;13:63",
"KPT Yu, HM Luk, CT Gordon, G Fung, M Oufadem, MM Garcia-Barcelo, J Amiel, BHY Chung, IFM Lo, YT Tiong. Mandibulofacial dysostosis guion-almeida type caused by novel EFTUD2 splice site variants in two Asian children.. Clin Dysmorphol. 2018;27:31-5"
] |
3/7/2014
|
12/11/2020
|
6/4/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mfm
|
mfm
|
[
"Desminopathy",
"Alpha-B Crystallinopathy",
"Myotilinopathy",
"Filaminopathy",
"Zaspopathy",
"BAG3-Related Myofibrillar Myopathy",
"DNAJB6-Related Myofibrillar Myopathy",
"FHL1-Related Myofibrillar Myopathy",
"Alpha-crystallin B chain",
"BAG family molecular chaperone regulator 3",
"Desmin",
"DnaJ homolog subfamily B member 6",
"Filamin-C",
"Four and a half LIM domains protein 1",
"LIM domain-binding protein 3",
"Myotilin",
"BAG3",
"CRYAB",
"DES",
"DNAJB6",
"FHL1",
"FLNC",
"LDB3",
"MYOT",
"Myofibrillar Myopathy"
] |
Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Duygu Selcen, Andrew G Engel
|
Summary Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%. A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps. Peripheral neuropathy is present in about 20% of affected individuals. Overt cardiomyopathy is present in 15%-30%. The diagnosis of myofibrillar myopathy is based on clinical findings, electromyography (EMG), nerve conduction studies, and, most importantly, muscle histology. To date, the genetic basis of myofibrillar myopathy has been elucidated in only about 50% of cases. Pathogenic variants have been identified in Myofibrillar myopathy is most commonly inherited in an autosomal dominant manner. Exceptions include: X-linked inheritance of
|
Alpha-B crystallinopathy
Desminopathy
Filaminopathy
Myotilinopathy
Zaspopathy
For synonyms and outdated names see
• Alpha-B crystallinopathy
• Desminopathy
• Filaminopathy
• Myotilinopathy
• Zaspopathy
## Diagnosis
The term myofibrillar myopathy refers to a group of genetically distinct disorders linked by common morphologic features observed on muscle histology.
The diagnosis of myofibrillar myopathy rests on the following:
Characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers;
Sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions;
Intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics; and
Small vacuoles in a variable number of fibers
Peripheral nerve biopsies, in a few descriptions, show accumulation of neurofilaments, neurotubules, and formation of axonal spheroids.
Myocardial biopsies show desmin-immunoreactive cytoplasmic inclusions, especially near intercalated disks and interstitial fibrosis.
Peripheral nerve pathology [
Molecular Genetic Testing Used in Myofibrillar Myopathy
See
Frequencies based on Mayo Clinic MFM cohort
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Expected to identify approximately 99% of pathogenic variants in the coding region.
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No large deletions or duplications of
Exons sequenced may vary among laboratories.
Generic diagnosis of an MFM can be made on clinical and histologic grounds.
The diagnosis of a specific MFM is based on molecular genetic testing:
If the proband's symptoms suggest a candidate gene (see
If no pathogenic variant is identified, perform sequence analysis for the remaining genes (
At present no clear criteria for testing for deletions/duplications exist.
• Characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers;
• Sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions;
• Intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics; and
• Small vacuoles in a variable number of fibers
• Characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers;
• Sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions;
• Intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics; and
• Small vacuoles in a variable number of fibers
•
• Peripheral nerve biopsies, in a few descriptions, show accumulation of neurofilaments, neurotubules, and formation of axonal spheroids.
• Myocardial biopsies show desmin-immunoreactive cytoplasmic inclusions, especially near intercalated disks and interstitial fibrosis.
• Peripheral nerve pathology [
• Peripheral nerve biopsies, in a few descriptions, show accumulation of neurofilaments, neurotubules, and formation of axonal spheroids.
• Myocardial biopsies show desmin-immunoreactive cytoplasmic inclusions, especially near intercalated disks and interstitial fibrosis.
• Peripheral nerve pathology [
• Characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers;
• Sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions;
• Intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics; and
• Small vacuoles in a variable number of fibers
• Peripheral nerve biopsies, in a few descriptions, show accumulation of neurofilaments, neurotubules, and formation of axonal spheroids.
• Myocardial biopsies show desmin-immunoreactive cytoplasmic inclusions, especially near intercalated disks and interstitial fibrosis.
• Peripheral nerve pathology [
• Generic diagnosis of an MFM can be made on clinical and histologic grounds.
• The diagnosis of a specific MFM is based on molecular genetic testing:
• If the proband's symptoms suggest a candidate gene (see
• If no pathogenic variant is identified, perform sequence analysis for the remaining genes (
• At present no clear criteria for testing for deletions/duplications exist.
• If the proband's symptoms suggest a candidate gene (see
• If no pathogenic variant is identified, perform sequence analysis for the remaining genes (
• At present no clear criteria for testing for deletions/duplications exist.
• If the proband's symptoms suggest a candidate gene (see
• If no pathogenic variant is identified, perform sequence analysis for the remaining genes (
• At present no clear criteria for testing for deletions/duplications exist.
## Clinical Diagnosis
The term myofibrillar myopathy refers to a group of genetically distinct disorders linked by common morphologic features observed on muscle histology.
The diagnosis of myofibrillar myopathy rests on the following:
Characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers;
Sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions;
Intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics; and
Small vacuoles in a variable number of fibers
Peripheral nerve biopsies, in a few descriptions, show accumulation of neurofilaments, neurotubules, and formation of axonal spheroids.
Myocardial biopsies show desmin-immunoreactive cytoplasmic inclusions, especially near intercalated disks and interstitial fibrosis.
Peripheral nerve pathology [
• Characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers;
• Sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions;
• Intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics; and
• Small vacuoles in a variable number of fibers
• Characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers;
• Sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions;
• Intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics; and
• Small vacuoles in a variable number of fibers
•
• Peripheral nerve biopsies, in a few descriptions, show accumulation of neurofilaments, neurotubules, and formation of axonal spheroids.
• Myocardial biopsies show desmin-immunoreactive cytoplasmic inclusions, especially near intercalated disks and interstitial fibrosis.
• Peripheral nerve pathology [
• Peripheral nerve biopsies, in a few descriptions, show accumulation of neurofilaments, neurotubules, and formation of axonal spheroids.
• Myocardial biopsies show desmin-immunoreactive cytoplasmic inclusions, especially near intercalated disks and interstitial fibrosis.
• Peripheral nerve pathology [
• Characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers;
• Sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions;
• Intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics; and
• Small vacuoles in a variable number of fibers
• Peripheral nerve biopsies, in a few descriptions, show accumulation of neurofilaments, neurotubules, and formation of axonal spheroids.
• Myocardial biopsies show desmin-immunoreactive cytoplasmic inclusions, especially near intercalated disks and interstitial fibrosis.
• Peripheral nerve pathology [
## Molecular Genetic Testing
Molecular Genetic Testing Used in Myofibrillar Myopathy
See
Frequencies based on Mayo Clinic MFM cohort
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Expected to identify approximately 99% of pathogenic variants in the coding region.
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No large deletions or duplications of
Exons sequenced may vary among laboratories.
## Testing Strategy
Generic diagnosis of an MFM can be made on clinical and histologic grounds.
The diagnosis of a specific MFM is based on molecular genetic testing:
If the proband's symptoms suggest a candidate gene (see
If no pathogenic variant is identified, perform sequence analysis for the remaining genes (
At present no clear criteria for testing for deletions/duplications exist.
• Generic diagnosis of an MFM can be made on clinical and histologic grounds.
• The diagnosis of a specific MFM is based on molecular genetic testing:
• If the proband's symptoms suggest a candidate gene (see
• If no pathogenic variant is identified, perform sequence analysis for the remaining genes (
• At present no clear criteria for testing for deletions/duplications exist.
• If the proband's symptoms suggest a candidate gene (see
• If no pathogenic variant is identified, perform sequence analysis for the remaining genes (
• At present no clear criteria for testing for deletions/duplications exist.
• If the proband's symptoms suggest a candidate gene (see
• If no pathogenic variant is identified, perform sequence analysis for the remaining genes (
• At present no clear criteria for testing for deletions/duplications exist.
## Clinical Characteristics
In the Mayo Clinic series of 80 individuals with myofibrillar myopathy (MFM), the age of onset varied from two to 77 years. The age at diagnosis ranged from 11 to 82 years.
The predominant presenting symptom in MFM is slowly progressive weakness; a minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps. The weakness can involve both proximal and distal muscles; however, distal muscle weakness is 25% more common than proximal weakness.
Objective clinical signs or EMG findings of peripheral neuropathy are present in approximately 20% of affected individuals, but muscle biopsy studies suggest an even higher frequency of peripheral nerve involvement.
Overt cardiomyopathy can be a presenting manifestation or can appear during the evolution of myofibrillar myopathy in 15%-30% of affected individuals.
A restrictive ventilatory defect can result from respiratory muscle weakness.
Variable expressivity has been observed in kinships with pathogenic variants in
No morphologic features consistently or reliably predict mutation of a given gene.
The only genotype-phenotype correlations detected to date are:
Cataracts were present in affected members of one of the three reported kinships with pathogenic variants in
Neuropathy and cardiomyopathy were observed in families with pathogenic variants in
Rigid spine has been observed in Bag3opathy [
Neuropathy and cardiomyopathy also occur in individuals in whom the genetic basis of myofibrillar myopathy has not been established.
Data are insufficient to draw conclusions about penetrance.
No convincing evidence of anticipation has been documented.
"… The light microscopic features of myofibrillar myopathy were described in the 1970s and 1980s under such names as "myopathy with inclusion bodies" [
[
Myofibrillar myopathy has also been referred to as desmin storage myopathy, desmin-related myopathy, or protein surplus myopathy. Because myofibrillar myopathy is genetically heterogeneous and the disease-causing protein or involved gene is known only in a minority of cases, because multiple other proteins besides desmin are also overexpressed in muscle, and because myotilin is not related to desmin, the generic term "myofibrillar myopathy" is the preferred designation until the gene(s) in which pathogenic variants occur are determined. When the disease-associated gene or protein is identified, designations such as desminopathy, α-B crystallinopathy, myotilinopathy, zaspopathy (Markesbery-Griggs late-onset distal myopathy), filaminopathy, or
The prevalence of myofibrillar myopathy cannot be estimated at this time.
• Cataracts were present in affected members of one of the three reported kinships with pathogenic variants in
• Neuropathy and cardiomyopathy were observed in families with pathogenic variants in
• Rigid spine has been observed in Bag3opathy [
• Neuropathy and cardiomyopathy also occur in individuals in whom the genetic basis of myofibrillar myopathy has not been established.
## Clinical Description
In the Mayo Clinic series of 80 individuals with myofibrillar myopathy (MFM), the age of onset varied from two to 77 years. The age at diagnosis ranged from 11 to 82 years.
The predominant presenting symptom in MFM is slowly progressive weakness; a minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps. The weakness can involve both proximal and distal muscles; however, distal muscle weakness is 25% more common than proximal weakness.
Objective clinical signs or EMG findings of peripheral neuropathy are present in approximately 20% of affected individuals, but muscle biopsy studies suggest an even higher frequency of peripheral nerve involvement.
Overt cardiomyopathy can be a presenting manifestation or can appear during the evolution of myofibrillar myopathy in 15%-30% of affected individuals.
A restrictive ventilatory defect can result from respiratory muscle weakness.
Variable expressivity has been observed in kinships with pathogenic variants in
## Genotype-Phenotype Correlations
No morphologic features consistently or reliably predict mutation of a given gene.
The only genotype-phenotype correlations detected to date are:
Cataracts were present in affected members of one of the three reported kinships with pathogenic variants in
Neuropathy and cardiomyopathy were observed in families with pathogenic variants in
Rigid spine has been observed in Bag3opathy [
Neuropathy and cardiomyopathy also occur in individuals in whom the genetic basis of myofibrillar myopathy has not been established.
• Cataracts were present in affected members of one of the three reported kinships with pathogenic variants in
• Neuropathy and cardiomyopathy were observed in families with pathogenic variants in
• Rigid spine has been observed in Bag3opathy [
• Neuropathy and cardiomyopathy also occur in individuals in whom the genetic basis of myofibrillar myopathy has not been established.
## Penetrance
Data are insufficient to draw conclusions about penetrance.
## Anticipation
No convincing evidence of anticipation has been documented.
## Nomenclature
"… The light microscopic features of myofibrillar myopathy were described in the 1970s and 1980s under such names as "myopathy with inclusion bodies" [
[
Myofibrillar myopathy has also been referred to as desmin storage myopathy, desmin-related myopathy, or protein surplus myopathy. Because myofibrillar myopathy is genetically heterogeneous and the disease-causing protein or involved gene is known only in a minority of cases, because multiple other proteins besides desmin are also overexpressed in muscle, and because myotilin is not related to desmin, the generic term "myofibrillar myopathy" is the preferred designation until the gene(s) in which pathogenic variants occur are determined. When the disease-associated gene or protein is identified, designations such as desminopathy, α-B crystallinopathy, myotilinopathy, zaspopathy (Markesbery-Griggs late-onset distal myopathy), filaminopathy, or
## Prevalence
The prevalence of myofibrillar myopathy cannot be estimated at this time.
## Genetically Related (Allelic) Disorders
Cardiomyopathy can occur with each genetically defined type of MFM.
Mutation of
Mutation of
Mutation of
Mutation of
## Differential Diagnosis
The principle differential diagnoses are late-onset myopathies and especially myopathies with a predominantly distal distribution:
•
## Management
To establish the extent of disease in an individual diagnosed with myofibrillar myopathy (MFM), the following evaluations are recommended:
EMG
Routine ECG to identify arrhythmias and cardiac conduction defects; Holter monitoring if symptoms suggest an intermittent arrhythmia; echocardiogram if cardiac symptoms are present
Respiratory function tests if respiratory symptoms are present
Consultation with a clinical geneticist and/or genetic counselor
Pacemaker and implantable cardioverter defibrillator (ICD) should be considered in individuals with arrhythmia and/or cardiac conduction defects. Individuals with progressive or life-threatening cardiomyopathy are candidates for cardiac transplantation.
Respiratory support, consisting of continuous or bilevel positive airway pressure (CPAP or BIPAP), initially at night and later in the daytime, is indicated in individuals with hypercapnea and other signs of incipient ventilatory failure.
Range of motion physical therapy and assistive devices are appropriate for those with advanced muscle weakness. Treatment of scoliosis by spinal fusion is appropriate. Orthoses are indicated for treatment of foot drop.
Pacemaker or implantable cardioverter defibrillator placement for individuals with arrhythmogenic cardiomyopathy.
The following are appropriate:
Physical examination to monitor disease progression yearly or less often depending on rate of progression
Electrocardiogram and/or echocardiogram yearly for early detection of cardiomyopathy
Pulmonary function tests for individuals with exertional or nocturnal dyspnea.
Search
Affected pregnant women may need assistance during delivery if they have significant weakness of their abdominal muscles.
Search
The role of strengthening exercises has not been defined.
• EMG
• Routine ECG to identify arrhythmias and cardiac conduction defects; Holter monitoring if symptoms suggest an intermittent arrhythmia; echocardiogram if cardiac symptoms are present
• Respiratory function tests if respiratory symptoms are present
• Consultation with a clinical geneticist and/or genetic counselor
• Physical examination to monitor disease progression yearly or less often depending on rate of progression
• Electrocardiogram and/or echocardiogram yearly for early detection of cardiomyopathy
• Pulmonary function tests for individuals with exertional or nocturnal dyspnea.
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with myofibrillar myopathy (MFM), the following evaluations are recommended:
EMG
Routine ECG to identify arrhythmias and cardiac conduction defects; Holter monitoring if symptoms suggest an intermittent arrhythmia; echocardiogram if cardiac symptoms are present
Respiratory function tests if respiratory symptoms are present
Consultation with a clinical geneticist and/or genetic counselor
• EMG
• Routine ECG to identify arrhythmias and cardiac conduction defects; Holter monitoring if symptoms suggest an intermittent arrhythmia; echocardiogram if cardiac symptoms are present
• Respiratory function tests if respiratory symptoms are present
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Pacemaker and implantable cardioverter defibrillator (ICD) should be considered in individuals with arrhythmia and/or cardiac conduction defects. Individuals with progressive or life-threatening cardiomyopathy are candidates for cardiac transplantation.
Respiratory support, consisting of continuous or bilevel positive airway pressure (CPAP or BIPAP), initially at night and later in the daytime, is indicated in individuals with hypercapnea and other signs of incipient ventilatory failure.
Range of motion physical therapy and assistive devices are appropriate for those with advanced muscle weakness. Treatment of scoliosis by spinal fusion is appropriate. Orthoses are indicated for treatment of foot drop.
## Prevention of Secondary Complications
Pacemaker or implantable cardioverter defibrillator placement for individuals with arrhythmogenic cardiomyopathy.
## Surveillance
The following are appropriate:
Physical examination to monitor disease progression yearly or less often depending on rate of progression
Electrocardiogram and/or echocardiogram yearly for early detection of cardiomyopathy
Pulmonary function tests for individuals with exertional or nocturnal dyspnea.
• Physical examination to monitor disease progression yearly or less often depending on rate of progression
• Electrocardiogram and/or echocardiogram yearly for early detection of cardiomyopathy
• Pulmonary function tests for individuals with exertional or nocturnal dyspnea.
## Evaluation of Relatives at Risk
Search
## Pregnancy Management
Affected pregnant women may need assistance during delivery if they have significant weakness of their abdominal muscles.
## Therapies Under Investigation
Search
## Other
The role of strengthening exercises has not been defined.
## Genetic Counseling
Myofibrillar myopathy (MFM) is most commonly inherited in an autosomal dominant manner. Exceptions include:
Autosomal recessive inheritance of
X-linked inheritance of
Approximately 25% of individuals diagnosed with autosomal dominant (AD) myofibrillar myopathy have an affected parent.
A proband with AD myofibrillar myopathy may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Note: Twenty-five percent of individuals diagnosed with myofibrillar myopathy have an affected parent; in other individuals, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband cannot be determined with confidence.
Although no instances of germline mosaicism have been reported, it remains a possibility.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutated allele).
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Carrier testing for at-risk family members is possible if the
The father of an affected male will not have MFM nor will he be a carrier of the
In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
The risk to sibs depends on the carrier status of the mother.
If the mother of the proband has a
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.
Note: Molecular genetic testing may be able to identify the family member in whom a
Carrier testing for at-risk female relatives is possible if the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being affected or carriers.
Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
• Autosomal recessive inheritance of
• X-linked inheritance of
• Approximately 25% of individuals diagnosed with autosomal dominant (AD) myofibrillar myopathy have an affected parent.
• A proband with AD myofibrillar myopathy may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband cannot be determined with confidence.
• Although no instances of germline mosaicism have been reported, it remains a possibility.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutated allele).
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
• The father of an affected male will not have MFM nor will he be a carrier of the
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
• Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
• The risk to sibs depends on the carrier status of the mother.
• If the mother of the proband has a
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being affected or carriers.
## Mode of Inheritance
Myofibrillar myopathy (MFM) is most commonly inherited in an autosomal dominant manner. Exceptions include:
Autosomal recessive inheritance of
X-linked inheritance of
• Autosomal recessive inheritance of
• X-linked inheritance of
## Risk to Family Members – Autosomal Dominant Inheritance
Approximately 25% of individuals diagnosed with autosomal dominant (AD) myofibrillar myopathy have an affected parent.
A proband with AD myofibrillar myopathy may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Note: Twenty-five percent of individuals diagnosed with myofibrillar myopathy have an affected parent; in other individuals, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband cannot be determined with confidence.
Although no instances of germline mosaicism have been reported, it remains a possibility.
• Approximately 25% of individuals diagnosed with autosomal dominant (AD) myofibrillar myopathy have an affected parent.
• A proband with AD myofibrillar myopathy may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband cannot be determined with confidence.
• Although no instances of germline mosaicism have been reported, it remains a possibility.
## Risk to Family Members – Autosomal Recessive Inheritance
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutated allele).
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutated allele).
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
## Carrier (Heterozygote) Detection
Carrier testing for at-risk family members is possible if the
## Risk to Family Members – X-Linked Inheritance
The father of an affected male will not have MFM nor will he be a carrier of the
In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
The risk to sibs depends on the carrier status of the mother.
If the mother of the proband has a
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.
Note: Molecular genetic testing may be able to identify the family member in whom a
• The father of an affected male will not have MFM nor will he be a carrier of the
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
• Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
• The risk to sibs depends on the carrier status of the mother.
• If the mother of the proband has a
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.
## Heterozygote (Carrier) Detection
Carrier testing for at-risk female relatives is possible if the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being affected or carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being affected or carriers.
## Prenatal Testing and Preimplantation Genetic Diagnosis
Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
## Resources
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
508 East South Temple
Suite #202
Salt Lake City UT 84102
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
•
• 508 East South Temple
• Suite #202
• Salt Lake City UT 84102
•
## Molecular Genetics
Myofibrillar Myopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Myofibrillar Myopathy (
Because myofibrillar myopathy is caused by pathogenic variants in any of eight different genes and each disease-associated gene may have different types of pathogenic variants, the molecular pathogenesis may vary from case to case. However, in all myofibrillar myopathies, the initial pathologic change involves disintegration of the Z-disk, and all disease proteins identified to date are involved in maintaining the structural integrity of the Z-disk. Because the Z-disks are sites of tension transmission between sarcomeres, the myofibrils fall apart when the Z-disks disintegrate.
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
Homozygosity in an affected individual for this pathogenic variant in an autosomal recessive form of MFM [
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
Presents as a distal myopathy (see
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
## Molecular Genetic Pathogenesis
Because myofibrillar myopathy is caused by pathogenic variants in any of eight different genes and each disease-associated gene may have different types of pathogenic variants, the molecular pathogenesis may vary from case to case. However, in all myofibrillar myopathies, the initial pathologic change involves disintegration of the Z-disk, and all disease proteins identified to date are involved in maintaining the structural integrity of the Z-disk. Because the Z-disks are sites of tension transmission between sarcomeres, the myofibrils fall apart when the Z-disks disintegrate.
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
Homozygosity in an affected individual for this pathogenic variant in an autosomal recessive form of MFM [
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
Presents as a distal myopathy (see
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
##
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
##
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
Homozygosity in an affected individual for this pathogenic variant in an autosomal recessive form of MFM [
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
Presents as a distal myopathy (see
##
##
Selected
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
##
##
## References
## Literature Cited
## Suggested Reading
## Chapter Notes
9 May 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
29 October 2012 (me) Comprehensive update posted live
27 July 2010 (cd) Revision: sequence analysis for
2 February 2010 (me) Comprehensive update posted live
10 March 2008 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for zaspopathy
1 March 2007 (me) Comprehensive update posted live
9 January 2006 (ds) Revision: included disorders added (zaspopathy, filaminopathy)
1 July 2005 (ds) Revision:
28 January 2005 (me) Review posted live
2 August 2004 (ds) Original submission
• 9 May 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 29 October 2012 (me) Comprehensive update posted live
• 27 July 2010 (cd) Revision: sequence analysis for
• 2 February 2010 (me) Comprehensive update posted live
• 10 March 2008 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for zaspopathy
• 1 March 2007 (me) Comprehensive update posted live
• 9 January 2006 (ds) Revision: included disorders added (zaspopathy, filaminopathy)
• 1 July 2005 (ds) Revision:
• 28 January 2005 (me) Review posted live
• 2 August 2004 (ds) Original submission
## Revision History
9 May 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
29 October 2012 (me) Comprehensive update posted live
27 July 2010 (cd) Revision: sequence analysis for
2 February 2010 (me) Comprehensive update posted live
10 March 2008 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for zaspopathy
1 March 2007 (me) Comprehensive update posted live
9 January 2006 (ds) Revision: included disorders added (zaspopathy, filaminopathy)
1 July 2005 (ds) Revision:
28 January 2005 (me) Review posted live
2 August 2004 (ds) Original submission
• 9 May 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 29 October 2012 (me) Comprehensive update posted live
• 27 July 2010 (cd) Revision: sequence analysis for
• 2 February 2010 (me) Comprehensive update posted live
• 10 March 2008 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for zaspopathy
• 1 March 2007 (me) Comprehensive update posted live
• 9 January 2006 (ds) Revision: included disorders added (zaspopathy, filaminopathy)
• 1 July 2005 (ds) Revision:
• 28 January 2005 (me) Review posted live
• 2 August 2004 (ds) Original submission
Muscle histology observed in myofibrillar myopathy
|
[
"SC Abraham, D DeNofrio, E Loh, JM Minda, JE Tomaszewski, GG Pietra, C Reynolds. Desmin myopathy involving cardiac, skeletal, and vascular smooth muscle: report of a case with immunoelectron microscopy.. Hum Pathol. 1998;29:876-82",
"E Arbustini, P Morbini, M Grasso, R Fasani, L Verga, O Bellini, B Dal Bello, C Campana, G Piccolo, O Febo, C Opasich, A Gavazzi, VJ Ferrans. Restrictive cardiomyopathy, atrioventricular block and mild to subclinical myopathy in patients with desmin-immunoreactive material deposits.. J Am Coll Cardiol. 1998;31:645-53",
"H Bär, N Mücke, P Ringler, SA Müller, L Kreplak, HA Katus, U Aebi, H Herrmann. Impact of disease mutations on the desmin filament assembly process.. J Mol Biol. 2006;360:1031-42",
"A Calderon, LE Becker, EG Murphy. Subsarcolemmal vermiform deposits in skeletal muscle, associated with familial cardiomyopathy: report of two cases of a new entity.. Pediatr Neurosci. 1987;13:108-12",
"Y Capetanaki, DJ Milner, G Weitzer. Desmin in muscle formation and maintenance: knockouts and consequences.. Cell Struct Funct. 1997;22:103-16",
"JR Clark, AN D'Agostino, J Wilson, RR Brooks, GC Cole. Autosomal dominant myofibrillar inclusion body myopathy: clinical, histologic, histochemical, and ultrastructural characteristics.. Neurology 1978;28A:399",
"MC Dalakas, KY Park, C Semino-Mora, HS Lee, K Sivakumar, LG Goldfarb. Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene.. N Engl J Med. 2000;342:770-80",
"JL De Bleecker, AG Engel, BB Ertl. Myofibrillar myopathy with abnormal foci of desmin positivity. II. Immunocytochemical analysis reveals accumulation of multiple other proteins.. J Neuropathol Exp Neurol. 1996;55:563-77",
"MR Del Bigio, AE Chudley, HB Sarnat, C Campbell, S Goobie, BN Chodirker, D Selcen. Infantile muscular dystrophy in Canadian aboriginals is an αB-crystallinopathy.. Ann Neurol. 2011;69:866-71",
"L Edström, LE Thornell, A Eriksson. A new type of hereditary distal myopathy with characteristic sarcoplasmic bodies and intermediate (skeletin) filaments.. J Neurol Sci. 1980;47:171-90",
"M Fardeau, J Godet-Guillain, FM Tome, H Collin, S Gaudeau, C Boffety, P Vernant. Rev Neurol (Paris) 1978;134:411-25",
"A Fidzianska, HH Goebel, M Osborn, HG Lenard, G Osse, U Langenbeck. Mallory body-like inclusions in a hereditary congenital neuromuscular disease.. Muscle Nerve. 1983;6:195-200",
"D Fischer, CS Clemen, M Olivé, I Ferrer, B Goudeau, U Roth, P Badorf, MP Wattjes, G Lutterbey, T Kral, PF van der Ven, DO Fürst, P Vicart, LG Goldfarb, M Moza, O Carpen, J Reichelt, R Schröder. Different early pathogenesis in myotilinopathy compared to primary desminopathy.. Neuromuscul Disord. 2006;16:361-7",
"KM Forrest, S Al-Sarraj, C Sewry, S Buk, SV Tan, M Pitt, A Durward, M McDougall, M Irving, MG Hanna, E Matthews, A Sarkozy, J Hudson, R Barresi, K Bushby, H Jungbluth, E Wraige. Infantile onset myofibrillar myopathy due to recessive CRYAB mutations.. Neuromuscul Disord. 2011;21:37-40",
"SM Garvey, SE Miller, DR Claflin, JA Faulkner, MA Hauser. Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM.. Hum Mol Genet. 2006;15:2348-62",
"HH Goebel, J Muller, HW Gillen, AD Merritt. Autosomal dominant \"spheroid body myopathy.\". Muscle Nerve 1978;1:14-26",
"HH Goebel. Desmin-related myopathies.. Curr Opin Neurol 1997;10:426-9",
"LG Goldfarb, KY Park, L Cervenáková, S Gorokhova, HS Lee, O Vasconcelos, JW Nagle, C Semino-Mora, K Sivakumar, MC Dalakas. Missense mutations in desmin associated with familial cardiac and skeletal myopathy.. Nat Genet. 1998;19:402-3",
"LG Goldfarb, P Vicart, HH Goebel, MC Dalakas. Desmin myopathy.. Brain. 2004;127:723-34",
"MB Harms, RB Sommerville, P Allred, S Bell, D Ma, P Cooper, G Lopate, A Pestronk, CC Weihl, RH Baloh. Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy.. Ann Neurol. 2012;71:407-16",
"MA Hauser, CB Conde, V Kowaljow, G Zeppa, AL Taratuto, UM Torian, J Vance, MA Pericak-Vance, MC Speer, AL Rosa. myotilin Mutation found in second pedigree with LGMD1A.. Am J Hum Genet. 2002;71:1428-32",
"MA Hauser, SK Horrigan, P Salmikangas, UM Torian, KD Viles, R Dancel, RW Tim, A Taivainen, L Bartoloni, JM Gilchrist, JM Stajich, PC Gaskell, JR Gilbert, JM Vance, MA Pericak-Vance, O Carpen, CA Westbrook, MC Speer. Myotilin is mutated in limb girdle muscular dystrophy 1A.. Hum Mol Genet. 2000;9:2141-7",
"SH Horowitz, H Schmalbruch. Autosomal dominant distal myopathy with desmin storage: a clinicopathologic and electrophysiologic study of a large kinship.. Muscle Nerve. 1994;17:151-60",
"M Kinoshita, E Satoyoshi, Y Suzuki. Atypical myopathy with myofibrillar aggregates.. Arch Neurol. 1975;32:417-20",
"JA Lobrinus, RC Janzer, T Kuntzer, JM Matthieu, G Pfend, JJ Goy, J Bogousslavsky. Familial cardiomyopathy and distal myopathy with abnormal desmin accumulation and migration.. Neuromuscul Disord 1998;8:77-86",
"X Luan, D Hong, W Zhang, Z Wang, Y Yuan. A novel heterozygous deletion-insertion mutation (2695-2712 del/GTTTGT ins) in exon 18 of the filamin C gene causes filaminopathy in a large Chinese family.. Neuromuscul Disord. 2010;20:390-6",
"AM Muñoz-Mármol, G Strasser, M Isamat, PA Coulombe, Y Yang, X Roca, E Vela, JL Mate, J Coll, MT Fernández-Figueras, JJ Navas-Palacios, A Ariza, E Fuchs. A dysfunctional desmin mutation in a patient with severe generalized myopathy.. Proc Natl Acad Sci U S A 1998;95:11312-7",
"S Nakano, AG Engel, I Akiguchi, J Kimura. Myofibrillar myopathy. III. Abnormal expression of cyclin-dependent kinases and nuclear proteins.. J Neuropathol Exp Neurol 1997;56:850-6",
"N Nakashima, Z Tamura, S Okamoto, H Goto. Inclusion bodies in human neuromuscular disorder.. Arch Neurol. 1970;22:270-8",
"I Pénisson-Besnier, K Talvinen, C Dumez, A Vihola, F Dubas, M Fardeau, P Hackman, O Carpen, B Udd. Myotilinopathy in a family with late onset myopathy.. Neuromuscul Disord 2006;16:427-31",
"CM Quinzii, TH Vu, KC Min, K Tanji, S Barral, RP Grewal, A Kattah, P Camaño, D Otaegui, T Kunimatsu, DM Blake, KC Wilhelmsen, LP Rowland, AP Hays, E Bonilla, M Hirano. X-linked dominant scapuloperoneal myopathy is due to a mutation in the gene encoding four-and-a-half-LIM protein 1.. Am J Hum Genet. 2008;82:208-13",
"M Sabatelli, E Bertini, E Ricci, G Salviati, S Magi, M Papacci, P Tonali. Peripheral neuropathy with giant axons and cardiomyopathy associated with desmin type intermediate filaments in skeletal muscle.. J Neurol Sci 1992;109:1-10",
"J Sarparanta, PH Jonson, C Golzio, S Sandell, H Luque, M Screen, K McDonald, JM Stajich, I Mahjneh, A Vihola, O Raheem, S Penttilä, S Lehtinen, S Huovinen, J Palmio, G Tasca, E Ricci, P Hackman, M Hauser, N Katsanis, B Udd. Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.. Nat Genet. 2012;44:450-5",
"J Schessl, Y Zou, MJ McGrath, BS Cowling, B Maiti, SS Chin, C Sewry, R Battini, Y Hu, DL Cottle, M Rosenblatt, L Spruce, A Ganguly, J Kirschner, AR Judkins, JA Golden, HH Goebel, F Muntoni, KM Flanigan, CA Mitchell, CG Bönnemann. Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy.. J Clin Invest. 2008;118:904-12",
"D Selcen, MB Bromberg, SS Chin, AG Engel. Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy.. Neurology. 2011;77:1951-9",
"D Selcen, AG Engel. Mutations in myotilin cause myofibrillar myopathy.. Neurology 2004;62:1363-71",
"D Selcen, AG Engel. Mutations in ZASP define a novel form of muscular dystrophy in humans.. Ann Neurol 2005;57:269-76",
"D Selcen, AG Engel. Myofibrillar myopathy caused by novel dominant negative alpha B-crystallin mutations.. Ann Neurol 2003;54:804-10",
"D Selcen, F Muntoni, BK Burton, E Pegoraro, C Sewry, AV Bite, AG Engel. Mutation in BAG3 causes severe dominant childhood muscular dystrophy.. Ann Neurol 2009;65:83-9",
"D Selcen, K Ohno, AG Engel. Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients.. Brain 2004;127:439-51",
"A Shatunov, M Olivé, Z Odgerel, C Stadelmann-Nessler, K Irlbacher, F van Landeghem, M Bayarsaikhan, HS Lee, B Goudeau, PF Chinnery, V Straub, D Hilton-Jones, MS Damian, A Kaminska, P Vicart, K Bushby, MC Dalakas, N Sambuughin, I Ferrer, HH Goebel, LG Goldfarb. In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy.. Eur J Hum Genet 2009;17:656-63",
"P Vicart, A Caron, P Guicheney, Z Li, MC Prevost, A Faure, D Chateau, F Chapon, F Tome, JM Dupret, D Paulin, M Fardeau. A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy.. Nat Genet 1998;20:92-5",
"M Vorgerd, PF van der Ven, V Bruchertseifer, T Löwe, RA Kley, R Schröder, H Lochmüller, M Himmel, K Koehler, DO Fürst, A Huebner. A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy.. Am J Hum Genet 2005;77:297-304",
"X Wang, H Osinska, R Klevitsky, AM Gerdes, M Nieman, J Lorenz, T Hewett, J Robbins. Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice.. Circ Res. 2001;89:84-91",
"C Windpassinger, B Schoser, V Straub, S Hochmeister, A Noor, B Lohberger, N Farra, E Petek, T Schwarzbraun, L Ofner, WN Löscher, K Wagner, H Lochmüller, JB Vincent, S Quasthoff. An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1.. Am J Hum Genet. 2008;82:88-99",
"H Wolburg, W Schlote, HD Langohr, J Peiffer, KH Reiher, RW Heckl. Slowly progressive congenital myopathy with cytoplasmic bodies--report of two cases and a review of the literature.. Clin Neuropathol 1982;1:55-66"
] |
28/1/2005
|
29/10/2012
|
27/7/2010
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mga3
|
mga3
|
[
"3-Methylglutaconic Aciduria Type 3",
"OPA3 Defect",
"3-Methylglutaconic Aciduria Type 3",
"OPA3 Defect",
"Optic atrophy 3 protein",
"OPA3",
"Costeff Syndrome"
] |
Costeff Syndrome
|
Yair Anikster
|
Summary Costeff syndrome is characterized by optic atrophy and/or choreoathetoid movement disorder with onset before age ten years. Optic atrophy is associated with progressive decrease in visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus. Most individuals have chorea, often severe enough to restrict ambulation. Some are confined to a wheelchair from an early age. Although most individuals develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable. The diagnosis of Costeff syndrome is established in a proband with suggestive findings by identification of biallelic Costeff syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
The diagnosis of Costeff syndrome
Relatively normal early development and growth
Bilateral early-onset optic atrophy (pathologically pale optic discs, attenuated papillary vasculature, and visual evoked potentials that show bilateral prolonged latencies consistent with optic atrophy)
Choreoathetoid movement disorder
Progressive spasticity
Cerebellar ataxia
Cognitive deterioration (in a minority of individuals)
The
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Costeff syndrome is broad, individuals with the distinctive findings described in
Note:
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Costeff Syndrome
See
See
The variant
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Relatively normal early development and growth
• Bilateral early-onset optic atrophy (pathologically pale optic discs, attenuated papillary vasculature, and visual evoked potentials that show bilateral prolonged latencies consistent with optic atrophy)
• Choreoathetoid movement disorder
• Progressive spasticity
• Cerebellar ataxia
• Cognitive deterioration (in a minority of individuals)
## Suggestive Findings
The diagnosis of Costeff syndrome
Relatively normal early development and growth
Bilateral early-onset optic atrophy (pathologically pale optic discs, attenuated papillary vasculature, and visual evoked potentials that show bilateral prolonged latencies consistent with optic atrophy)
Choreoathetoid movement disorder
Progressive spasticity
Cerebellar ataxia
Cognitive deterioration (in a minority of individuals)
• Relatively normal early development and growth
• Bilateral early-onset optic atrophy (pathologically pale optic discs, attenuated papillary vasculature, and visual evoked potentials that show bilateral prolonged latencies consistent with optic atrophy)
• Choreoathetoid movement disorder
• Progressive spasticity
• Cerebellar ataxia
• Cognitive deterioration (in a minority of individuals)
## Clinical Findings
Relatively normal early development and growth
Bilateral early-onset optic atrophy (pathologically pale optic discs, attenuated papillary vasculature, and visual evoked potentials that show bilateral prolonged latencies consistent with optic atrophy)
Choreoathetoid movement disorder
Progressive spasticity
Cerebellar ataxia
Cognitive deterioration (in a minority of individuals)
• Relatively normal early development and growth
• Bilateral early-onset optic atrophy (pathologically pale optic discs, attenuated papillary vasculature, and visual evoked potentials that show bilateral prolonged latencies consistent with optic atrophy)
• Choreoathetoid movement disorder
• Progressive spasticity
• Cerebellar ataxia
• Cognitive deterioration (in a minority of individuals)
## Laboratory Findings
## Establishing the Diagnosis
The
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Costeff syndrome is broad, individuals with the distinctive findings described in
Note:
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Costeff Syndrome
See
See
The variant
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Option 1
Note:
For an introduction to multigene panels click
## Option 2
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Costeff Syndrome
See
See
The variant
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
Most individuals with Costeff syndrome present within the first ten years of life with decreased visual acuity and/or choreoathetoid movement disorder. Although most develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable.
The following description of the phenotypic features of Costeff syndrome is based on two reports:
Optic atrophy manifests as decreased visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus.
In 36 individuals with Costeff syndrome, visual acuity decreased with age:
In two children age two years, visual acuity appeared to be normal.
In 14 individuals age three to 21 years (14.2±5.5), visual acuity was 6/21 or less.
In 20 individuals age five to 37 years (18±9.5), visual acuity was 3/60 or less.
Some children have strabismus and gaze apraxia.
Motor disability is primarily caused by extrapyramidal dysfunction and spasticity.
Major disability in 17 individuals age two to 37 years (mean 16.1±17.8)
Minor disability in maintaining stable posture and fine motor activities in 12 individuals age two to 26 years (11.7±8.1)
Mild manifestations with no resulting disability in three individuals age 15 to 36 years
No extrapyramidal involvement was observed in four individuals ages 13 to 32 years.
Nine individuals age two to 12 years (5.9±3.5) did not have spasticity.
Four individuals age 11 to 26 years had mild spasticity but no related disability.
Eleven individuals age 13 to 37 years (21.4±9.3) had mild spasticity-related disability.
Twelve individuals age nine to 26 years (17.0±4.8) had severe spasticity-related disability.
Cognitive impairment was previously noted in some individuals. Of 36 individuals:
Nineteen individuals age two to 36 years (16±18.7) had an IQ of 71 or higher.
Thirteen individuals age two to 37 years (14.7±9.2) had an IQ between 55 and 71.
Four individuals age nine to 26 years had an IQ between 40 and 54.
More recently, however, a study of the neuropsychological profile of 16 adults with Costeff syndrome reported intact global cognition and learning abilities and strong auditory memory performance [
Several affected individuals were reported to have married, four of whom (all female) had healthy offspring [
Affected adults in the seventh decade of life have been reported [
Seizures are not typical in Costeff syndrome. Partial seizures were reported in one individual. In addition, two individuals with Costeff syndrome were reported with electrical status epilepticus during slow-wave sleep (ESESS) (also known as continuous spike-wave of slow sleep (CSWSS) [
Cranial nerve functions, sensation, and muscle tone are normal.
No cardiac or structural brain abnormalities have been reported.
The level of 3-methylglutaconate (3-MGC) or 3-methylglutaric acid (3-MGA) in urine does not correlate with the degree of neurologic damage.
Electroretinogram is normal.
Genotype-phenotype correlations cannot be made due to the limited number of
All individuals of Iraqi Jewish origin with Costeff syndrome have the same pathogenic variant (
Costeff syndrome has also been referred to as "optic atrophy plus syndrome" and "Costeff optic atrophy syndrome."
Costeff syndrome has been reported in more than 40 individuals of Iraqi Jewish origin [
The carrier rate in Iraqi Jews was initially estimated at 1:10 [
• In two children age two years, visual acuity appeared to be normal.
• In 14 individuals age three to 21 years (14.2±5.5), visual acuity was 6/21 or less.
• In 20 individuals age five to 37 years (18±9.5), visual acuity was 3/60 or less.
• Major disability in 17 individuals age two to 37 years (mean 16.1±17.8)
• Minor disability in maintaining stable posture and fine motor activities in 12 individuals age two to 26 years (11.7±8.1)
• Mild manifestations with no resulting disability in three individuals age 15 to 36 years
• Nine individuals age two to 12 years (5.9±3.5) did not have spasticity.
• Four individuals age 11 to 26 years had mild spasticity but no related disability.
• Eleven individuals age 13 to 37 years (21.4±9.3) had mild spasticity-related disability.
• Twelve individuals age nine to 26 years (17.0±4.8) had severe spasticity-related disability.
• Nineteen individuals age two to 36 years (16±18.7) had an IQ of 71 or higher.
• Thirteen individuals age two to 37 years (14.7±9.2) had an IQ between 55 and 71.
• Four individuals age nine to 26 years had an IQ between 40 and 54.
## Clinical Description
Most individuals with Costeff syndrome present within the first ten years of life with decreased visual acuity and/or choreoathetoid movement disorder. Although most develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable.
The following description of the phenotypic features of Costeff syndrome is based on two reports:
Optic atrophy manifests as decreased visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus.
In 36 individuals with Costeff syndrome, visual acuity decreased with age:
In two children age two years, visual acuity appeared to be normal.
In 14 individuals age three to 21 years (14.2±5.5), visual acuity was 6/21 or less.
In 20 individuals age five to 37 years (18±9.5), visual acuity was 3/60 or less.
Some children have strabismus and gaze apraxia.
Motor disability is primarily caused by extrapyramidal dysfunction and spasticity.
Major disability in 17 individuals age two to 37 years (mean 16.1±17.8)
Minor disability in maintaining stable posture and fine motor activities in 12 individuals age two to 26 years (11.7±8.1)
Mild manifestations with no resulting disability in three individuals age 15 to 36 years
No extrapyramidal involvement was observed in four individuals ages 13 to 32 years.
Nine individuals age two to 12 years (5.9±3.5) did not have spasticity.
Four individuals age 11 to 26 years had mild spasticity but no related disability.
Eleven individuals age 13 to 37 years (21.4±9.3) had mild spasticity-related disability.
Twelve individuals age nine to 26 years (17.0±4.8) had severe spasticity-related disability.
Cognitive impairment was previously noted in some individuals. Of 36 individuals:
Nineteen individuals age two to 36 years (16±18.7) had an IQ of 71 or higher.
Thirteen individuals age two to 37 years (14.7±9.2) had an IQ between 55 and 71.
Four individuals age nine to 26 years had an IQ between 40 and 54.
More recently, however, a study of the neuropsychological profile of 16 adults with Costeff syndrome reported intact global cognition and learning abilities and strong auditory memory performance [
Several affected individuals were reported to have married, four of whom (all female) had healthy offspring [
Affected adults in the seventh decade of life have been reported [
Seizures are not typical in Costeff syndrome. Partial seizures were reported in one individual. In addition, two individuals with Costeff syndrome were reported with electrical status epilepticus during slow-wave sleep (ESESS) (also known as continuous spike-wave of slow sleep (CSWSS) [
Cranial nerve functions, sensation, and muscle tone are normal.
No cardiac or structural brain abnormalities have been reported.
The level of 3-methylglutaconate (3-MGC) or 3-methylglutaric acid (3-MGA) in urine does not correlate with the degree of neurologic damage.
Electroretinogram is normal.
• In two children age two years, visual acuity appeared to be normal.
• In 14 individuals age three to 21 years (14.2±5.5), visual acuity was 6/21 or less.
• In 20 individuals age five to 37 years (18±9.5), visual acuity was 3/60 or less.
• Major disability in 17 individuals age two to 37 years (mean 16.1±17.8)
• Minor disability in maintaining stable posture and fine motor activities in 12 individuals age two to 26 years (11.7±8.1)
• Mild manifestations with no resulting disability in three individuals age 15 to 36 years
• Nine individuals age two to 12 years (5.9±3.5) did not have spasticity.
• Four individuals age 11 to 26 years had mild spasticity but no related disability.
• Eleven individuals age 13 to 37 years (21.4±9.3) had mild spasticity-related disability.
• Twelve individuals age nine to 26 years (17.0±4.8) had severe spasticity-related disability.
• Nineteen individuals age two to 36 years (16±18.7) had an IQ of 71 or higher.
• Thirteen individuals age two to 37 years (14.7±9.2) had an IQ between 55 and 71.
• Four individuals age nine to 26 years had an IQ between 40 and 54.
## Optic Atrophy
Optic atrophy manifests as decreased visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus.
In 36 individuals with Costeff syndrome, visual acuity decreased with age:
In two children age two years, visual acuity appeared to be normal.
In 14 individuals age three to 21 years (14.2±5.5), visual acuity was 6/21 or less.
In 20 individuals age five to 37 years (18±9.5), visual acuity was 3/60 or less.
Some children have strabismus and gaze apraxia.
• In two children age two years, visual acuity appeared to be normal.
• In 14 individuals age three to 21 years (14.2±5.5), visual acuity was 6/21 or less.
• In 20 individuals age five to 37 years (18±9.5), visual acuity was 3/60 or less.
## Motor Disability
Motor disability is primarily caused by extrapyramidal dysfunction and spasticity.
Major disability in 17 individuals age two to 37 years (mean 16.1±17.8)
Minor disability in maintaining stable posture and fine motor activities in 12 individuals age two to 26 years (11.7±8.1)
Mild manifestations with no resulting disability in three individuals age 15 to 36 years
No extrapyramidal involvement was observed in four individuals ages 13 to 32 years.
Nine individuals age two to 12 years (5.9±3.5) did not have spasticity.
Four individuals age 11 to 26 years had mild spasticity but no related disability.
Eleven individuals age 13 to 37 years (21.4±9.3) had mild spasticity-related disability.
Twelve individuals age nine to 26 years (17.0±4.8) had severe spasticity-related disability.
• Major disability in 17 individuals age two to 37 years (mean 16.1±17.8)
• Minor disability in maintaining stable posture and fine motor activities in 12 individuals age two to 26 years (11.7±8.1)
• Mild manifestations with no resulting disability in three individuals age 15 to 36 years
• Nine individuals age two to 12 years (5.9±3.5) did not have spasticity.
• Four individuals age 11 to 26 years had mild spasticity but no related disability.
• Eleven individuals age 13 to 37 years (21.4±9.3) had mild spasticity-related disability.
• Twelve individuals age nine to 26 years (17.0±4.8) had severe spasticity-related disability.
## Cognitive Impairment
Cognitive impairment was previously noted in some individuals. Of 36 individuals:
Nineteen individuals age two to 36 years (16±18.7) had an IQ of 71 or higher.
Thirteen individuals age two to 37 years (14.7±9.2) had an IQ between 55 and 71.
Four individuals age nine to 26 years had an IQ between 40 and 54.
More recently, however, a study of the neuropsychological profile of 16 adults with Costeff syndrome reported intact global cognition and learning abilities and strong auditory memory performance [
• Nineteen individuals age two to 36 years (16±18.7) had an IQ of 71 or higher.
• Thirteen individuals age two to 37 years (14.7±9.2) had an IQ between 55 and 71.
• Four individuals age nine to 26 years had an IQ between 40 and 54.
## Other
Several affected individuals were reported to have married, four of whom (all female) had healthy offspring [
Affected adults in the seventh decade of life have been reported [
Seizures are not typical in Costeff syndrome. Partial seizures were reported in one individual. In addition, two individuals with Costeff syndrome were reported with electrical status epilepticus during slow-wave sleep (ESESS) (also known as continuous spike-wave of slow sleep (CSWSS) [
Cranial nerve functions, sensation, and muscle tone are normal.
No cardiac or structural brain abnormalities have been reported.
The level of 3-methylglutaconate (3-MGC) or 3-methylglutaric acid (3-MGA) in urine does not correlate with the degree of neurologic damage.
Electroretinogram is normal.
## Genotype-Phenotype Correlations
Genotype-phenotype correlations cannot be made due to the limited number of
All individuals of Iraqi Jewish origin with Costeff syndrome have the same pathogenic variant (
## Nomenclature
Costeff syndrome has also been referred to as "optic atrophy plus syndrome" and "Costeff optic atrophy syndrome."
## Prevalence
Costeff syndrome has been reported in more than 40 individuals of Iraqi Jewish origin [
The carrier rate in Iraqi Jews was initially estimated at 1:10 [
## Genetically Related (Allelic) Disorders
The heterozygous
Another autosomal dominant phenotype of optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy was associated with a
## Differential Diagnosis
Increased urinary excretion of the branched-chain organic acid 3-methylglutaconate (3-MGC) is a relatively common finding in children investigated for suspected inborn errors of metabolism [
A classification of inborn errors of metabolism with 3-methylglutaconic aciduria (3-MGCA) as the discriminative feature was published by
Inborn Errors of Metabolism Associated with 3-Methylglutaconic Aciduria
Nonspecific speech & language delay w/o metabolic derangement in some individuals & w/hypoglycemia & metabolic acidosis in others
Failure to thrive, ID, & DD common
Microcephaly & progressive neurologic impairment w/spastic quadriplegia, seizures, & dystonia reported
Cardiomyopathy; DD & ID; growth restriction; cerebellar ataxia; may be assoc w/optic atrophy
Seen in Dariusleut Hutterite population of Canada.
3-MGCA = 3-methylglutaconic aciduria; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
Features shown in ( )s are rare.
Adapted from
Dilated cardiomyopathy presents within the first year of life or even prenatally [
Ataxia, an obligatory finding in Behr syndrome, is not seen in approximately half of individuals with Costeff syndrome; conversely, most individuals with Behr syndrome do not manifest extrapyramidal dysfunction, one of the major features of Costeff syndrome. Given that some individuals with Costeff syndrome do not have extrapyramidal dysfunction, it is not possible to distinguish Behr syndrome from Costeff syndrome based on clinical findings alone. Costeff syndrome can be distinguished from Behr syndrome by the presence of elevated excretion of 3-MGC and 3-MGA in urine.
• Nonspecific speech & language delay w/o metabolic derangement in some individuals & w/hypoglycemia & metabolic acidosis in others
• Failure to thrive, ID, & DD common
• Microcephaly & progressive neurologic impairment w/spastic quadriplegia, seizures, & dystonia reported
• Cardiomyopathy; DD & ID; growth restriction; cerebellar ataxia; may be assoc w/optic atrophy
• Seen in Dariusleut Hutterite population of Canada.
## 3-Methylglutaconic Aciduria
Increased urinary excretion of the branched-chain organic acid 3-methylglutaconate (3-MGC) is a relatively common finding in children investigated for suspected inborn errors of metabolism [
A classification of inborn errors of metabolism with 3-methylglutaconic aciduria (3-MGCA) as the discriminative feature was published by
Inborn Errors of Metabolism Associated with 3-Methylglutaconic Aciduria
Nonspecific speech & language delay w/o metabolic derangement in some individuals & w/hypoglycemia & metabolic acidosis in others
Failure to thrive, ID, & DD common
Microcephaly & progressive neurologic impairment w/spastic quadriplegia, seizures, & dystonia reported
Cardiomyopathy; DD & ID; growth restriction; cerebellar ataxia; may be assoc w/optic atrophy
Seen in Dariusleut Hutterite population of Canada.
3-MGCA = 3-methylglutaconic aciduria; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
Features shown in ( )s are rare.
Adapted from
Dilated cardiomyopathy presents within the first year of life or even prenatally [
• Nonspecific speech & language delay w/o metabolic derangement in some individuals & w/hypoglycemia & metabolic acidosis in others
• Failure to thrive, ID, & DD common
• Microcephaly & progressive neurologic impairment w/spastic quadriplegia, seizures, & dystonia reported
• Cardiomyopathy; DD & ID; growth restriction; cerebellar ataxia; may be assoc w/optic atrophy
• Seen in Dariusleut Hutterite population of Canada.
## Clinical Findings of Costeff Syndrome
Ataxia, an obligatory finding in Behr syndrome, is not seen in approximately half of individuals with Costeff syndrome; conversely, most individuals with Behr syndrome do not manifest extrapyramidal dysfunction, one of the major features of Costeff syndrome. Given that some individuals with Costeff syndrome do not have extrapyramidal dysfunction, it is not possible to distinguish Behr syndrome from Costeff syndrome based on clinical findings alone. Costeff syndrome can be distinguished from Behr syndrome by the presence of elevated excretion of 3-MGC and 3-MGA in urine.
## Management
To establish the extent of disease and needs in an individual diagnosed with Costeff syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Costeff Syndrome
Extraocular movement, best corrected visual acuity, color vision testing, visual field testing, visual evoked potentials, fundus exam;
Need for visual aids.
Gross motor & fine motor skills
Mobility, activities of daily living, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Contact w/a
Assess need for social work involvement for caregiver support and help coordinating multidisciplinary care.
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment is supportive. A multidisciplinary team including a neurologist, orthopedic surgeon, ophthalmologist, biochemical geneticist, and physical therapist is required for the care of affected individuals.
Treatment of Manifestations in Individuals with Costeff Syndrome
Eval for visual aids
Community vision services through early intervention or school district
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordination of care to manage multiple subspecialty appointments, equipment, medications, & supplies
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Recommended Surveillance for Individuals with Costeff Syndrome
Ophthalmologic exam incl best corrected visual acuity, color vision testing, & visual field testing
Appropriateness of visual aids
Neurologic exam for progression of findings
Orthopedics (eval of Achilles tendon shortening); OT/PT eval
Speech & language assessment
OT = occupational therapy; PT = physical therapy
Shortening of Achilles tendon
The following should be avoided:
Tobacco and alcohol use
Medications known to impair mitochondrial function
See
Search
• Extraocular movement, best corrected visual acuity, color vision testing, visual field testing, visual evoked potentials, fundus exam;
• Need for visual aids.
• Gross motor & fine motor skills
• Mobility, activities of daily living, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Contact w/a
• Assess need for social work involvement for caregiver support and help coordinating multidisciplinary care.
• Eval for visual aids
• Community vision services through early intervention or school district
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordination of care to manage multiple subspecialty appointments, equipment, medications, & supplies
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Ophthalmologic exam incl best corrected visual acuity, color vision testing, & visual field testing
• Appropriateness of visual aids
• Neurologic exam for progression of findings
• Orthopedics (eval of Achilles tendon shortening); OT/PT eval
• Speech & language assessment
• Tobacco and alcohol use
• Medications known to impair mitochondrial function
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Costeff syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Costeff Syndrome
Extraocular movement, best corrected visual acuity, color vision testing, visual field testing, visual evoked potentials, fundus exam;
Need for visual aids.
Gross motor & fine motor skills
Mobility, activities of daily living, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Contact w/a
Assess need for social work involvement for caregiver support and help coordinating multidisciplinary care.
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Extraocular movement, best corrected visual acuity, color vision testing, visual field testing, visual evoked potentials, fundus exam;
• Need for visual aids.
• Gross motor & fine motor skills
• Mobility, activities of daily living, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Contact w/a
• Assess need for social work involvement for caregiver support and help coordinating multidisciplinary care.
## Treatment of Manifestations
Treatment is supportive. A multidisciplinary team including a neurologist, orthopedic surgeon, ophthalmologist, biochemical geneticist, and physical therapist is required for the care of affected individuals.
Treatment of Manifestations in Individuals with Costeff Syndrome
Eval for visual aids
Community vision services through early intervention or school district
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordination of care to manage multiple subspecialty appointments, equipment, medications, & supplies
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Eval for visual aids
• Community vision services through early intervention or school district
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordination of care to manage multiple subspecialty appointments, equipment, medications, & supplies
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Surveillance
Recommended Surveillance for Individuals with Costeff Syndrome
Ophthalmologic exam incl best corrected visual acuity, color vision testing, & visual field testing
Appropriateness of visual aids
Neurologic exam for progression of findings
Orthopedics (eval of Achilles tendon shortening); OT/PT eval
Speech & language assessment
OT = occupational therapy; PT = physical therapy
Shortening of Achilles tendon
• Ophthalmologic exam incl best corrected visual acuity, color vision testing, & visual field testing
• Appropriateness of visual aids
• Neurologic exam for progression of findings
• Orthopedics (eval of Achilles tendon shortening); OT/PT eval
• Speech & language assessment
## Agents/Circumstances to Avoid
The following should be avoided:
Tobacco and alcohol use
Medications known to impair mitochondrial function
• Tobacco and alcohol use
• Medications known to impair mitochondrial function
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Costeff syndrome is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an individual with Costeff syndrome has children with an affected individual or a carrier, the offspring of a proband will be obligate heterozygotes (carriers) for a pathogenic variant in
Note: The carrier frequency in individuals of Iraqi Jewish descent was formerly estimated at 1:10 [
Carrier testing for at-risk relatives requires prior identification of the
Carrier testing in individuals of Iraqi Jewish origin relies on targeted analysis for the
Note: Because carriers have normal urinary excretion of 3-methylglutaric acid (3-MGA) and 3-methylglutaconate (3-MGC), carrier status cannot be determined using biochemical genetic testing.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an individual with Costeff syndrome has children with an affected individual or a carrier, the offspring of a proband will be obligate heterozygotes (carriers) for a pathogenic variant in
• Note: The carrier frequency in individuals of Iraqi Jewish descent was formerly estimated at 1:10 [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Costeff syndrome is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an individual with Costeff syndrome has children with an affected individual or a carrier, the offspring of a proband will be obligate heterozygotes (carriers) for a pathogenic variant in
Note: The carrier frequency in individuals of Iraqi Jewish descent was formerly estimated at 1:10 [
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an individual with Costeff syndrome has children with an affected individual or a carrier, the offspring of a proband will be obligate heterozygotes (carriers) for a pathogenic variant in
• Note: The carrier frequency in individuals of Iraqi Jewish descent was formerly estimated at 1:10 [
## Carrier (Heterozygote) Detection
Carrier testing for at-risk relatives requires prior identification of the
Carrier testing in individuals of Iraqi Jewish origin relies on targeted analysis for the
Note: Because carriers have normal urinary excretion of 3-methylglutaric acid (3-MGA) and 3-methylglutaconate (3-MGC), carrier status cannot be determined using biochemical genetic testing.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Sheba Medical Center
Tel Hashomer 52621
Israel
United Kingdom
•
• Sheba Medical Center
• Tel Hashomer 52621
• Israel
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
Costeff Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Costeff Syndrome (
The resulting lack of mRNA expression manifests as the absence of an
The effect of the
Notable
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
First pathogenic variant found to date in an individual of non-Iraqi Jewish origin
Homozygous pathogenic variant; the second pathogenic variant found to date in an individual of non-Iraqi Jewish origin
## Molecular Pathogenesis
The resulting lack of mRNA expression manifests as the absence of an
The effect of the
Notable
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
First pathogenic variant found to date in an individual of non-Iraqi Jewish origin
Homozygous pathogenic variant; the second pathogenic variant found to date in an individual of non-Iraqi Jewish origin
## References
## Literature Cited
## Chapter Notes
Readers are welcome to contact Dr Anikster with questions at the
Yair Anikster, MD, PhD (2006-present)William A Gahl, MD, PhD; National Institutes of Health (2006-2013)Meral Gunay-Aygun, MD; National Institutes of Health (2006-2020)Marian Huizing, PhD; National Institutes of Health (2013-2020)
30 April 2020 (bp) Comprehensive update posted live
19 December 2013 (me) Comprehensive update posted live
31 March 2009 (me) Comprehensive update posted live
28 July 2006 (me) Review posted live
27 April 2006 (mga) Original submission
• 30 April 2020 (bp) Comprehensive update posted live
• 19 December 2013 (me) Comprehensive update posted live
• 31 March 2009 (me) Comprehensive update posted live
• 28 July 2006 (me) Review posted live
• 27 April 2006 (mga) Original submission
## Author Notes
Readers are welcome to contact Dr Anikster with questions at the
## Author History
Yair Anikster, MD, PhD (2006-present)William A Gahl, MD, PhD; National Institutes of Health (2006-2013)Meral Gunay-Aygun, MD; National Institutes of Health (2006-2020)Marian Huizing, PhD; National Institutes of Health (2013-2020)
## Revision History
30 April 2020 (bp) Comprehensive update posted live
19 December 2013 (me) Comprehensive update posted live
31 March 2009 (me) Comprehensive update posted live
28 July 2006 (me) Review posted live
27 April 2006 (mga) Original submission
• 30 April 2020 (bp) Comprehensive update posted live
• 19 December 2013 (me) Comprehensive update posted live
• 31 March 2009 (me) Comprehensive update posted live
• 28 July 2006 (me) Review posted live
• 27 April 2006 (mga) Original submission
Metabolic pathway diagram showing branched-chain organic acid 3-MGC as an intermediate of leucine degradation and the mevalonate shunt pathway that links sterol synthesis with mitochondrial acetyl-CoA
|
[
"Y Anikster, R Kleta, A Shaag, WA Gahl, O Elpeleg. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews.. Am J Hum Genet 2001;69:1218-24",
"PG Barth, F Valianpour, VM Bowen, J Lam, M Duran, FM Vaz, RJ Wanders. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update.. Am J Med Genet A 2004;126A:349-54",
"SC Bourne, KN Townsend, C Shyr, A Matthews, SA Lear, R Attariwala, A Lehman, WW Wasserman, C van Karnebeek, G Sinclair, H Vallance, WT Gibson. Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation.. Cold Spring Harb Mol Case Stud. 2017;3",
"N Carmi, D Lev, E Leshinsky-Silver, Y Anikster, L Blumkin, S Kivity, T Lerman-Sagie, A. Zerem. Atypical presentation of Costeff syndrome-severe psychomotor involvement and electrical status epilepticus during slow wave sleep.. Eur J Paediatr Neurol. 2015;19:733-6",
"L Copeliovitch, K Katz, N Arbel, N Harries, E Bar-On, M Soudry. Musculoskeletal deformities in Behr syndrome.. J Pediatr Orthop 2001;21:512-4",
"KM Davey, JS Parboosingh, DR McLeod, A Chan, R Casey, P Ferreira, FF Snyder, PJ Bridge, FP Bernier. Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition.. J Med Genet 2006;43:385-93",
"ON Elpeleg, H Costeff, A Joseph, Y Shental, R Weitz, KM Gibson. 3-Methylglutaconic aciduria in the Iraqi-Jewish \"optic atrophy plus\" (Costeff) syndrome.. Dev Med Child Neurol 1994;36:167-72",
"ED Gaier, I Sahai, JL Wiggs, B McGeeney, J Hoffman, CE Peeler. Novel homozygous OPA3 mutation in an Afghani family with 3-methylglutaconic aciduria type III and optic atrophy.. Ophthalmic Genet. 2019;40:570-3",
"M Gunay-Aygun. 3-Methylglutaconic aciduria: a common biochemical marker in various syndromes with diverse clinical features.. Mol Genet Metab 2005;84:1-3",
"G Ho, JH Walter, J Christodoulou. Costeff optic atrophy syndrome: New clinical case and novel molecular findings.. J Inherit Metab Dis. 2008;31:S419-23",
"L Ijlst, FJ Loupatty, JP Ruiter, M Duran, W Lehnert, RJ Wanders. 3-Methylglutaconic aciduria type I is caused by mutations in AUH.. Am J Hum Genet 2002;71:1463-6",
"S Illsinger, T Lucke, J Zschocke, KM Gibson, AM Das. 3-methylglutaconic aciduria type I in a boy with fever-associated seizures.. Pediatr Neurol 2004;30:213-5",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"M Kessi, J Peng, L Yang, J Xiong, H Duan, N Pang, F Yin. Genetic etiologies of the electrical status epilepticus during slow wave sleep: systematic review.. BMC Genet. 2018;19:40",
"R Kleta, F Skovby, E Christensen, T Rosenberg, WA Gahl, Y Anikster. 3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings.. Mol Genet Metab. 2002;76:201-6",
"R Kovacs-Nagy, G Morin, MA Nouri, O Brandau, NW Saadi, MA Nouri, F van den Broek, H Prokisch, JA Mayr, SB Wortmann. HTRA2 defect: a recognizable inborn error of metabolism with 3-methylglutaconic aciduria as discriminating feature characterized by neonatal movement disorder and epilepsy-report of 11 patients.. Neuropediatrics. 2018;49:373-8",
"C Lam, LK Gallo, R Dineen, C Ciccone, H Dorward, GE Hoganson, L Wolfe, WA Gahl, M Huizing. Two novel compound heterozygous mutations in OPA3 in two siblings with OPA3-related 3-methylglutaconic aciduria.. Mol Genet Metab Rep. 2014;1:114-23",
"S Sofer, A Schweiger, L Blumkin, G Yahalom, Y Anikster, D Lev, B Ben-Zeev, T Lerman-Sagie, S Hassin-Baer. The neuropsychological profile of patients with 3-methylglutaconic aciduria type III, Costeff syndrome.. Am J Med Genet B Neuropsychiatr Genet 2015;168B:197-203",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"SB Wortmann, M Duran, Y Anikster, PG Barth, W Sperl, J Zschocke, E Morava, RA Wevers. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature.. J Inherit Metab Dis. 2013a;36:923-8",
"SB Wortmann, LA Kluijtmans, RJ Rodenburg, JO Sass, J Nouws, EP van Kaauwen, T Kleefstra, L Tranebjaerg, MC de Vries, P Isohanni, K Walter, FS Alkuraya, I Smuts, CJ Reinecke, FH van der Westhuizen, D Thorburn, JA Smeitink, E Morava, RA Wevers. 3-Methylglutaconic aciduria-lessons from 50 genes and 977 patients.. J Inherit Metab Dis. 2013b;36:913-21",
"G Yahalom, Y Anikster, R Huna-Baron, C Hoffmann, L Blumkin, D Lev, R Tsabari, Z Nitsan, SF Lerman, B Ben-Zeev, B Pode-Shakked, S Sofer, A Schweiger, T Lerman-Sagie, S Hassin-Baer. Costeff syndrome: clinical features and natural history.. J Neurol. 2014;261:2275-82"
] |
28/7/2006
|
30/4/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mhs
|
mhs
|
[
"Malignant Hyperpyrexia",
"Malignant Hyperpyrexia",
"Ryanodine receptor 1",
"SH3 and cysteine-rich domain-containing protein 3",
"Voltage-dependent L-type calcium channel subunit alpha-1S",
"CACNA1S",
"RYR1",
"STAC3",
"Nonsyndromic Malignant Hyperthermia Susceptibility"
] |
Nonsyndromic Malignant Hyperthermia Susceptibility
|
Sheila Riazi, Leslie G Biesecker, Henry Rosenberg, Robert T Dirksen
|
Summary Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances cause uncontrolled release of calcium from the sarcoplasmic reticulum and may promote entry of extracellular calcium into the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even cardiac arrest, and myoglobinuria with a risk for kidney failure. In nearly all individuals, the first manifestations of MH (hypercapnia, tachycardia, and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some individuals with MHS will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality can be over 80%. The diagnosis of MHS is established with in vitro muscle contracture testing by measuring the contracture responses of biopsied muscle samples to halothane and graded concentrations of caffeine. The diagnosis of MHS can also be established by identification of a pathogenic variant in MHS is inherited in an autosomal dominant manner. Most individuals diagnosed with MHS have a parent with MHS, although the parent may not have experienced an episode of MH. Each child of an individual with MHS has a 50% chance of being MH susceptible. If an MHS-causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
|
## Diagnosis
Consensus guidelines for the diagnosis of malignant hyperthermia susceptibility (MHS) have been published [
MHS
Each clinical finding is weighted as to significance in being associated with MHS as determined by malignant hyperthermia (MH) experts using a Delphi method. Points are assigned according to weight and are then summed to produce a raw score, which translates to a likelihood of MH score, ranging from a raw score of 0 (MH rank 1: almost never / very unlikely) to a raw score ≥50 (MH rank 6: almost certain) [
Criteria Used in the Clinical Grading Scale for Malignant Hyperthermia
CK = creatine kinase; CO
From
Clinical findings (except family history) are in descending order of relative importance.
Signs occurring during or shortly after general anesthesia in the untreated individual
Proband with a suspected clinical history of MH
First-degree relative of an individual with a clinical history of MH, if the individual with a clinical history of MH cannot be tested (e.g., too young, too old, MH death, not willing to undergo the muscle biopsy, no test center available)
At-risk family members when the MH-causing variant is not known
Severe masseter muscle rigidity along with generalized rigidity during anesthesia with MH-triggering agents
Isolated masseter muscle rigidity with succinylcholine
Limited masseter muscle rigidity along with rhabdomyolysis and/or elevated plasma CK level (hyperCKemia)
Military service. The military requires determination of MHS by contracture testing in persons with a suspected personal or known family history of MH because individuals with MHS are not eligible for military service.
Postoperative rhabdomyolysis and marked elevation of serum CK concentration without other signs of classic MH
Repeated exercise-related rhabdomyolysis in the absence of a known myopathy
Weight less than about 20 kg or age younger than five years
Diagnosis of neuroleptic malignant syndrome or serotonin syndrome
* Because contracture testing is available on a limited basis (three centers in North America [
Confirmed clinical episode of MH
Positive contracture test
High likelihood of having experienced an MH episode, as determined by biopsy center / hotline consultants, and/or likely MH based on the clinical grading scale (see
Relative with a positive contracture test or a known MH-causing variant
Unexplained death with signs of MH during or immediately after anesthesia
Repeated exercise-related rhabdomyolysis and/or heat stroke
The diagnosis of MHS
A positive diagnostic contracture test
A heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in
Note: (1) Molecular genetic testing is not 100% sensitive; MHS cannot be excluded based on failure to identify a pathogenic or likely pathogenic variant in one of the genes listed in
Since the mid-1970s, the standard diagnostic test for MHS has been the in vitro measurement of contracture response of biopsied muscle to graded concentrations of caffeine and the anesthetic halothane. The test is referred to as the
The test must be performed on a biopsy of approximately 2.0 g of muscle from the vastus lateralis or medialis (some centers have used biopsies from other muscle groups, but the test has only been standardized for the vastus muscle group) within five hours of harvesting. Usually, the individual must be at an MH diagnostic center to undergo testing – biopsy samples cannot be shipped from a separate center to the testing laboratory.
The individual is anesthetized with total intravenous general anesthesia, spinal anesthetic, or with a femoral nerve block or one of its variants.
Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
The anesthetic drugs used must be safe for MH-susceptible individuals.
The surgeon must not use electrocautery or stretch the muscle.
Muscle bundles weighing 100-150 mg each are mounted in a chamber containing buffered solution and, after a period of stabilization, are caused to contract with supramaximal electrical stimuli. The isometric contracture that develops following exposure to pharmacologic agents that cause sarcoplasmic reticulum calcium release (e.g., halothane, caffeine, and ryanodine) is measured.
The two versions of the testing protocol with international standards of test performance and interpretation are the North American [
Testing Protocols for Malignant Hyperthermia
Contracture of ≥0.7 g to 3% halothane; OR
Contracture of ≥0.3 g to 2.0 mmol/L caffeine
Contracture of ≥0.2 g to ≤2% halothane; AND
Contracture of ≥0.2 g to ≤2.0 mmol/L caffeine
Halothane only; OR
Caffeine only
Halothane only; OR
Caffeine only
No contracture; OR
Contracture of <0.7 g to halothane; OR
Contracture of <0.3 g to 2.0 mmol/L caffeine
MHN = malignant hyperthermia negative; MHS = malignant hyperthermia susceptible; MHS
Studies to determine the sensitivity and specificity of the contracture test show that both protocols have a sensitivity of over 95%. Specificity is generally between 80% and 97%, according to several studies with these protocols [
Some laboratories employ 1.0 or 2.0 μmol/L ryanodine or 4-chloro-m-chlorocresol in addition to halothane and caffeine to clarify equivocal results.
In the North American protocol, most centers report results as MHS or MHN.
MHS
When the clinical and laboratory findings suggest the diagnosis of MHS, molecular genetic testing approaches should include use of a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Malignant Hyperthermia Susceptibility
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Large exon or multiexon deletions/duplications have not been reported but are not expected to be associated with MHS given the gain-of-function mechanism of disease.
Some exome capture reagents have reduced coverage of
Up to 40% of individuals with MHS do not have an identified pathogenic variant in any of the genes in
• Proband with a suspected clinical history of MH
• First-degree relative of an individual with a clinical history of MH, if the individual with a clinical history of MH cannot be tested (e.g., too young, too old, MH death, not willing to undergo the muscle biopsy, no test center available)
• At-risk family members when the MH-causing variant is not known
• Severe masseter muscle rigidity along with generalized rigidity during anesthesia with MH-triggering agents
• Isolated masseter muscle rigidity with succinylcholine
• Limited masseter muscle rigidity along with rhabdomyolysis and/or elevated plasma CK level (hyperCKemia)
• Military service. The military requires determination of MHS by contracture testing in persons with a suspected personal or known family history of MH because individuals with MHS are not eligible for military service.
• Postoperative rhabdomyolysis and marked elevation of serum CK concentration without other signs of classic MH
• Repeated exercise-related rhabdomyolysis in the absence of a known myopathy
• Weight less than about 20 kg or age younger than five years
• Diagnosis of neuroleptic malignant syndrome or serotonin syndrome
• Confirmed clinical episode of MH
• Positive contracture test
• High likelihood of having experienced an MH episode, as determined by biopsy center / hotline consultants, and/or likely MH based on the clinical grading scale (see
• Relative with a positive contracture test or a known MH-causing variant
• Unexplained death with signs of MH during or immediately after anesthesia
• Repeated exercise-related rhabdomyolysis and/or heat stroke
• A positive diagnostic contracture test
• A heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in
• The test must be performed on a biopsy of approximately 2.0 g of muscle from the vastus lateralis or medialis (some centers have used biopsies from other muscle groups, but the test has only been standardized for the vastus muscle group) within five hours of harvesting. Usually, the individual must be at an MH diagnostic center to undergo testing – biopsy samples cannot be shipped from a separate center to the testing laboratory.
• The individual is anesthetized with total intravenous general anesthesia, spinal anesthetic, or with a femoral nerve block or one of its variants.
• Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
• The anesthetic drugs used must be safe for MH-susceptible individuals.
• Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
• The anesthetic drugs used must be safe for MH-susceptible individuals.
• The surgeon must not use electrocautery or stretch the muscle.
• Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
• The anesthetic drugs used must be safe for MH-susceptible individuals.
• Contracture of ≥0.7 g to 3% halothane; OR
• Contracture of ≥0.3 g to 2.0 mmol/L caffeine
• Contracture of ≥0.2 g to ≤2% halothane; AND
• Contracture of ≥0.2 g to ≤2.0 mmol/L caffeine
• Halothane only; OR
• Caffeine only
• Halothane only; OR
• Caffeine only
• No contracture; OR
• Contracture of <0.7 g to halothane; OR
• Contracture of <0.3 g to 2.0 mmol/L caffeine
## Suggestive Findings
MHS
Each clinical finding is weighted as to significance in being associated with MHS as determined by malignant hyperthermia (MH) experts using a Delphi method. Points are assigned according to weight and are then summed to produce a raw score, which translates to a likelihood of MH score, ranging from a raw score of 0 (MH rank 1: almost never / very unlikely) to a raw score ≥50 (MH rank 6: almost certain) [
Criteria Used in the Clinical Grading Scale for Malignant Hyperthermia
CK = creatine kinase; CO
From
Clinical findings (except family history) are in descending order of relative importance.
Signs occurring during or shortly after general anesthesia in the untreated individual
Proband with a suspected clinical history of MH
First-degree relative of an individual with a clinical history of MH, if the individual with a clinical history of MH cannot be tested (e.g., too young, too old, MH death, not willing to undergo the muscle biopsy, no test center available)
At-risk family members when the MH-causing variant is not known
Severe masseter muscle rigidity along with generalized rigidity during anesthesia with MH-triggering agents
Isolated masseter muscle rigidity with succinylcholine
Limited masseter muscle rigidity along with rhabdomyolysis and/or elevated plasma CK level (hyperCKemia)
Military service. The military requires determination of MHS by contracture testing in persons with a suspected personal or known family history of MH because individuals with MHS are not eligible for military service.
Postoperative rhabdomyolysis and marked elevation of serum CK concentration without other signs of classic MH
Repeated exercise-related rhabdomyolysis in the absence of a known myopathy
Weight less than about 20 kg or age younger than five years
Diagnosis of neuroleptic malignant syndrome or serotonin syndrome
* Because contracture testing is available on a limited basis (three centers in North America [
Confirmed clinical episode of MH
Positive contracture test
High likelihood of having experienced an MH episode, as determined by biopsy center / hotline consultants, and/or likely MH based on the clinical grading scale (see
Relative with a positive contracture test or a known MH-causing variant
Unexplained death with signs of MH during or immediately after anesthesia
Repeated exercise-related rhabdomyolysis and/or heat stroke
• Proband with a suspected clinical history of MH
• First-degree relative of an individual with a clinical history of MH, if the individual with a clinical history of MH cannot be tested (e.g., too young, too old, MH death, not willing to undergo the muscle biopsy, no test center available)
• At-risk family members when the MH-causing variant is not known
• Severe masseter muscle rigidity along with generalized rigidity during anesthesia with MH-triggering agents
• Isolated masseter muscle rigidity with succinylcholine
• Limited masseter muscle rigidity along with rhabdomyolysis and/or elevated plasma CK level (hyperCKemia)
• Military service. The military requires determination of MHS by contracture testing in persons with a suspected personal or known family history of MH because individuals with MHS are not eligible for military service.
• Postoperative rhabdomyolysis and marked elevation of serum CK concentration without other signs of classic MH
• Repeated exercise-related rhabdomyolysis in the absence of a known myopathy
• Weight less than about 20 kg or age younger than five years
• Diagnosis of neuroleptic malignant syndrome or serotonin syndrome
• Confirmed clinical episode of MH
• Positive contracture test
• High likelihood of having experienced an MH episode, as determined by biopsy center / hotline consultants, and/or likely MH based on the clinical grading scale (see
• Relative with a positive contracture test or a known MH-causing variant
• Unexplained death with signs of MH during or immediately after anesthesia
• Repeated exercise-related rhabdomyolysis and/or heat stroke
## Indications for
Proband with a suspected clinical history of MH
First-degree relative of an individual with a clinical history of MH, if the individual with a clinical history of MH cannot be tested (e.g., too young, too old, MH death, not willing to undergo the muscle biopsy, no test center available)
At-risk family members when the MH-causing variant is not known
Severe masseter muscle rigidity along with generalized rigidity during anesthesia with MH-triggering agents
Isolated masseter muscle rigidity with succinylcholine
Limited masseter muscle rigidity along with rhabdomyolysis and/or elevated plasma CK level (hyperCKemia)
Military service. The military requires determination of MHS by contracture testing in persons with a suspected personal or known family history of MH because individuals with MHS are not eligible for military service.
Postoperative rhabdomyolysis and marked elevation of serum CK concentration without other signs of classic MH
Repeated exercise-related rhabdomyolysis in the absence of a known myopathy
Weight less than about 20 kg or age younger than five years
Diagnosis of neuroleptic malignant syndrome or serotonin syndrome
* Because contracture testing is available on a limited basis (three centers in North America [
• Proband with a suspected clinical history of MH
• First-degree relative of an individual with a clinical history of MH, if the individual with a clinical history of MH cannot be tested (e.g., too young, too old, MH death, not willing to undergo the muscle biopsy, no test center available)
• At-risk family members when the MH-causing variant is not known
• Severe masseter muscle rigidity along with generalized rigidity during anesthesia with MH-triggering agents
• Isolated masseter muscle rigidity with succinylcholine
• Limited masseter muscle rigidity along with rhabdomyolysis and/or elevated plasma CK level (hyperCKemia)
• Military service. The military requires determination of MHS by contracture testing in persons with a suspected personal or known family history of MH because individuals with MHS are not eligible for military service.
• Postoperative rhabdomyolysis and marked elevation of serum CK concentration without other signs of classic MH
• Repeated exercise-related rhabdomyolysis in the absence of a known myopathy
• Weight less than about 20 kg or age younger than five years
• Diagnosis of neuroleptic malignant syndrome or serotonin syndrome
## Indications for
Confirmed clinical episode of MH
Positive contracture test
High likelihood of having experienced an MH episode, as determined by biopsy center / hotline consultants, and/or likely MH based on the clinical grading scale (see
Relative with a positive contracture test or a known MH-causing variant
Unexplained death with signs of MH during or immediately after anesthesia
Repeated exercise-related rhabdomyolysis and/or heat stroke
• Confirmed clinical episode of MH
• Positive contracture test
• High likelihood of having experienced an MH episode, as determined by biopsy center / hotline consultants, and/or likely MH based on the clinical grading scale (see
• Relative with a positive contracture test or a known MH-causing variant
• Unexplained death with signs of MH during or immediately after anesthesia
• Repeated exercise-related rhabdomyolysis and/or heat stroke
## Establishing the Diagnosis
The diagnosis of MHS
A positive diagnostic contracture test
A heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in
Note: (1) Molecular genetic testing is not 100% sensitive; MHS cannot be excluded based on failure to identify a pathogenic or likely pathogenic variant in one of the genes listed in
Since the mid-1970s, the standard diagnostic test for MHS has been the in vitro measurement of contracture response of biopsied muscle to graded concentrations of caffeine and the anesthetic halothane. The test is referred to as the
The test must be performed on a biopsy of approximately 2.0 g of muscle from the vastus lateralis or medialis (some centers have used biopsies from other muscle groups, but the test has only been standardized for the vastus muscle group) within five hours of harvesting. Usually, the individual must be at an MH diagnostic center to undergo testing – biopsy samples cannot be shipped from a separate center to the testing laboratory.
The individual is anesthetized with total intravenous general anesthesia, spinal anesthetic, or with a femoral nerve block or one of its variants.
Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
The anesthetic drugs used must be safe for MH-susceptible individuals.
The surgeon must not use electrocautery or stretch the muscle.
Muscle bundles weighing 100-150 mg each are mounted in a chamber containing buffered solution and, after a period of stabilization, are caused to contract with supramaximal electrical stimuli. The isometric contracture that develops following exposure to pharmacologic agents that cause sarcoplasmic reticulum calcium release (e.g., halothane, caffeine, and ryanodine) is measured.
The two versions of the testing protocol with international standards of test performance and interpretation are the North American [
Testing Protocols for Malignant Hyperthermia
Contracture of ≥0.7 g to 3% halothane; OR
Contracture of ≥0.3 g to 2.0 mmol/L caffeine
Contracture of ≥0.2 g to ≤2% halothane; AND
Contracture of ≥0.2 g to ≤2.0 mmol/L caffeine
Halothane only; OR
Caffeine only
Halothane only; OR
Caffeine only
No contracture; OR
Contracture of <0.7 g to halothane; OR
Contracture of <0.3 g to 2.0 mmol/L caffeine
MHN = malignant hyperthermia negative; MHS = malignant hyperthermia susceptible; MHS
Studies to determine the sensitivity and specificity of the contracture test show that both protocols have a sensitivity of over 95%. Specificity is generally between 80% and 97%, according to several studies with these protocols [
Some laboratories employ 1.0 or 2.0 μmol/L ryanodine or 4-chloro-m-chlorocresol in addition to halothane and caffeine to clarify equivocal results.
In the North American protocol, most centers report results as MHS or MHN.
MHS
When the clinical and laboratory findings suggest the diagnosis of MHS, molecular genetic testing approaches should include use of a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Malignant Hyperthermia Susceptibility
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Large exon or multiexon deletions/duplications have not been reported but are not expected to be associated with MHS given the gain-of-function mechanism of disease.
Some exome capture reagents have reduced coverage of
Up to 40% of individuals with MHS do not have an identified pathogenic variant in any of the genes in
• A positive diagnostic contracture test
• A heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in
• The test must be performed on a biopsy of approximately 2.0 g of muscle from the vastus lateralis or medialis (some centers have used biopsies from other muscle groups, but the test has only been standardized for the vastus muscle group) within five hours of harvesting. Usually, the individual must be at an MH diagnostic center to undergo testing – biopsy samples cannot be shipped from a separate center to the testing laboratory.
• The individual is anesthetized with total intravenous general anesthesia, spinal anesthetic, or with a femoral nerve block or one of its variants.
• Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
• The anesthetic drugs used must be safe for MH-susceptible individuals.
• Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
• The anesthetic drugs used must be safe for MH-susceptible individuals.
• The surgeon must not use electrocautery or stretch the muscle.
• Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
• The anesthetic drugs used must be safe for MH-susceptible individuals.
• Contracture of ≥0.7 g to 3% halothane; OR
• Contracture of ≥0.3 g to 2.0 mmol/L caffeine
• Contracture of ≥0.2 g to ≤2% halothane; AND
• Contracture of ≥0.2 g to ≤2.0 mmol/L caffeine
• Halothane only; OR
• Caffeine only
• Halothane only; OR
• Caffeine only
• No contracture; OR
• Contracture of <0.7 g to halothane; OR
• Contracture of <0.3 g to 2.0 mmol/L caffeine
## Contracture Test
Since the mid-1970s, the standard diagnostic test for MHS has been the in vitro measurement of contracture response of biopsied muscle to graded concentrations of caffeine and the anesthetic halothane. The test is referred to as the
The test must be performed on a biopsy of approximately 2.0 g of muscle from the vastus lateralis or medialis (some centers have used biopsies from other muscle groups, but the test has only been standardized for the vastus muscle group) within five hours of harvesting. Usually, the individual must be at an MH diagnostic center to undergo testing – biopsy samples cannot be shipped from a separate center to the testing laboratory.
The individual is anesthetized with total intravenous general anesthesia, spinal anesthetic, or with a femoral nerve block or one of its variants.
Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
The anesthetic drugs used must be safe for MH-susceptible individuals.
The surgeon must not use electrocautery or stretch the muscle.
Muscle bundles weighing 100-150 mg each are mounted in a chamber containing buffered solution and, after a period of stabilization, are caused to contract with supramaximal electrical stimuli. The isometric contracture that develops following exposure to pharmacologic agents that cause sarcoplasmic reticulum calcium release (e.g., halothane, caffeine, and ryanodine) is measured.
The two versions of the testing protocol with international standards of test performance and interpretation are the North American [
Testing Protocols for Malignant Hyperthermia
Contracture of ≥0.7 g to 3% halothane; OR
Contracture of ≥0.3 g to 2.0 mmol/L caffeine
Contracture of ≥0.2 g to ≤2% halothane; AND
Contracture of ≥0.2 g to ≤2.0 mmol/L caffeine
Halothane only; OR
Caffeine only
Halothane only; OR
Caffeine only
No contracture; OR
Contracture of <0.7 g to halothane; OR
Contracture of <0.3 g to 2.0 mmol/L caffeine
MHN = malignant hyperthermia negative; MHS = malignant hyperthermia susceptible; MHS
Studies to determine the sensitivity and specificity of the contracture test show that both protocols have a sensitivity of over 95%. Specificity is generally between 80% and 97%, according to several studies with these protocols [
Some laboratories employ 1.0 or 2.0 μmol/L ryanodine or 4-chloro-m-chlorocresol in addition to halothane and caffeine to clarify equivocal results.
In the North American protocol, most centers report results as MHS or MHN.
MHS
• The test must be performed on a biopsy of approximately 2.0 g of muscle from the vastus lateralis or medialis (some centers have used biopsies from other muscle groups, but the test has only been standardized for the vastus muscle group) within five hours of harvesting. Usually, the individual must be at an MH diagnostic center to undergo testing – biopsy samples cannot be shipped from a separate center to the testing laboratory.
• The individual is anesthetized with total intravenous general anesthesia, spinal anesthetic, or with a femoral nerve block or one of its variants.
• Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
• The anesthetic drugs used must be safe for MH-susceptible individuals.
• Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
• The anesthetic drugs used must be safe for MH-susceptible individuals.
• The surgeon must not use electrocautery or stretch the muscle.
• Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
• The anesthetic drugs used must be safe for MH-susceptible individuals.
• Contracture of ≥0.7 g to 3% halothane; OR
• Contracture of ≥0.3 g to 2.0 mmol/L caffeine
• Contracture of ≥0.2 g to ≤2% halothane; AND
• Contracture of ≥0.2 g to ≤2.0 mmol/L caffeine
• Halothane only; OR
• Caffeine only
• Halothane only; OR
• Caffeine only
• No contracture; OR
• Contracture of <0.7 g to halothane; OR
• Contracture of <0.3 g to 2.0 mmol/L caffeine
## Molecular Genetic Testing: Recommended Tier 1 Testing
When the clinical and laboratory findings suggest the diagnosis of MHS, molecular genetic testing approaches should include use of a
For an introduction to multigene panels click
## Molecular Genetic Testing: Tier 2 Testing
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Malignant Hyperthermia Susceptibility
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Large exon or multiexon deletions/duplications have not been reported but are not expected to be associated with MHS given the gain-of-function mechanism of disease.
Some exome capture reagents have reduced coverage of
Up to 40% of individuals with MHS do not have an identified pathogenic variant in any of the genes in
## Clinical Characteristics
The manifestations of malignant hyperthermia (MH) result from exposure to volatile anesthetic agents (i.e., halothane, isoflurane, sevoflurane, desflurane, and enflurane) that act as triggers either alone or in conjunction with succinylcholine, a depolarizing muscle relaxant. MH is an inherited pharmacogenetic disorder of calcium regulation resulting in uncontrolled skeletal muscle hypermetabolism [
The triggering substances initiate uncontrolled release of calcium from the sarcoplasmic reticulum via the skeletal muscle calcium release channel and may promote entry of extracellular calcium into the myoplasm leading to the sustained pathologic increase in cytosolic calcium in skeletal muscle cells [
MH clinical manifestations are variable; with prompt and rapid clinical response, some signs may not appear. Hypercapnia is common, as is tachycardia. Hyperthermia may be one of the early signs of MH. However, failure to monitor core temperature may lead to a delay in detecting hyperthermia. Skin temperature measurement is often misleading during MH crises [
In survivors, normalization of edematous muscle and serum CK concentration occurs within ten to 15 days, but symptom resolution may take longer (see
MH may appear at any point during anesthesia or within an hour or so after termination of anesthesia. If succinylcholine is used during induction of anesthesia, an acceleration of the manifestations of MH may occur; tachycardia, elevation of end-tidal carbon dioxide (CO
In most instances, the first manifestations of MH occur in the operating room. In classic MH, the initial signs are tachycardia, rapidly rising end-tidal CO
At the same time, the CO
Death results unless the individual is promptly treated (see
Early diagnosis and rapid therapy are lifesaving and lead to a reduction of clinical symptoms. Modern anesthetic care and monitoring often allow early detection of MH. Treatment with dantrolene results in much lower morbidity and mortality than when MH was first recognized in the 1960s; however, mortality may be as high as 11% [
The presentation of MH outside a hospital setting may pose special problems. Several deaths from MH have occurred when the episode began in an ambulatory surgery setting. Probable causes include inadequate preparation for treating MH (including absence of dantrolene), insufficient and unprepared personnel, and problems in stabilizing an affected individual before transfer to a hospital. It is suggested that all facilities have a plan to deal with MH and hold practice drills at regular intervals (see
MH may also occur in the early postoperative period, usually within the first hour of recovery from anesthesia. Characteristic tachycardia, tachypnea, hypertension, and arrhythmias presage an episode of MH. Isolated myoglobinuria without an obvious increase in metabolism in the postoperative period (≤24 hours) should alert the anesthesiologist to the possibility of MH.
Note: An MH episode may not occur with every exposure to "trigger" agents; clinical manifestations depend on genetic predisposition, dose of trigger agents, duration of trigger exposure, and other preoperative factors including intense exercise and pyrexia [
Signs similar to MH have also been reported without exposure to anesthetic agents. In some instances, similar signs follow overdose of MDMA agonists, or with heat and exercise.
Clinical, genetic, and laboratory studies using animal models provide evidence for a relationship of environmental or exertional heat stress (EHS) to MHS [
Three novel
Retrospective data on Canadian individuals with MHS and ER showed that either an
While
Individuals with several distinct
In addition,
Stronger contractures and shorter response times in response to caffeine exposure have been reported in individuals with an
Genotype-phenotype correlations in individuals with MHS are limited. A few studies specifically addressed genotype-phenotype correlations in individuals with
No clinically relevant genotype-phenotype correlations for
In a multicenter case-control study, the overall penetrance for
The incidence of MH is best described by the reported incidence per anesthesia procedure. The estimates of the incidence range from one in 3,000 anesthesia procedures to one in 50,000 anesthesia procedures, with most estimating an incidence in children of about one in 10,000 anesthesia procedures and in adults of one in 50,000 anesthesia procedures. The prevalence of MH in individuals undergoing surgery in New York State hospitals was estimated at one in 100,000 for adults [
## Clinical Description
The manifestations of malignant hyperthermia (MH) result from exposure to volatile anesthetic agents (i.e., halothane, isoflurane, sevoflurane, desflurane, and enflurane) that act as triggers either alone or in conjunction with succinylcholine, a depolarizing muscle relaxant. MH is an inherited pharmacogenetic disorder of calcium regulation resulting in uncontrolled skeletal muscle hypermetabolism [
The triggering substances initiate uncontrolled release of calcium from the sarcoplasmic reticulum via the skeletal muscle calcium release channel and may promote entry of extracellular calcium into the myoplasm leading to the sustained pathologic increase in cytosolic calcium in skeletal muscle cells [
MH clinical manifestations are variable; with prompt and rapid clinical response, some signs may not appear. Hypercapnia is common, as is tachycardia. Hyperthermia may be one of the early signs of MH. However, failure to monitor core temperature may lead to a delay in detecting hyperthermia. Skin temperature measurement is often misleading during MH crises [
In survivors, normalization of edematous muscle and serum CK concentration occurs within ten to 15 days, but symptom resolution may take longer (see
MH may appear at any point during anesthesia or within an hour or so after termination of anesthesia. If succinylcholine is used during induction of anesthesia, an acceleration of the manifestations of MH may occur; tachycardia, elevation of end-tidal carbon dioxide (CO
In most instances, the first manifestations of MH occur in the operating room. In classic MH, the initial signs are tachycardia, rapidly rising end-tidal CO
At the same time, the CO
Death results unless the individual is promptly treated (see
Early diagnosis and rapid therapy are lifesaving and lead to a reduction of clinical symptoms. Modern anesthetic care and monitoring often allow early detection of MH. Treatment with dantrolene results in much lower morbidity and mortality than when MH was first recognized in the 1960s; however, mortality may be as high as 11% [
The presentation of MH outside a hospital setting may pose special problems. Several deaths from MH have occurred when the episode began in an ambulatory surgery setting. Probable causes include inadequate preparation for treating MH (including absence of dantrolene), insufficient and unprepared personnel, and problems in stabilizing an affected individual before transfer to a hospital. It is suggested that all facilities have a plan to deal with MH and hold practice drills at regular intervals (see
MH may also occur in the early postoperative period, usually within the first hour of recovery from anesthesia. Characteristic tachycardia, tachypnea, hypertension, and arrhythmias presage an episode of MH. Isolated myoglobinuria without an obvious increase in metabolism in the postoperative period (≤24 hours) should alert the anesthesiologist to the possibility of MH.
Note: An MH episode may not occur with every exposure to "trigger" agents; clinical manifestations depend on genetic predisposition, dose of trigger agents, duration of trigger exposure, and other preoperative factors including intense exercise and pyrexia [
Signs similar to MH have also been reported without exposure to anesthetic agents. In some instances, similar signs follow overdose of MDMA agonists, or with heat and exercise.
Clinical, genetic, and laboratory studies using animal models provide evidence for a relationship of environmental or exertional heat stress (EHS) to MHS [
Three novel
Retrospective data on Canadian individuals with MHS and ER showed that either an
While
Individuals with several distinct
In addition,
## Environmental/Exertional Heat Stress
Clinical, genetic, and laboratory studies using animal models provide evidence for a relationship of environmental or exertional heat stress (EHS) to MHS [
Three novel
Retrospective data on Canadian individuals with MHS and ER showed that either an
While
## Other Disorders that May Have MH Reactions to Anesthesia
Individuals with several distinct
In addition,
## Phenotype Correlations by Gene
Stronger contractures and shorter response times in response to caffeine exposure have been reported in individuals with an
## Genotype-Phenotype Correlations
Genotype-phenotype correlations in individuals with MHS are limited. A few studies specifically addressed genotype-phenotype correlations in individuals with
No clinically relevant genotype-phenotype correlations for
## Penetrance
In a multicenter case-control study, the overall penetrance for
## Prevalence
The incidence of MH is best described by the reported incidence per anesthesia procedure. The estimates of the incidence range from one in 3,000 anesthesia procedures to one in 50,000 anesthesia procedures, with most estimating an incidence in children of about one in 10,000 anesthesia procedures and in adults of one in 50,000 anesthesia procedures. The prevalence of MH in individuals undergoing surgery in New York State hospitals was estimated at one in 100,000 for adults [
## Genetically Related (Allelic) Disorders
Myopathies characterized by muscle weakness that can range from mild to severe.
Most affected individuals have mild disease w/symmetric proximal muscle weakness & variable involvement of facial & neck muscles.
Motor development is usually delayed, but most affected persons acquire independent ambulation.
Severe disease is early in onset with profound hypotonia often accompanied by poor fetal movement, spinal deformities, hip dislocation, joint contractures, poor suck, & respiratory insufficiency requiring assisted ventilation.
Multiminicore disease is broadly classified into 4 groups: classic form, moderate form w/hand involvement, antenatal form w/arthrogryposis multiplex congenita, & ophthalmoplegic form.
~75% of affected individuals have classic symptoms characterized by neonatal hypotonia, delayed motor development, & axial muscle weakness, which leads to development of scoliosis & significant respiratory involvement; varying severity of spinal rigidity is present.
Each of the other three forms is seen in <10% of individuals w/multiminicore disease.
Characterized by distinctive facies, ptosis, downslanted palpebral fissures, widely spaced eyes, epicanthal folds, low-set ears, malar hypoplasia, micrognathia, high-arched palate, clinodactyly, single palmar crease, pectus excavatum, winging of scapulae, lumbar lordosis, & mild thoracic scoliosis
Persons present w/hypotonia at birth, slightly delayed motor development, diffuse joint hyperextensibility, & mild proximal muscle weakness.
Muscle biopsy shows minimal but identifiable changes represented by fiber size variability, type I fiber predominance & atrophy, perimysial fibrous infiltration, & some disarray of intermyofibrillary network.
Characterized by congenital myopathy & musculoskeletal involvement of trunk & extremities
Most children have weakness w/myopathic facies, progressive kyphoscoliosis, & contractures.
Other common findings are palatal anomalies (incl cleft palate) & short stature.
Intellect is typically normal.
Risks for MH & restrictive lung disease are ↑.
AD = autosomal dominant; AR = autosomal recessive; MH = malignant hyperthermia; MOI = mode of inheritance
Pathogenic variants in
Note: The two reports suggesting a relationship of hypoPP to MH are not widely accepted because both lack adequate data to support the association [
• Myopathies characterized by muscle weakness that can range from mild to severe.
• Most affected individuals have mild disease w/symmetric proximal muscle weakness & variable involvement of facial & neck muscles.
• Motor development is usually delayed, but most affected persons acquire independent ambulation.
• Severe disease is early in onset with profound hypotonia often accompanied by poor fetal movement, spinal deformities, hip dislocation, joint contractures, poor suck, & respiratory insufficiency requiring assisted ventilation.
• Multiminicore disease is broadly classified into 4 groups: classic form, moderate form w/hand involvement, antenatal form w/arthrogryposis multiplex congenita, & ophthalmoplegic form.
• ~75% of affected individuals have classic symptoms characterized by neonatal hypotonia, delayed motor development, & axial muscle weakness, which leads to development of scoliosis & significant respiratory involvement; varying severity of spinal rigidity is present.
• Each of the other three forms is seen in <10% of individuals w/multiminicore disease.
• Characterized by distinctive facies, ptosis, downslanted palpebral fissures, widely spaced eyes, epicanthal folds, low-set ears, malar hypoplasia, micrognathia, high-arched palate, clinodactyly, single palmar crease, pectus excavatum, winging of scapulae, lumbar lordosis, & mild thoracic scoliosis
• Persons present w/hypotonia at birth, slightly delayed motor development, diffuse joint hyperextensibility, & mild proximal muscle weakness.
• Muscle biopsy shows minimal but identifiable changes represented by fiber size variability, type I fiber predominance & atrophy, perimysial fibrous infiltration, & some disarray of intermyofibrillary network.
• Characterized by congenital myopathy & musculoskeletal involvement of trunk & extremities
• Most children have weakness w/myopathic facies, progressive kyphoscoliosis, & contractures.
• Other common findings are palatal anomalies (incl cleft palate) & short stature.
• Intellect is typically normal.
• Risks for MH & restrictive lung disease are ↑.
## Differential Diagnosis
Heritable Myopathies to Consider in the Differential Diagnosis of Malignant Hyperthermia
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Acquired Conditions to Consider in the Differential Diagnosis of Malignant Hyperthermia
Rigidity & marked ↑ of serum CK concentration are uncommon in sepsis.
Leukocytosis (typically present w/sepsis) is uncommon in MH.
Hypertension, tachycardia, & sometimes fever
May be mistaken for MH, esp in postoperative period
Manifests after administration of neuroleptic agents such as atypical antipsychotics, haloperidol, & drugs used in treatment of schizophrenia
Occurs in non-anesthetized persons
Rare reaction from serotonin uptake inhibitor drugs
Occurs in non-anesthetized persons
CK = creatine kinase; MH = malignant hyperthermia
Postmortem high-resolution melting followed by sequencing of selected exons of
Succinylcholine may cause rhabdomyolysis that is not obvious on cursory physical examination in individuals who have any of the myotonic syndromes or dystrophinopathies.
Rhabdomyolysis may occur in the perioperative period in some individuals taking inhibitors of cholesterol formation [
• Rigidity & marked ↑ of serum CK concentration are uncommon in sepsis.
• Leukocytosis (typically present w/sepsis) is uncommon in MH.
• Hypertension, tachycardia, & sometimes fever
• May be mistaken for MH, esp in postoperative period
• Manifests after administration of neuroleptic agents such as atypical antipsychotics, haloperidol, & drugs used in treatment of schizophrenia
• Occurs in non-anesthetized persons
• Rare reaction from serotonin uptake inhibitor drugs
• Occurs in non-anesthetized persons
• Succinylcholine may cause rhabdomyolysis that is not obvious on cursory physical examination in individuals who have any of the myotonic syndromes or dystrophinopathies.
• Rhabdomyolysis may occur in the perioperative period in some individuals taking inhibitors of cholesterol formation [
## Management
Clinical management guidelines for malignant hyperthermia susceptibility (MHS) have been published, see
To establish the extent of disease and needs in an individual diagnosed with MHS, the evaluations summarized in
Malignant Hyperthermia Susceptibility: Recommended Evaluations Following Initial Diagnosis
Arterial blood gas analysis
Measurement of serum electrolytes (Na, K, Cl)
Lactate
Measurement of serum CK concentrations until normalized
Coagulation studies (INR, PTT, D-dimer)
Urine myoglobin
Serum myoglobin concentration
Liver function tests (AST, ALT, ALP, bilirubin)
Continuous core temperature monitoring until episode resolves
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; Cl = chloride; K = potassium; INR = international normalized ratio; MH = malignant hyperthermia; MHS = malignant hyperthermia susceptibility; MOI = mode of inheritance; Na = sodium; PTT = partial thromboplastin time
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
For management guidelines, see
Malignant Hyperthermia Susceptibility: Targeted Therapy
Initial dose is 2.5 mg/kg IV.
Initial dose of dantrolene sodium should be repeated every 10 min (or as often as possible if administration takes >10 min).
Suggested upper limit is 10 mg/kg; however, more may be given as needed.
Dantrolene should be repeated until cardiac & respiratory systems stabilize.
Tachycardia, hypercarbia, & muscle rigidity respond rapidly.
Toxicity profile of dantrolene is extremely benign.
Ca channel blocking agents should not be administered w/dantrolene because life-threatening hyperkalemia may result.
Dantrolene may aggravate previously existing muscle weakness.
Ca = calcium; IV = intravenous
Dantrolene sodium is a hydantoin molecule that binds to a specific region of the ryanodine receptor 1 channel. It decreases the uncontrolled release of intracellular calcium [
Early diagnosis of malignant hyperthermia (MH), together with the administration of dantrolene sodium, is essential in the successful treatment of an acute episode of MH.
Discontinue use of potent inhalation agents and succinylcholine.
Increase minute ventilation to lower end-tidal carbon dioxide (CO
Get help. One resource is the Malignant Hyperthermia Association of the US (MHAUS) hotline for acute cases: 800-MH-HYPER (800-644-9737). Similar hotlines exist in other countries, specifically the UK, Germany, and Brazil.
Begin cooling measures. If the individual is hyperthermic, administer iced solutions, ice packs to groin, axilla, and neck, nasogastric lavage with iced solution, or more aggressive measures as needed. Monitor body temperature every 30 minutes. Stop cooling measures at core body temperature of 38.5 °C.
Treat cardiac arrhythmias as needed. Do not use calcium channel blockers.
Obtain blood gases, serum concentration of electrolytes and creatine kinase (CK), blood and urine for myoglobin, and coagulation profile (international normalized ratio [INR], partial thromboplastin time [PTT], D-dimer) every six to 12 hours. The earliest sign of rhabdomyolysis is myoglobinuria/myoglobinemia. Serum CK levels may not rise for several hours. Serum CK concentration may remain elevated for days and should be monitored until it returns to normal.
Treat hyperkalemia with hyperventilation, glucose and insulin, and calcium as dictated by laboratory and cardiovascular changes.
Ensure urine output of 2.0 mL/kg per hour with mannitol, furosemide, and fluids as needed.
Evaluate need for invasive monitoring and continued mechanical ventilation.
Observe the individual in an ICU for at least 24-36 hours because of the 25% chance of recrudescence following initial treatment [
Affected individuals who display extreme hyperthermia are at risk for disseminated intravascular coagulation. A coagulation profile (INR, PTT, D-dimer) should be obtained on all individuals experiencing fulminant MH.
Refer the affected individual to MHAUS for information and counseling. Complete the Adverse Metabolic Reaction to Anesthesia form for enrollment in the North American MH Registry.
Refer the individual to a MH diagnostic center for muscle biopsy and contracture testing after discussion with MH consultants associated with MHAUS.
Preventive measures for individuals known to be susceptible to MH:
For any individual undergoing anesthesia, obtain a thorough anesthetic history to determine the possibility of the individual or a family member having experienced an MH episode. When suspicion of MHS exists, family members should not be given trigger anesthetic agents (i.e., potent volatile anesthetic agents such as halothane, sevoflurane, desflurane, enflurane, and isoflurane or the depolarizing agent succinylcholine).
In general, individuals undergoing general anesthesia that exceeds 30 minutes in duration should have their temperature monitored using an electronic temperature probe. Skin liquid crystal temperature sensors are not recommended as they have been found to be unreliable indicators of changing temperature during MH events.
Individuals with any form of myotonia (see
Individuals with central core disease (OMIM
Individuals with MHS should carry proper identification as to their susceptibility; identification bracelets are available through the
Individuals with MHS should avoid potent inhalation anesthetics and succinylcholine.
Calcium channel blockers should not be given together with dantrolene because life-threatening hyperkalemia may result.
Serotonin antagonist (5-HT3 antagonist) antiemetics should be used cautiously, as sudden death has been reported in a child with multiminicore disease caused by a pathogenic variant in
Individuals with MHS are generally advised to avoid extremes of heat but not to restrict athletic activity or lifestyle unless they have experienced overt rhabdomyolysis and/or heat stroke. Strenuous activities at high ambient temperatures should be avoided or performed with caution.
In individuals with MHS undergoing cardiac bypass surgery, aggressive rewarming should be avoided, as it may be associated with development of clinical signs of MH [
It is appropriate to clarify the status of at-risk relatives of an individual diagnosed with MHS to identify those who also have an increased susceptibility to MH and thus would benefit from avoiding anesthetic agents that increase the risk for an MH episode. Evaluations include the following:
See
If a pregnant woman with MHS requires non-emergent surgery during the pregnancy, a non-triggering anesthetic (local, nerve block, epidural, spinal anesthesia, or a total intravenous general anesthetic) should be administered. Standard American Society of Anesthesiologists mandated monitoring should be used, along with core temperature monitoring. Fetal monitoring should follow standard guidelines. Dantrolene should not be administered in preparation for surgery or labor and delivery.
Continuous epidural analgesia is highly recommended for labor and delivery. If a cesarean delivery is indicated in a woman who does not have an epidural catheter in place, neuraxial (spinal, epidural, or combined spinal-epidural) anesthesia is recommended, if not otherwise contraindicated. If a general anesthetic is indicated, a total intravenous anesthetic technique should be administered, with an anesthesia machine that has been prepared for an individual with MHS.
In the case of a fetus whose father has MHS but whose mother is not known to have MHS, regional anesthesia or general anesthesia without trigger agents is recommended. This is because administration of a triggering agent (specifically volatile anesthetics that can cross the placenta) to the unaffected mother can trigger an MH reaction in an affected fetus, which could be severe or fatal to the fetus.
For further information regarding the management of pregnant women with MHS, see 2009
Various agents (i.e., salbutamol, pyridostigmine, and N-acetylcysteine) have been investigated as potential treatments for
Rycal
Search
• Arterial blood gas analysis
• Measurement of serum electrolytes (Na, K, Cl)
• Lactate
• Measurement of serum CK concentrations until normalized
• Coagulation studies (INR, PTT, D-dimer)
• Urine myoglobin
• Serum myoglobin concentration
• Liver function tests (AST, ALT, ALP, bilirubin)
• Continuous core temperature monitoring until episode resolves
• Initial dose is 2.5 mg/kg IV.
• Initial dose of dantrolene sodium should be repeated every 10 min (or as often as possible if administration takes >10 min).
• Suggested upper limit is 10 mg/kg; however, more may be given as needed.
• Dantrolene should be repeated until cardiac & respiratory systems stabilize.
• Tachycardia, hypercarbia, & muscle rigidity respond rapidly.
• Toxicity profile of dantrolene is extremely benign.
• Ca channel blocking agents should not be administered w/dantrolene because life-threatening hyperkalemia may result.
• Dantrolene may aggravate previously existing muscle weakness.
• Discontinue use of potent inhalation agents and succinylcholine.
• Increase minute ventilation to lower end-tidal carbon dioxide (CO
• Get help. One resource is the Malignant Hyperthermia Association of the US (MHAUS) hotline for acute cases: 800-MH-HYPER (800-644-9737). Similar hotlines exist in other countries, specifically the UK, Germany, and Brazil.
• Begin cooling measures. If the individual is hyperthermic, administer iced solutions, ice packs to groin, axilla, and neck, nasogastric lavage with iced solution, or more aggressive measures as needed. Monitor body temperature every 30 minutes. Stop cooling measures at core body temperature of 38.5 °C.
• Treat cardiac arrhythmias as needed. Do not use calcium channel blockers.
• Obtain blood gases, serum concentration of electrolytes and creatine kinase (CK), blood and urine for myoglobin, and coagulation profile (international normalized ratio [INR], partial thromboplastin time [PTT], D-dimer) every six to 12 hours. The earliest sign of rhabdomyolysis is myoglobinuria/myoglobinemia. Serum CK levels may not rise for several hours. Serum CK concentration may remain elevated for days and should be monitored until it returns to normal.
• Treat hyperkalemia with hyperventilation, glucose and insulin, and calcium as dictated by laboratory and cardiovascular changes.
• Ensure urine output of 2.0 mL/kg per hour with mannitol, furosemide, and fluids as needed.
• Evaluate need for invasive monitoring and continued mechanical ventilation.
• Observe the individual in an ICU for at least 24-36 hours because of the 25% chance of recrudescence following initial treatment [
• Affected individuals who display extreme hyperthermia are at risk for disseminated intravascular coagulation. A coagulation profile (INR, PTT, D-dimer) should be obtained on all individuals experiencing fulminant MH.
• Refer the affected individual to MHAUS for information and counseling. Complete the Adverse Metabolic Reaction to Anesthesia form for enrollment in the North American MH Registry.
• Refer the individual to a MH diagnostic center for muscle biopsy and contracture testing after discussion with MH consultants associated with MHAUS.
• For any individual undergoing anesthesia, obtain a thorough anesthetic history to determine the possibility of the individual or a family member having experienced an MH episode. When suspicion of MHS exists, family members should not be given trigger anesthetic agents (i.e., potent volatile anesthetic agents such as halothane, sevoflurane, desflurane, enflurane, and isoflurane or the depolarizing agent succinylcholine).
• In general, individuals undergoing general anesthesia that exceeds 30 minutes in duration should have their temperature monitored using an electronic temperature probe. Skin liquid crystal temperature sensors are not recommended as they have been found to be unreliable indicators of changing temperature during MH events.
• Individuals with any form of myotonia (see
• Individuals with central core disease (OMIM
• Individuals with MHS should carry proper identification as to their susceptibility; identification bracelets are available through the
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MHS, the evaluations summarized in
Malignant Hyperthermia Susceptibility: Recommended Evaluations Following Initial Diagnosis
Arterial blood gas analysis
Measurement of serum electrolytes (Na, K, Cl)
Lactate
Measurement of serum CK concentrations until normalized
Coagulation studies (INR, PTT, D-dimer)
Urine myoglobin
Serum myoglobin concentration
Liver function tests (AST, ALT, ALP, bilirubin)
Continuous core temperature monitoring until episode resolves
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; Cl = chloride; K = potassium; INR = international normalized ratio; MH = malignant hyperthermia; MHS = malignant hyperthermia susceptibility; MOI = mode of inheritance; Na = sodium; PTT = partial thromboplastin time
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Arterial blood gas analysis
• Measurement of serum electrolytes (Na, K, Cl)
• Lactate
• Measurement of serum CK concentrations until normalized
• Coagulation studies (INR, PTT, D-dimer)
• Urine myoglobin
• Serum myoglobin concentration
• Liver function tests (AST, ALT, ALP, bilirubin)
• Continuous core temperature monitoring until episode resolves
## Treatment of Manifestations
For management guidelines, see
Malignant Hyperthermia Susceptibility: Targeted Therapy
Initial dose is 2.5 mg/kg IV.
Initial dose of dantrolene sodium should be repeated every 10 min (or as often as possible if administration takes >10 min).
Suggested upper limit is 10 mg/kg; however, more may be given as needed.
Dantrolene should be repeated until cardiac & respiratory systems stabilize.
Tachycardia, hypercarbia, & muscle rigidity respond rapidly.
Toxicity profile of dantrolene is extremely benign.
Ca channel blocking agents should not be administered w/dantrolene because life-threatening hyperkalemia may result.
Dantrolene may aggravate previously existing muscle weakness.
Ca = calcium; IV = intravenous
Dantrolene sodium is a hydantoin molecule that binds to a specific region of the ryanodine receptor 1 channel. It decreases the uncontrolled release of intracellular calcium [
Early diagnosis of malignant hyperthermia (MH), together with the administration of dantrolene sodium, is essential in the successful treatment of an acute episode of MH.
Discontinue use of potent inhalation agents and succinylcholine.
Increase minute ventilation to lower end-tidal carbon dioxide (CO
Get help. One resource is the Malignant Hyperthermia Association of the US (MHAUS) hotline for acute cases: 800-MH-HYPER (800-644-9737). Similar hotlines exist in other countries, specifically the UK, Germany, and Brazil.
Begin cooling measures. If the individual is hyperthermic, administer iced solutions, ice packs to groin, axilla, and neck, nasogastric lavage with iced solution, or more aggressive measures as needed. Monitor body temperature every 30 minutes. Stop cooling measures at core body temperature of 38.5 °C.
Treat cardiac arrhythmias as needed. Do not use calcium channel blockers.
Obtain blood gases, serum concentration of electrolytes and creatine kinase (CK), blood and urine for myoglobin, and coagulation profile (international normalized ratio [INR], partial thromboplastin time [PTT], D-dimer) every six to 12 hours. The earliest sign of rhabdomyolysis is myoglobinuria/myoglobinemia. Serum CK levels may not rise for several hours. Serum CK concentration may remain elevated for days and should be monitored until it returns to normal.
Treat hyperkalemia with hyperventilation, glucose and insulin, and calcium as dictated by laboratory and cardiovascular changes.
Ensure urine output of 2.0 mL/kg per hour with mannitol, furosemide, and fluids as needed.
Evaluate need for invasive monitoring and continued mechanical ventilation.
Observe the individual in an ICU for at least 24-36 hours because of the 25% chance of recrudescence following initial treatment [
Affected individuals who display extreme hyperthermia are at risk for disseminated intravascular coagulation. A coagulation profile (INR, PTT, D-dimer) should be obtained on all individuals experiencing fulminant MH.
Refer the affected individual to MHAUS for information and counseling. Complete the Adverse Metabolic Reaction to Anesthesia form for enrollment in the North American MH Registry.
Refer the individual to a MH diagnostic center for muscle biopsy and contracture testing after discussion with MH consultants associated with MHAUS.
• Initial dose is 2.5 mg/kg IV.
• Initial dose of dantrolene sodium should be repeated every 10 min (or as often as possible if administration takes >10 min).
• Suggested upper limit is 10 mg/kg; however, more may be given as needed.
• Dantrolene should be repeated until cardiac & respiratory systems stabilize.
• Tachycardia, hypercarbia, & muscle rigidity respond rapidly.
• Toxicity profile of dantrolene is extremely benign.
• Ca channel blocking agents should not be administered w/dantrolene because life-threatening hyperkalemia may result.
• Dantrolene may aggravate previously existing muscle weakness.
• Discontinue use of potent inhalation agents and succinylcholine.
• Increase minute ventilation to lower end-tidal carbon dioxide (CO
• Get help. One resource is the Malignant Hyperthermia Association of the US (MHAUS) hotline for acute cases: 800-MH-HYPER (800-644-9737). Similar hotlines exist in other countries, specifically the UK, Germany, and Brazil.
• Begin cooling measures. If the individual is hyperthermic, administer iced solutions, ice packs to groin, axilla, and neck, nasogastric lavage with iced solution, or more aggressive measures as needed. Monitor body temperature every 30 minutes. Stop cooling measures at core body temperature of 38.5 °C.
• Treat cardiac arrhythmias as needed. Do not use calcium channel blockers.
• Obtain blood gases, serum concentration of electrolytes and creatine kinase (CK), blood and urine for myoglobin, and coagulation profile (international normalized ratio [INR], partial thromboplastin time [PTT], D-dimer) every six to 12 hours. The earliest sign of rhabdomyolysis is myoglobinuria/myoglobinemia. Serum CK levels may not rise for several hours. Serum CK concentration may remain elevated for days and should be monitored until it returns to normal.
• Treat hyperkalemia with hyperventilation, glucose and insulin, and calcium as dictated by laboratory and cardiovascular changes.
• Ensure urine output of 2.0 mL/kg per hour with mannitol, furosemide, and fluids as needed.
• Evaluate need for invasive monitoring and continued mechanical ventilation.
• Observe the individual in an ICU for at least 24-36 hours because of the 25% chance of recrudescence following initial treatment [
• Affected individuals who display extreme hyperthermia are at risk for disseminated intravascular coagulation. A coagulation profile (INR, PTT, D-dimer) should be obtained on all individuals experiencing fulminant MH.
• Refer the affected individual to MHAUS for information and counseling. Complete the Adverse Metabolic Reaction to Anesthesia form for enrollment in the North American MH Registry.
• Refer the individual to a MH diagnostic center for muscle biopsy and contracture testing after discussion with MH consultants associated with MHAUS.
## Targeted Therapy
Malignant Hyperthermia Susceptibility: Targeted Therapy
Initial dose is 2.5 mg/kg IV.
Initial dose of dantrolene sodium should be repeated every 10 min (or as often as possible if administration takes >10 min).
Suggested upper limit is 10 mg/kg; however, more may be given as needed.
Dantrolene should be repeated until cardiac & respiratory systems stabilize.
Tachycardia, hypercarbia, & muscle rigidity respond rapidly.
Toxicity profile of dantrolene is extremely benign.
Ca channel blocking agents should not be administered w/dantrolene because life-threatening hyperkalemia may result.
Dantrolene may aggravate previously existing muscle weakness.
Ca = calcium; IV = intravenous
Dantrolene sodium is a hydantoin molecule that binds to a specific region of the ryanodine receptor 1 channel. It decreases the uncontrolled release of intracellular calcium [
Early diagnosis of malignant hyperthermia (MH), together with the administration of dantrolene sodium, is essential in the successful treatment of an acute episode of MH.
Discontinue use of potent inhalation agents and succinylcholine.
Increase minute ventilation to lower end-tidal carbon dioxide (CO
Get help. One resource is the Malignant Hyperthermia Association of the US (MHAUS) hotline for acute cases: 800-MH-HYPER (800-644-9737). Similar hotlines exist in other countries, specifically the UK, Germany, and Brazil.
Begin cooling measures. If the individual is hyperthermic, administer iced solutions, ice packs to groin, axilla, and neck, nasogastric lavage with iced solution, or more aggressive measures as needed. Monitor body temperature every 30 minutes. Stop cooling measures at core body temperature of 38.5 °C.
Treat cardiac arrhythmias as needed. Do not use calcium channel blockers.
Obtain blood gases, serum concentration of electrolytes and creatine kinase (CK), blood and urine for myoglobin, and coagulation profile (international normalized ratio [INR], partial thromboplastin time [PTT], D-dimer) every six to 12 hours. The earliest sign of rhabdomyolysis is myoglobinuria/myoglobinemia. Serum CK levels may not rise for several hours. Serum CK concentration may remain elevated for days and should be monitored until it returns to normal.
Treat hyperkalemia with hyperventilation, glucose and insulin, and calcium as dictated by laboratory and cardiovascular changes.
Ensure urine output of 2.0 mL/kg per hour with mannitol, furosemide, and fluids as needed.
Evaluate need for invasive monitoring and continued mechanical ventilation.
Observe the individual in an ICU for at least 24-36 hours because of the 25% chance of recrudescence following initial treatment [
Affected individuals who display extreme hyperthermia are at risk for disseminated intravascular coagulation. A coagulation profile (INR, PTT, D-dimer) should be obtained on all individuals experiencing fulminant MH.
Refer the affected individual to MHAUS for information and counseling. Complete the Adverse Metabolic Reaction to Anesthesia form for enrollment in the North American MH Registry.
Refer the individual to a MH diagnostic center for muscle biopsy and contracture testing after discussion with MH consultants associated with MHAUS.
• Initial dose is 2.5 mg/kg IV.
• Initial dose of dantrolene sodium should be repeated every 10 min (or as often as possible if administration takes >10 min).
• Suggested upper limit is 10 mg/kg; however, more may be given as needed.
• Dantrolene should be repeated until cardiac & respiratory systems stabilize.
• Tachycardia, hypercarbia, & muscle rigidity respond rapidly.
• Toxicity profile of dantrolene is extremely benign.
• Ca channel blocking agents should not be administered w/dantrolene because life-threatening hyperkalemia may result.
• Dantrolene may aggravate previously existing muscle weakness.
• Discontinue use of potent inhalation agents and succinylcholine.
• Increase minute ventilation to lower end-tidal carbon dioxide (CO
• Get help. One resource is the Malignant Hyperthermia Association of the US (MHAUS) hotline for acute cases: 800-MH-HYPER (800-644-9737). Similar hotlines exist in other countries, specifically the UK, Germany, and Brazil.
• Begin cooling measures. If the individual is hyperthermic, administer iced solutions, ice packs to groin, axilla, and neck, nasogastric lavage with iced solution, or more aggressive measures as needed. Monitor body temperature every 30 minutes. Stop cooling measures at core body temperature of 38.5 °C.
• Treat cardiac arrhythmias as needed. Do not use calcium channel blockers.
• Obtain blood gases, serum concentration of electrolytes and creatine kinase (CK), blood and urine for myoglobin, and coagulation profile (international normalized ratio [INR], partial thromboplastin time [PTT], D-dimer) every six to 12 hours. The earliest sign of rhabdomyolysis is myoglobinuria/myoglobinemia. Serum CK levels may not rise for several hours. Serum CK concentration may remain elevated for days and should be monitored until it returns to normal.
• Treat hyperkalemia with hyperventilation, glucose and insulin, and calcium as dictated by laboratory and cardiovascular changes.
• Ensure urine output of 2.0 mL/kg per hour with mannitol, furosemide, and fluids as needed.
• Evaluate need for invasive monitoring and continued mechanical ventilation.
• Observe the individual in an ICU for at least 24-36 hours because of the 25% chance of recrudescence following initial treatment [
• Affected individuals who display extreme hyperthermia are at risk for disseminated intravascular coagulation. A coagulation profile (INR, PTT, D-dimer) should be obtained on all individuals experiencing fulminant MH.
• Refer the affected individual to MHAUS for information and counseling. Complete the Adverse Metabolic Reaction to Anesthesia form for enrollment in the North American MH Registry.
• Refer the individual to a MH diagnostic center for muscle biopsy and contracture testing after discussion with MH consultants associated with MHAUS.
## Prevention of Primary Manifestations
Preventive measures for individuals known to be susceptible to MH:
For any individual undergoing anesthesia, obtain a thorough anesthetic history to determine the possibility of the individual or a family member having experienced an MH episode. When suspicion of MHS exists, family members should not be given trigger anesthetic agents (i.e., potent volatile anesthetic agents such as halothane, sevoflurane, desflurane, enflurane, and isoflurane or the depolarizing agent succinylcholine).
In general, individuals undergoing general anesthesia that exceeds 30 minutes in duration should have their temperature monitored using an electronic temperature probe. Skin liquid crystal temperature sensors are not recommended as they have been found to be unreliable indicators of changing temperature during MH events.
Individuals with any form of myotonia (see
Individuals with central core disease (OMIM
Individuals with MHS should carry proper identification as to their susceptibility; identification bracelets are available through the
• For any individual undergoing anesthesia, obtain a thorough anesthetic history to determine the possibility of the individual or a family member having experienced an MH episode. When suspicion of MHS exists, family members should not be given trigger anesthetic agents (i.e., potent volatile anesthetic agents such as halothane, sevoflurane, desflurane, enflurane, and isoflurane or the depolarizing agent succinylcholine).
• In general, individuals undergoing general anesthesia that exceeds 30 minutes in duration should have their temperature monitored using an electronic temperature probe. Skin liquid crystal temperature sensors are not recommended as they have been found to be unreliable indicators of changing temperature during MH events.
• Individuals with any form of myotonia (see
• Individuals with central core disease (OMIM
• Individuals with MHS should carry proper identification as to their susceptibility; identification bracelets are available through the
## Agents/Circumstances to Avoid
Individuals with MHS should avoid potent inhalation anesthetics and succinylcholine.
Calcium channel blockers should not be given together with dantrolene because life-threatening hyperkalemia may result.
Serotonin antagonist (5-HT3 antagonist) antiemetics should be used cautiously, as sudden death has been reported in a child with multiminicore disease caused by a pathogenic variant in
Individuals with MHS are generally advised to avoid extremes of heat but not to restrict athletic activity or lifestyle unless they have experienced overt rhabdomyolysis and/or heat stroke. Strenuous activities at high ambient temperatures should be avoided or performed with caution.
In individuals with MHS undergoing cardiac bypass surgery, aggressive rewarming should be avoided, as it may be associated with development of clinical signs of MH [
## Evaluation of Relatives at Risk
It is appropriate to clarify the status of at-risk relatives of an individual diagnosed with MHS to identify those who also have an increased susceptibility to MH and thus would benefit from avoiding anesthetic agents that increase the risk for an MH episode. Evaluations include the following:
See
## Pregnancy Management
If a pregnant woman with MHS requires non-emergent surgery during the pregnancy, a non-triggering anesthetic (local, nerve block, epidural, spinal anesthesia, or a total intravenous general anesthetic) should be administered. Standard American Society of Anesthesiologists mandated monitoring should be used, along with core temperature monitoring. Fetal monitoring should follow standard guidelines. Dantrolene should not be administered in preparation for surgery or labor and delivery.
Continuous epidural analgesia is highly recommended for labor and delivery. If a cesarean delivery is indicated in a woman who does not have an epidural catheter in place, neuraxial (spinal, epidural, or combined spinal-epidural) anesthesia is recommended, if not otherwise contraindicated. If a general anesthetic is indicated, a total intravenous anesthetic technique should be administered, with an anesthesia machine that has been prepared for an individual with MHS.
In the case of a fetus whose father has MHS but whose mother is not known to have MHS, regional anesthesia or general anesthesia without trigger agents is recommended. This is because administration of a triggering agent (specifically volatile anesthetics that can cross the placenta) to the unaffected mother can trigger an MH reaction in an affected fetus, which could be severe or fatal to the fetus.
For further information regarding the management of pregnant women with MHS, see 2009
## Therapies Under Investigations
Various agents (i.e., salbutamol, pyridostigmine, and N-acetylcysteine) have been investigated as potential treatments for
Rycal
Search
## Genetic Counseling
Malignant hyperthermia susceptibility (MHS) is inherited in an autosomal dominant manner.
Note: Genetic counseling for myopathic disorders that predispose to classic malignant hyperthermia (MH) is not addressed in this section (see
Most individuals diagnosed with MHS have a parent with MHS, although the parent may not have experienced an episode of MH.
An individual diagnosed with MHS may have the disorder as the result of a
If neither parent is known to have MHS, evaluation of the parents is recommended to inform recurrence risk counseling and assess their risk for MH. Evaluations include:
Molecular genetic testing using a multigene panel (as described in
Muscle contracture testing (performed at an MH muscle biopsy center) (see
If a molecular diagnosis has been established in the proband, the MHS-causative pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
The family history of some individuals diagnosed with MHS may appear to be negative because of reduced penetrance of the MHS-causative pathogenic variant or absence of a triggering event in heterozygous family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations have been performed on the parents of the proband.
If a parent of the proband has MHS and/or is known to have an MHS-causative pathogenic variant, the risk to the sibs of having MHS is 50%.
If the proband has a known MHS-causative pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the risk to the sibs of inheriting the pathogenic variant is estimated to be 1% because of the possibility of parental gonadal mosaicism [
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
If an MHS-causative variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with MHS have a parent with MHS, although the parent may not have experienced an episode of MH.
• An individual diagnosed with MHS may have the disorder as the result of a
• If neither parent is known to have MHS, evaluation of the parents is recommended to inform recurrence risk counseling and assess their risk for MH. Evaluations include:
• Molecular genetic testing using a multigene panel (as described in
• Muscle contracture testing (performed at an MH muscle biopsy center) (see
• Molecular genetic testing using a multigene panel (as described in
• Muscle contracture testing (performed at an MH muscle biopsy center) (see
• If a molecular diagnosis has been established in the proband, the MHS-causative pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with MHS may appear to be negative because of reduced penetrance of the MHS-causative pathogenic variant or absence of a triggering event in heterozygous family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations have been performed on the parents of the proband.
• Molecular genetic testing using a multigene panel (as described in
• Muscle contracture testing (performed at an MH muscle biopsy center) (see
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband has MHS and/or is known to have an MHS-causative pathogenic variant, the risk to the sibs of having MHS is 50%.
• If the proband has a known MHS-causative pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the risk to the sibs of inheriting the pathogenic variant is estimated to be 1% because of the possibility of parental gonadal mosaicism [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Malignant hyperthermia susceptibility (MHS) is inherited in an autosomal dominant manner.
Note: Genetic counseling for myopathic disorders that predispose to classic malignant hyperthermia (MH) is not addressed in this section (see
## Risk to Family Members
Most individuals diagnosed with MHS have a parent with MHS, although the parent may not have experienced an episode of MH.
An individual diagnosed with MHS may have the disorder as the result of a
If neither parent is known to have MHS, evaluation of the parents is recommended to inform recurrence risk counseling and assess their risk for MH. Evaluations include:
Molecular genetic testing using a multigene panel (as described in
Muscle contracture testing (performed at an MH muscle biopsy center) (see
If a molecular diagnosis has been established in the proband, the MHS-causative pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
The family history of some individuals diagnosed with MHS may appear to be negative because of reduced penetrance of the MHS-causative pathogenic variant or absence of a triggering event in heterozygous family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations have been performed on the parents of the proband.
If a parent of the proband has MHS and/or is known to have an MHS-causative pathogenic variant, the risk to the sibs of having MHS is 50%.
If the proband has a known MHS-causative pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the risk to the sibs of inheriting the pathogenic variant is estimated to be 1% because of the possibility of parental gonadal mosaicism [
• Most individuals diagnosed with MHS have a parent with MHS, although the parent may not have experienced an episode of MH.
• An individual diagnosed with MHS may have the disorder as the result of a
• If neither parent is known to have MHS, evaluation of the parents is recommended to inform recurrence risk counseling and assess their risk for MH. Evaluations include:
• Molecular genetic testing using a multigene panel (as described in
• Muscle contracture testing (performed at an MH muscle biopsy center) (see
• Molecular genetic testing using a multigene panel (as described in
• Muscle contracture testing (performed at an MH muscle biopsy center) (see
• If a molecular diagnosis has been established in the proband, the MHS-causative pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with MHS may appear to be negative because of reduced penetrance of the MHS-causative pathogenic variant or absence of a triggering event in heterozygous family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations have been performed on the parents of the proband.
• Molecular genetic testing using a multigene panel (as described in
• Muscle contracture testing (performed at an MH muscle biopsy center) (see
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband has MHS and/or is known to have an MHS-causative pathogenic variant, the risk to the sibs of having MHS is 50%.
• If the proband has a known MHS-causative pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the risk to the sibs of inheriting the pathogenic variant is estimated to be 1% because of the possibility of parental gonadal mosaicism [
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
If an MHS-causative variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
## Molecular Genetics
Nonsyndromic Malignant Hyperthermia Susceptibility: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Nonsyndromic Malignant Hyperthermia Susceptibility (
Changes in intracellular calcium levels in skeletal muscle are largely controlled through calcium storage, release, and reuptake via the sarcoplasmic reticulum (SR), the primary intracellular calcium storage and release organelle in muscle. Ryanodine receptor 1 (RYR1), encoded by
In MHS, pathogenic variants in
Dantrolene sodium inhibits RYR1 calcium release/leak from the SR and thus reverses the process.
The consequence of
Measurement of calcium release in response to trigger agents in HEK293 cells [
Measurement of calcium release in response to trigger agents in myotubes derived from dyspedic (
In addition, MHS diagnosis can be established by calcium measurements and ligand-binding studies of the following preparation derived from affected individuals:
Myotubes [
Microsomal SR preparations from muscle biopsy [
Microsomal SR preparations from lymphoblasts [
All assays should be performed on samples from at least two independent affected individuals with the same variant.
Individuals with MHS with a positive halothane contracture response but not a positive caffeine contracture response exhibit a high incidence of both musculoskeletal clinical symptoms (e.g., weakness/fatigue, pain/cramps, sensitivity to heat or exercise, hyperCKemia, and altered histopathology) and abnormal calcium events in muscle [
An in vitro caffeine-induced Ca
In addition to pathogenic
Exon 91 of
Pathogenic Variants Referenced in This
EHS = exertional heat stress; ER = exercise-induced rhabdomyolysis; MHS = malignant hyperthermia susceptibility
Variants listed in the table have been provided by the authors.
• Measurement of calcium release in response to trigger agents in HEK293 cells [
• Measurement of calcium release in response to trigger agents in myotubes derived from dyspedic (
• Myotubes [
• Microsomal SR preparations from muscle biopsy [
• Microsomal SR preparations from lymphoblasts [
## Molecular Pathogenesis
Changes in intracellular calcium levels in skeletal muscle are largely controlled through calcium storage, release, and reuptake via the sarcoplasmic reticulum (SR), the primary intracellular calcium storage and release organelle in muscle. Ryanodine receptor 1 (RYR1), encoded by
In MHS, pathogenic variants in
Dantrolene sodium inhibits RYR1 calcium release/leak from the SR and thus reverses the process.
The consequence of
Measurement of calcium release in response to trigger agents in HEK293 cells [
Measurement of calcium release in response to trigger agents in myotubes derived from dyspedic (
In addition, MHS diagnosis can be established by calcium measurements and ligand-binding studies of the following preparation derived from affected individuals:
Myotubes [
Microsomal SR preparations from muscle biopsy [
Microsomal SR preparations from lymphoblasts [
All assays should be performed on samples from at least two independent affected individuals with the same variant.
Individuals with MHS with a positive halothane contracture response but not a positive caffeine contracture response exhibit a high incidence of both musculoskeletal clinical symptoms (e.g., weakness/fatigue, pain/cramps, sensitivity to heat or exercise, hyperCKemia, and altered histopathology) and abnormal calcium events in muscle [
An in vitro caffeine-induced Ca
In addition to pathogenic
Exon 91 of
Pathogenic Variants Referenced in This
EHS = exertional heat stress; ER = exercise-induced rhabdomyolysis; MHS = malignant hyperthermia susceptibility
Variants listed in the table have been provided by the authors.
• Measurement of calcium release in response to trigger agents in HEK293 cells [
• Measurement of calcium release in response to trigger agents in myotubes derived from dyspedic (
• Myotubes [
• Microsomal SR preparations from muscle biopsy [
• Microsomal SR preparations from lymphoblasts [
## Chapter Notes
Sheila Riazi (
Sheila Riazi and Leslie Biesecker (
The authors are supported by grants from the National Institutes of Health (R01AR082209 and R01AR078000 to RTD and HG200328-19 and HG200388-11 to LGB) and University of Toronto (Department of Anesthesiology and Pain Medicine Merit award to SR).
Leslie G Biesecker, MD (2025-present)Robert T Dirksen, PhD (2006-present)Sheila Riazi, MD (2013-present)Henry Rosenberg, MD (2003-present) Nyamkhishig Sambuughin, PhD; Henry M Jackson Foundation (2003-2006; 2010-2025)
7 August 2025 (sw) Comprehensive update posted live
16 January 2020 (sw) Comprehensive update posted live
31 January 2013 (me) Comprehensive update posted live
19 January 2010 (me) Comprehensive update posted live
12 May 2006 (me) Comprehensive update posted live
19 December 2003 (me) Review posted live
19 June 2003 (hr) Original submission
• 7 August 2025 (sw) Comprehensive update posted live
• 16 January 2020 (sw) Comprehensive update posted live
• 31 January 2013 (me) Comprehensive update posted live
• 19 January 2010 (me) Comprehensive update posted live
• 12 May 2006 (me) Comprehensive update posted live
• 19 December 2003 (me) Review posted live
• 19 June 2003 (hr) Original submission
## Author Notes
Sheila Riazi (
Sheila Riazi and Leslie Biesecker (
## Acknowledgments
The authors are supported by grants from the National Institutes of Health (R01AR082209 and R01AR078000 to RTD and HG200328-19 and HG200388-11 to LGB) and University of Toronto (Department of Anesthesiology and Pain Medicine Merit award to SR).
## Author History
Leslie G Biesecker, MD (2025-present)Robert T Dirksen, PhD (2006-present)Sheila Riazi, MD (2013-present)Henry Rosenberg, MD (2003-present) Nyamkhishig Sambuughin, PhD; Henry M Jackson Foundation (2003-2006; 2010-2025)
## Revision History
7 August 2025 (sw) Comprehensive update posted live
16 January 2020 (sw) Comprehensive update posted live
31 January 2013 (me) Comprehensive update posted live
19 January 2010 (me) Comprehensive update posted live
12 May 2006 (me) Comprehensive update posted live
19 December 2003 (me) Review posted live
19 June 2003 (hr) Original submission
• 7 August 2025 (sw) Comprehensive update posted live
• 16 January 2020 (sw) Comprehensive update posted live
• 31 January 2013 (me) Comprehensive update posted live
• 19 January 2010 (me) Comprehensive update posted live
• 12 May 2006 (me) Comprehensive update posted live
• 19 December 2003 (me) Review posted live
• 19 June 2003 (hr) Original submission
## Key Sections in This
## References
Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018;65:709-21. [
See also guidelines on
Hopkins PM, Gupta PK, Bilmen JG. Malignant hyperthermia. Handb Clin Neurol. 2018;157:645-61. [
Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KP, Ellis FR, Müller CR, Urwyler A, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531-9. [
Glahn KPE, Girard T, Hellblom A, Hopkins PM, Johannsen S, Rüffert H, Snoeck MM, Urwyler A; European Malignant Hyperthermia Group. Recognition and management of a malignant hyperthermia crisis: updated 2024 guideline from the European Malignant Hyperthermia Group. Br J Anaesth. 2025;134:221-3. [
Larach MG, Dirksen SJ, Belani KG, Brandom BW, Metz KM, Policastro MA, Rosenberg H, Valedon A, Watson CB. Creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities. Anesth Analg. 2012;114:94-100. [
Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018a;65:709-21.
Rüffert H, Bastian B, Bendixen D, Girard T, Heiderich S, Hellblom A, Hopkins PM, Johannsen S, Snoeck MM, Urwyler A, Glahn KPE; European Malignant Hyperthermia Group. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021;126:120-30. [
MHAUS. Adverse effects of heat and exercise in relation to MH susceptibility. Available
MHAUS. MH susceptibility and operating room personnel. Available
MHAUS. Mitochondrial myopathies and malignant hyperthermia susceptibility. Available
MHAUS. Parturient with MHS partner. Available
MHAUS. Preparation of anesthesia workstations to anesthetize MH-susceptible patients. Available
MHAUS. Temperature monitoring during surgical procedures. Available
• Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018;65:709-21. [
• See also guidelines on
• Hopkins PM, Gupta PK, Bilmen JG. Malignant hyperthermia. Handb Clin Neurol. 2018;157:645-61. [
• Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KP, Ellis FR, Müller CR, Urwyler A, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531-9. [
• Glahn KPE, Girard T, Hellblom A, Hopkins PM, Johannsen S, Rüffert H, Snoeck MM, Urwyler A; European Malignant Hyperthermia Group. Recognition and management of a malignant hyperthermia crisis: updated 2024 guideline from the European Malignant Hyperthermia Group. Br J Anaesth. 2025;134:221-3. [
• Larach MG, Dirksen SJ, Belani KG, Brandom BW, Metz KM, Policastro MA, Rosenberg H, Valedon A, Watson CB. Creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities. Anesth Analg. 2012;114:94-100. [
• Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018a;65:709-21.
• Rüffert H, Bastian B, Bendixen D, Girard T, Heiderich S, Hellblom A, Hopkins PM, Johannsen S, Snoeck MM, Urwyler A, Glahn KPE; European Malignant Hyperthermia Group. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021;126:120-30. [
• MHAUS. Adverse effects of heat and exercise in relation to MH susceptibility. Available
• MHAUS. MH susceptibility and operating room personnel. Available
• MHAUS. Mitochondrial myopathies and malignant hyperthermia susceptibility. Available
• MHAUS. Parturient with MHS partner. Available
• MHAUS. Preparation of anesthesia workstations to anesthetize MH-susceptible patients. Available
• MHAUS. Temperature monitoring during surgical procedures. Available
## Published Guidelines / Consensus Statements
Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018;65:709-21. [
See also guidelines on
Hopkins PM, Gupta PK, Bilmen JG. Malignant hyperthermia. Handb Clin Neurol. 2018;157:645-61. [
Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KP, Ellis FR, Müller CR, Urwyler A, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531-9. [
Glahn KPE, Girard T, Hellblom A, Hopkins PM, Johannsen S, Rüffert H, Snoeck MM, Urwyler A; European Malignant Hyperthermia Group. Recognition and management of a malignant hyperthermia crisis: updated 2024 guideline from the European Malignant Hyperthermia Group. Br J Anaesth. 2025;134:221-3. [
Larach MG, Dirksen SJ, Belani KG, Brandom BW, Metz KM, Policastro MA, Rosenberg H, Valedon A, Watson CB. Creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities. Anesth Analg. 2012;114:94-100. [
Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018a;65:709-21.
Rüffert H, Bastian B, Bendixen D, Girard T, Heiderich S, Hellblom A, Hopkins PM, Johannsen S, Snoeck MM, Urwyler A, Glahn KPE; European Malignant Hyperthermia Group. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021;126:120-30. [
MHAUS. Adverse effects of heat and exercise in relation to MH susceptibility. Available
MHAUS. MH susceptibility and operating room personnel. Available
MHAUS. Mitochondrial myopathies and malignant hyperthermia susceptibility. Available
MHAUS. Parturient with MHS partner. Available
MHAUS. Preparation of anesthesia workstations to anesthetize MH-susceptible patients. Available
MHAUS. Temperature monitoring during surgical procedures. Available
• Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018;65:709-21. [
• See also guidelines on
• Hopkins PM, Gupta PK, Bilmen JG. Malignant hyperthermia. Handb Clin Neurol. 2018;157:645-61. [
• Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KP, Ellis FR, Müller CR, Urwyler A, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531-9. [
• Glahn KPE, Girard T, Hellblom A, Hopkins PM, Johannsen S, Rüffert H, Snoeck MM, Urwyler A; European Malignant Hyperthermia Group. Recognition and management of a malignant hyperthermia crisis: updated 2024 guideline from the European Malignant Hyperthermia Group. Br J Anaesth. 2025;134:221-3. [
• Larach MG, Dirksen SJ, Belani KG, Brandom BW, Metz KM, Policastro MA, Rosenberg H, Valedon A, Watson CB. Creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities. Anesth Analg. 2012;114:94-100. [
• Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018a;65:709-21.
• Rüffert H, Bastian B, Bendixen D, Girard T, Heiderich S, Hellblom A, Hopkins PM, Johannsen S, Snoeck MM, Urwyler A, Glahn KPE; European Malignant Hyperthermia Group. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021;126:120-30. [
• MHAUS. Adverse effects of heat and exercise in relation to MH susceptibility. Available
• MHAUS. MH susceptibility and operating room personnel. Available
• MHAUS. Mitochondrial myopathies and malignant hyperthermia susceptibility. Available
• MHAUS. Parturient with MHS partner. Available
• MHAUS. Preparation of anesthesia workstations to anesthetize MH-susceptible patients. Available
• MHAUS. Temperature monitoring during surgical procedures. Available
## North American Guidelines for Testing
Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018;65:709-21. [
See also guidelines on
• Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018;65:709-21. [
• See also guidelines on
## European Guidelines for Testing
Hopkins PM, Gupta PK, Bilmen JG. Malignant hyperthermia. Handb Clin Neurol. 2018;157:645-61. [
Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KP, Ellis FR, Müller CR, Urwyler A, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531-9. [
• Hopkins PM, Gupta PK, Bilmen JG. Malignant hyperthermia. Handb Clin Neurol. 2018;157:645-61. [
• Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KP, Ellis FR, Müller CR, Urwyler A, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531-9. [
## Guidelines on Diagnosis, Management, and Transfer of Care from Ambulatory Surgery Centers
Glahn KPE, Girard T, Hellblom A, Hopkins PM, Johannsen S, Rüffert H, Snoeck MM, Urwyler A; European Malignant Hyperthermia Group. Recognition and management of a malignant hyperthermia crisis: updated 2024 guideline from the European Malignant Hyperthermia Group. Br J Anaesth. 2025;134:221-3. [
Larach MG, Dirksen SJ, Belani KG, Brandom BW, Metz KM, Policastro MA, Rosenberg H, Valedon A, Watson CB. Creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities. Anesth Analg. 2012;114:94-100. [
Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018a;65:709-21.
Rüffert H, Bastian B, Bendixen D, Girard T, Heiderich S, Hellblom A, Hopkins PM, Johannsen S, Snoeck MM, Urwyler A, Glahn KPE; European Malignant Hyperthermia Group. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021;126:120-30. [
• Glahn KPE, Girard T, Hellblom A, Hopkins PM, Johannsen S, Rüffert H, Snoeck MM, Urwyler A; European Malignant Hyperthermia Group. Recognition and management of a malignant hyperthermia crisis: updated 2024 guideline from the European Malignant Hyperthermia Group. Br J Anaesth. 2025;134:221-3. [
• Larach MG, Dirksen SJ, Belani KG, Brandom BW, Metz KM, Policastro MA, Rosenberg H, Valedon A, Watson CB. Creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities. Anesth Analg. 2012;114:94-100. [
• Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018a;65:709-21.
• Rüffert H, Bastian B, Bendixen D, Girard T, Heiderich S, Hellblom A, Hopkins PM, Johannsen S, Snoeck MM, Urwyler A, Glahn KPE; European Malignant Hyperthermia Group. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021;126:120-30. [
## North American Recommendations
MHAUS. Adverse effects of heat and exercise in relation to MH susceptibility. Available
MHAUS. MH susceptibility and operating room personnel. Available
MHAUS. Mitochondrial myopathies and malignant hyperthermia susceptibility. Available
MHAUS. Parturient with MHS partner. Available
MHAUS. Preparation of anesthesia workstations to anesthetize MH-susceptible patients. Available
MHAUS. Temperature monitoring during surgical procedures. Available
• MHAUS. Adverse effects of heat and exercise in relation to MH susceptibility. Available
• MHAUS. MH susceptibility and operating room personnel. Available
• MHAUS. Mitochondrial myopathies and malignant hyperthermia susceptibility. Available
• MHAUS. Parturient with MHS partner. Available
• MHAUS. Preparation of anesthesia workstations to anesthetize MH-susceptible patients. Available
• MHAUS. Temperature monitoring during surgical procedures. Available
## Literature Cited
Clinical features of malignant hyperthermia susceptibility
Note: Early diagnosis and rapid therapy are both lifesaving and lead to a reduction of clinical symptoms.
Adapted from
MHAUS treatment guide for malignant hyperthermia
Copyright, The Malignant Hyperthermia Association of the United States (MHAUS)
|
[] |
19/12/2003
|
7/8/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
miccap-ms
|
miccap-ms
|
[
"MIC-CAP Syndrome",
"MIC-CAP Syndrome",
"STAM-binding protein",
"STAMBP",
"Microcephaly-Capillary Malformation Syndrome"
] |
Microcephaly-Capillary Malformation Syndrome
|
Melissa T Carter, Ghayda Mirzaa, Laura M McDonell, Kym M Boycott
|
Summary The defining clinical characteristics of the microcephaly-capillary malformation (MIC-CAP) syndrome are typically present at birth: microcephaly and generalized cutaneous capillary malformations (a few to hundreds of oval/circular macules or patches varying in size from 1-2 mm to several cm), hypoplastic distal phalanges of the hands and/or feet, early-onset intractable epilepsy, and profound developmental delay. Seizures, which can be focal, tonic, and complex partial and can include infantile spasms, appear to stabilize after age two years. Myoclonus of the limbs and eyelids is common; other abnormal movements (dyskinetic, choreiform) may be seen. To date, the diagnosis has been confirmed in 18 individuals from 15 families. The diagnosis of MIC-CAP syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in MIC-CAP syndrome is an autosomal recessive disorder caused by biallelic If both parents are known to be heterozygous for a If the proband has MIC-CAP syndrome as the result of uniparental isodisomy, only one parent is heterozygous for a Once the
|
## Diagnosis
No consensus clinical diagnostic criteria for microcephaly-capillary malformation (MIC-CAP) syndrome have been published.
MIC-CAP syndrome
Some may have an abnormal hair pattern in a "Mohawk" distribution (sparse laterally and longer along sagittal suture) and/or abnormal or multiple hair whorls.
Simplified gyral pattern (reduced number of gyri and shallow sulci) with increased extra-axial space and progressive cerebral atrophy is seen on brain imaging.
Cortical myelination may be reduced or abnormal.
Other common neuroimaging findings include hippocampal hypoplasia, thinning of the corpus callosum, hypoplasia of the optic nerves and/or optic chiasm and other malformations of cortical development.
The diagnosis of MIC-CAP syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and imaging findings suggest the diagnosis of MIC-CAP syndrome, molecular genetic testing approaches can include
Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
Uniparental isodisomy testing can be considered in probands who appear to be homozygous for a pathogenic variant that is heterozygous in one parent and not present in the other [
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by microcephaly and/or seizures,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Microcephaly-Capillary Malformation Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Various methods (e.g., SNP analysis, quantitative PCR, MLPA, massively parallel sequencing) can detect uniparental isodisomy. Testing may require parental blood specimens.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
•
• Some may have an abnormal hair pattern in a "Mohawk" distribution (sparse laterally and longer along sagittal suture) and/or abnormal or multiple hair whorls.
• Simplified gyral pattern (reduced number of gyri and shallow sulci) with increased extra-axial space and progressive cerebral atrophy is seen on brain imaging.
• Cortical myelination may be reduced or abnormal.
• Other common neuroimaging findings include hippocampal hypoplasia, thinning of the corpus callosum, hypoplasia of the optic nerves and/or optic chiasm and other malformations of cortical development.
• Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• Uniparental isodisomy testing can be considered in probands who appear to be homozygous for a pathogenic variant that is heterozygous in one parent and not present in the other [
• For an introduction to multigene panels click
## Suggestive Findings
MIC-CAP syndrome
Some may have an abnormal hair pattern in a "Mohawk" distribution (sparse laterally and longer along sagittal suture) and/or abnormal or multiple hair whorls.
Simplified gyral pattern (reduced number of gyri and shallow sulci) with increased extra-axial space and progressive cerebral atrophy is seen on brain imaging.
Cortical myelination may be reduced or abnormal.
Other common neuroimaging findings include hippocampal hypoplasia, thinning of the corpus callosum, hypoplasia of the optic nerves and/or optic chiasm and other malformations of cortical development.
•
• Some may have an abnormal hair pattern in a "Mohawk" distribution (sparse laterally and longer along sagittal suture) and/or abnormal or multiple hair whorls.
• Simplified gyral pattern (reduced number of gyri and shallow sulci) with increased extra-axial space and progressive cerebral atrophy is seen on brain imaging.
• Cortical myelination may be reduced or abnormal.
• Other common neuroimaging findings include hippocampal hypoplasia, thinning of the corpus callosum, hypoplasia of the optic nerves and/or optic chiasm and other malformations of cortical development.
## Establishing the Diagnosis
The diagnosis of MIC-CAP syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and imaging findings suggest the diagnosis of MIC-CAP syndrome, molecular genetic testing approaches can include
Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
Uniparental isodisomy testing can be considered in probands who appear to be homozygous for a pathogenic variant that is heterozygous in one parent and not present in the other [
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by microcephaly and/or seizures,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Microcephaly-Capillary Malformation Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Various methods (e.g., SNP analysis, quantitative PCR, MLPA, massively parallel sequencing) can detect uniparental isodisomy. Testing may require parental blood specimens.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• Uniparental isodisomy testing can be considered in probands who appear to be homozygous for a pathogenic variant that is heterozygous in one parent and not present in the other [
• For an introduction to multigene panels click
## Option 1
When the phenotypic and imaging findings suggest the diagnosis of MIC-CAP syndrome, molecular genetic testing approaches can include
Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
Uniparental isodisomy testing can be considered in probands who appear to be homozygous for a pathogenic variant that is heterozygous in one parent and not present in the other [
For an introduction to multigene panels click
• Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• Uniparental isodisomy testing can be considered in probands who appear to be homozygous for a pathogenic variant that is heterozygous in one parent and not present in the other [
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by microcephaly and/or seizures,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Microcephaly-Capillary Malformation Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Various methods (e.g., SNP analysis, quantitative PCR, MLPA, massively parallel sequencing) can detect uniparental isodisomy. Testing may require parental blood specimens.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
The defining clinical characteristics of the microcephaly-capillary malformation (MIC-CAP) syndrome are typically present at birth: microcephaly and generalized cutaneous capillary malformations, early-onset intractable epilepsy, and profound developmental delay [
Histologic examination shows dilated small-caliber vessels in the papillary dermis consistent with capillary malformations [
Multiple seizure types described include focal, tonic, and complex partial, as well as infantile spasms. Electroencephalogram shows diffuse epileptiform activity with frequent multifocal spikes, abnormally slow background activity, and/or burst suppression pattern.
In most individuals, seizures are refractory to anticonvulsant therapy and ketogenic diet. After age two years, the seizures may stabilize to some degree and fewer medications may be required to keep seizures under reasonable control.
Individuals are often not visually responsive; those tested have cortical visual impairment and/or optic atrophy.
Most have normal hearing by brain stem auditory evoked potential testing and respond to voice and music.
The majority require gastrostomy tube feeding because of poor swallowing mechanism, poor control of oral secretions, and/or aspiration with recurrent pneumonia. A few (3/18) have required tracheostomy for recurrent apnea and/or to manage secretions.
One individual with molecularly proven MIC-CAP syndrome has only moderate developmental delays (see
Myoclonus of limbs and eyelids is common (8/18 reported individuals) and tends to persist with age.
Dyskinetic and choreiform movements may also be seen in some individuals.
Optic atrophy (10/18 reported individuals)
Cortical vision impairment, roving eye movements, and nystagmus (reported in a few individuals)
Large anterior fontanelle at birth
Small size for gestational age (birth weight and length 2-4 SD below mean)
Postnatal growth deficiency and short stature
Sensorineural hearing impairment (1 individual)
Cerebellar angiomata (1 individual)
Cleft palate (1 individual)
Facial asymmetry due to bony deficiency of maxilla (1 individual)
Adrenal insufficiency (1 individual)
Hypoplastic scrotum and small testes (1 individual)
Kidney malformations (duplicated collecting system in 1 individual; unilateral dysplastic kidney in 1 individual) and vesicoureteral reflux
Structural cardiac defects such as ASD, VSD, PDA, PFO, and mild right ventricular hypertrophy (each reported in 1 individual)
Umbilical or inguinal hernia (2 sibs)
The effect of pathogenic variant(s) on the protein STAMBP likely influences the severity of the MIC-CAP syndrome phenotype, with complete absence of protein production leading to the most severe phenotypes.
One affected female had a milder phenotype with moderate developmental delay and a less severe form of epilepsy [
Prevalence is unknown. To date 18 affected individuals (including 3 sets of sibs) from 15 families worldwide have molecularly confirmed MIC-CAP syndrome.
Most reported individuals are of European descent; individuals from other ethnic backgrounds (African, Arab, Asian, and Polynesian) have also been reported.
• Myoclonus of limbs and eyelids is common (8/18 reported individuals) and tends to persist with age.
• Dyskinetic and choreiform movements may also be seen in some individuals.
• Optic atrophy (10/18 reported individuals)
• Cortical vision impairment, roving eye movements, and nystagmus (reported in a few individuals)
• Large anterior fontanelle at birth
• Small size for gestational age (birth weight and length 2-4 SD below mean)
• Postnatal growth deficiency and short stature
• Sensorineural hearing impairment (1 individual)
• Cerebellar angiomata (1 individual)
• Cleft palate (1 individual)
• Facial asymmetry due to bony deficiency of maxilla (1 individual)
• Adrenal insufficiency (1 individual)
• Hypoplastic scrotum and small testes (1 individual)
• Kidney malformations (duplicated collecting system in 1 individual; unilateral dysplastic kidney in 1 individual) and vesicoureteral reflux
• Structural cardiac defects such as ASD, VSD, PDA, PFO, and mild right ventricular hypertrophy (each reported in 1 individual)
• Umbilical or inguinal hernia (2 sibs)
## Clinical Description
The defining clinical characteristics of the microcephaly-capillary malformation (MIC-CAP) syndrome are typically present at birth: microcephaly and generalized cutaneous capillary malformations, early-onset intractable epilepsy, and profound developmental delay [
Histologic examination shows dilated small-caliber vessels in the papillary dermis consistent with capillary malformations [
Multiple seizure types described include focal, tonic, and complex partial, as well as infantile spasms. Electroencephalogram shows diffuse epileptiform activity with frequent multifocal spikes, abnormally slow background activity, and/or burst suppression pattern.
In most individuals, seizures are refractory to anticonvulsant therapy and ketogenic diet. After age two years, the seizures may stabilize to some degree and fewer medications may be required to keep seizures under reasonable control.
Individuals are often not visually responsive; those tested have cortical visual impairment and/or optic atrophy.
Most have normal hearing by brain stem auditory evoked potential testing and respond to voice and music.
The majority require gastrostomy tube feeding because of poor swallowing mechanism, poor control of oral secretions, and/or aspiration with recurrent pneumonia. A few (3/18) have required tracheostomy for recurrent apnea and/or to manage secretions.
One individual with molecularly proven MIC-CAP syndrome has only moderate developmental delays (see
Myoclonus of limbs and eyelids is common (8/18 reported individuals) and tends to persist with age.
Dyskinetic and choreiform movements may also be seen in some individuals.
Optic atrophy (10/18 reported individuals)
Cortical vision impairment, roving eye movements, and nystagmus (reported in a few individuals)
Large anterior fontanelle at birth
Small size for gestational age (birth weight and length 2-4 SD below mean)
Postnatal growth deficiency and short stature
Sensorineural hearing impairment (1 individual)
Cerebellar angiomata (1 individual)
Cleft palate (1 individual)
Facial asymmetry due to bony deficiency of maxilla (1 individual)
Adrenal insufficiency (1 individual)
Hypoplastic scrotum and small testes (1 individual)
Kidney malformations (duplicated collecting system in 1 individual; unilateral dysplastic kidney in 1 individual) and vesicoureteral reflux
Structural cardiac defects such as ASD, VSD, PDA, PFO, and mild right ventricular hypertrophy (each reported in 1 individual)
Umbilical or inguinal hernia (2 sibs)
• Myoclonus of limbs and eyelids is common (8/18 reported individuals) and tends to persist with age.
• Dyskinetic and choreiform movements may also be seen in some individuals.
• Optic atrophy (10/18 reported individuals)
• Cortical vision impairment, roving eye movements, and nystagmus (reported in a few individuals)
• Large anterior fontanelle at birth
• Small size for gestational age (birth weight and length 2-4 SD below mean)
• Postnatal growth deficiency and short stature
• Sensorineural hearing impairment (1 individual)
• Cerebellar angiomata (1 individual)
• Cleft palate (1 individual)
• Facial asymmetry due to bony deficiency of maxilla (1 individual)
• Adrenal insufficiency (1 individual)
• Hypoplastic scrotum and small testes (1 individual)
• Kidney malformations (duplicated collecting system in 1 individual; unilateral dysplastic kidney in 1 individual) and vesicoureteral reflux
• Structural cardiac defects such as ASD, VSD, PDA, PFO, and mild right ventricular hypertrophy (each reported in 1 individual)
• Umbilical or inguinal hernia (2 sibs)
## Genotype-Phenotype Correlations
The effect of pathogenic variant(s) on the protein STAMBP likely influences the severity of the MIC-CAP syndrome phenotype, with complete absence of protein production leading to the most severe phenotypes.
One affected female had a milder phenotype with moderate developmental delay and a less severe form of epilepsy [
## Prevalence
Prevalence is unknown. To date 18 affected individuals (including 3 sets of sibs) from 15 families worldwide have molecularly confirmed MIC-CAP syndrome.
Most reported individuals are of European descent; individuals from other ethnic backgrounds (African, Arab, Asian, and Polynesian) have also been reported.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Unlike individuals with MIC-CAP syndrome, individuals with CM-AVM syndrome are not microcephalic and do not have intractable epilepsy or neurologic impairment.
MIC-CAP syndrome is distinguished from primary autosomal recessive microcephaly by the presence of capillary malformations, intractable epilepsy, severe neurologic impairment, and distal limb anomalies.
## Management
No clinical practice guidelines for microcephaly-capillary malformation (MIC-CAP) syndrome have been published.
To establish the extent of disease and needs in an individual diagnosed with microcephaly-capillary malformation (MIC-CAP) syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Microcephaly-Capillary Malformation Syndrome
To incl brain MRI
EEG if seizures are a concern
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
To establish a baseline
To assess for hearing loss
Community or
Social work involvement for parental support;
Home nursing referral;
Pediatric palliative care consultation.
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Supportive care provided by multidisciplinary specialists including a medical geneticist, neurologist, feeding team, and developmental pediatrician is recommended.
Treatment of Manifestations in Individuals with Microcephaly-Capillary Malformation Syndrome
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy to optimize nutrition & weight gain
Gastrostomy tube placement may be required for persistent feeding issues &/or ↑ risk of aspiration.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
AED = antiepileptic drug; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Recommended Surveillance for Individuals with Microcephaly-Capillary Malformation Syndrome
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
OT = occupational therapy; PT = physical therapy
See
Search
• To incl brain MRI
• EEG if seizures are a concern
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
• To establish a baseline
• To assess for hearing loss
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Pediatric palliative care consultation.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy to optimize nutrition & weight gain
• Gastrostomy tube placement may be required for persistent feeding issues &/or ↑ risk of aspiration.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with microcephaly-capillary malformation (MIC-CAP) syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Microcephaly-Capillary Malformation Syndrome
To incl brain MRI
EEG if seizures are a concern
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
To establish a baseline
To assess for hearing loss
Community or
Social work involvement for parental support;
Home nursing referral;
Pediatric palliative care consultation.
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• To incl brain MRI
• EEG if seizures are a concern
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
• To establish a baseline
• To assess for hearing loss
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Pediatric palliative care consultation.
## Treatment of Manifestations
Supportive care provided by multidisciplinary specialists including a medical geneticist, neurologist, feeding team, and developmental pediatrician is recommended.
Treatment of Manifestations in Individuals with Microcephaly-Capillary Malformation Syndrome
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy to optimize nutrition & weight gain
Gastrostomy tube placement may be required for persistent feeding issues &/or ↑ risk of aspiration.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
AED = antiepileptic drug; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy to optimize nutrition & weight gain
• Gastrostomy tube placement may be required for persistent feeding issues &/or ↑ risk of aspiration.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Surveillance
Recommended Surveillance for Individuals with Microcephaly-Capillary Malformation Syndrome
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Microcephaly-capillary malformation (MIC-CAP) syndrome is an autosomal recessive disorder caused by biallelic
In most families, both parents of an affected child are carriers (i.e., heterozygotes) for a
Less commonly, only one parent is heterozygous for a
Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for a
And the child appears to have homozygous
And the child has compound heterozygous
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
If the proband has MIC-CAP syndrome as the result of uniparental isodisomy, only one parent is heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• In most families, both parents of an affected child are carriers (i.e., heterozygotes) for a
• Less commonly, only one parent is heterozygous for a
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• And the child appears to have homozygous
• And the child has compound heterozygous
• If both parents are known to be heterozygous for a
• If the proband has MIC-CAP syndrome as the result of uniparental isodisomy, only one parent is heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
Microcephaly-capillary malformation (MIC-CAP) syndrome is an autosomal recessive disorder caused by biallelic
## Risk to Family Members
In most families, both parents of an affected child are carriers (i.e., heterozygotes) for a
Less commonly, only one parent is heterozygous for a
Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for a
And the child appears to have homozygous
And the child has compound heterozygous
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
If the proband has MIC-CAP syndrome as the result of uniparental isodisomy, only one parent is heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• In most families, both parents of an affected child are carriers (i.e., heterozygotes) for a
• Less commonly, only one parent is heterozygous for a
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• And the child appears to have homozygous
• And the child has compound heterozygous
• If both parents are known to be heterozygous for a
• If the proband has MIC-CAP syndrome as the result of uniparental isodisomy, only one parent is heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Microcephaly-Capillary Malformation Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Microcephaly-Capillary Malformation Syndrome (
Observations of patient-derived cell lines suggest that ubiquitin-conjugated protein aggregation and ensuing progressive apoptosis as a potential mechanism for microcephaly. In addition, interrogation of several endpoints in the RAS-MAPK and PI3K-AKT-mTOR pathways has shown elevated and insensitive signal transduction in patient-derived cell lines. The constitutive activation of these two interconnected pathways as a result of impaired STAMBP function is believed to play a role in the vascular malformations and developmental characteristics typical of MIC-CAP syndrome [
## Molecular Pathogenesis
Observations of patient-derived cell lines suggest that ubiquitin-conjugated protein aggregation and ensuing progressive apoptosis as a potential mechanism for microcephaly. In addition, interrogation of several endpoints in the RAS-MAPK and PI3K-AKT-mTOR pathways has shown elevated and insensitive signal transduction in patient-derived cell lines. The constitutive activation of these two interconnected pathways as a result of impaired STAMBP function is believed to play a role in the vascular malformations and developmental characteristics typical of MIC-CAP syndrome [
## Chapter Notes
Dr Melissa Carter continues to collect clinical information about MIC-CAP syndrome. Through Dr Carter, families affected by MIC-CAP syndrome may connect with some of the families who made this research possible. Email: [email protected].
Dr Ghayda Mirzaa studies the developmental basis of developmental brain disorders with a particular focus on disorders of abnormal brain size at Seattle Children's Research Institute.
Dr Kym Boycott's research is focused on elucidating the molecular pathogenesis of rare inherited diseases using next-generation sequencing approaches. She leads two nationwide collaborative Canadian initiatives studying more than 1,000 rare disorders. For further information please visit
We thank the patients, their families, and our collaborators for their valuable contribution to research regarding this syndrome.
18 March 2021 (bp) Comprehensive update posted live
12 December 2013 (me) Review posted live
17 July 2013 (mtc) Original submission
• 18 March 2021 (bp) Comprehensive update posted live
• 12 December 2013 (me) Review posted live
• 17 July 2013 (mtc) Original submission
## Author Notes
Dr Melissa Carter continues to collect clinical information about MIC-CAP syndrome. Through Dr Carter, families affected by MIC-CAP syndrome may connect with some of the families who made this research possible. Email: [email protected].
Dr Ghayda Mirzaa studies the developmental basis of developmental brain disorders with a particular focus on disorders of abnormal brain size at Seattle Children's Research Institute.
Dr Kym Boycott's research is focused on elucidating the molecular pathogenesis of rare inherited diseases using next-generation sequencing approaches. She leads two nationwide collaborative Canadian initiatives studying more than 1,000 rare disorders. For further information please visit
## Acknowledgments
We thank the patients, their families, and our collaborators for their valuable contribution to research regarding this syndrome.
## Revision History
18 March 2021 (bp) Comprehensive update posted live
12 December 2013 (me) Review posted live
17 July 2013 (mtc) Original submission
• 18 March 2021 (bp) Comprehensive update posted live
• 12 December 2013 (me) Review posted live
• 17 July 2013 (mtc) Original submission
## References
## Literature Cited
|
[
"MT Carter, MT Geraghty, L De La Cruz, RR Reichard, L Boccuto, CE Schwartz, CL Clericuzio. A new syndrome with multiple capillary malformations, intractable seizures, and brain and limb anomalies.. Am J Med Genet. 2011;155A:301-6",
"CW Davies, LN Paul, M Kim, C Das. Structural and thermodynamic comparison of the catalytic domain of AMSH and AMSH-LP: nearly identical fold but different stability.. J Mol Biol. 2011;413:416-29",
"NS Demikova, VS Kakaulina, NL Pechatnikova, NA Polyakova, EY Zakharova, TD Krylova, MV Zubkova. First report of microcephaly-capillary malformations syndrome in Russia.. Egypt J Med Hum Genet. 2018;19:147-50",
"EA Faqeih, L Bastaki, RO Rosti, EG Spencer, AP Zada, MA Saleh, K Um, JG Gleeson. Novel STAMBP mutation and additional findings in an Arabic family.. Am J Med Genet A. 2015;167A:805-9",
"I Hori, F Miya, Y Negishi, A Hattori, N Ando, KA Boroevich, N Okamoto, M Kato, T Tsunoda, M Yamasaki, Y Kanemura, K Kosaki, S Saitoh. A novel homozygous missense mutation in the SH3-binding motif of STAMBP causing microcephaly-capillary malformation syndrome.. J Hum Genet. 2018;63:957-63",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"B Isidor, S Barbarot, C Beneteau, C Le Caignec, A David. Multiple capillary skin malformations, epilepsy, microcephaly, mental retardation, hypoplasia of the distal phalanges: report of a new case and further delineation of a new syndrome.. Am J Med Genet. 2011;155A:1458-60",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"J McCullough, PE Row, O Lorenzo, M Doherty, R Beynon, MJ Clague, S Urbé. Activation of the endosome-associated ubiquitin isopeptidase AMSH by STAM, a component of the multivesicular body-sorting machinery.. Curr Biol. 2006;16:160-5",
"LM McDonell, GM Mirzaa, D Alcantara, J Schwartzentruber, MT Carter, LJ Lee, CL Clericuzio, JM Graham, DJ Morris-Rosendahl, T Polster, G Acsadi, S Townshend, S Williams, A Halbert, B Isidor, A David, CD Smyser, AR Paciorkowski, M Willing, J Woulfe, S Das, CL Beaulieu, J Marcadier, MT Geraghty, BJ Frey, J Majewski, DE Bulman, WB Dobyns, M O'Driscoll, KM Boycott. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome.. Nature Genet. 2013;45:556-62",
"GM Mirzaa, RL Conway, KW Gripp, T Lerman-Sagie, DH Siegel, LS deVries, D Lev, N Kramer, E Hopkins, JM Graham, WB Dobyns. Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis.. Am J Med Genet A. 2012;158A:269-91",
"GM Mirzaa, AR Paciorkowski, CD Smyser, MC Willing, AC Lind, WB Dobyns. The microcephaly-capillary malformation syndrome.. Am J Med Genet. 2011;155A:2080-7",
"MI Naseer, S Sogaty, M Rasool, AG Chaudhary, YA Abutalib, S Walker, CR Marshall, D Merico, MT Carter, SW Scherer, MH Al-Qahtani, M Zarrei. Microcephaly-capillary malformation syndrome: Brothers with a homozygous STAMBP mutation, uncovered by exome sequencing.. Am J Med Genet A. 2016;170:3018-22",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"MI Sierra, MH Wright, PD Nash. AMSH interacts with ESCRT-0 to regulate the stability and trafficking of CXCR4.. J Biol Chem. 2010;285:13990-4004",
"N Tanaka, K Kaneko, H Asao, H Kasai, Y Endo, T Fujita, T Takeshita, K Sugamura. Possible involvement of a novel STAM-associated molecule 'AMSH' in intracellular signal transduction mediated by cytokines.. J Biol Chem. 1999;274:19129-35",
"HTH Tsang, JW Connell, SE Brown, A Thompson, E Reid, CM Sanderson. A systematic analysis of human CHMP protein interactions: Additional MIT domain-containing proteins bind to multiple components of the human ESCRT III complex.. Genomics. 2006;88:333-46",
"F Wu, Y Dai, J Wang, M Cheng, Y Wang, X Li, P Yuan, S Liao, L Jiang, J Chen, L Yan, M Zhong. Early‑onset epilepsy and microcephaly‑capillary malformation syndrome caused by a novel STAMBP mutation in a Chinese boy.. Mol Med Rep. 2019;20:5145-51"
] |
12/12/2013
|
18/3/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
microcephaly
|
microcephaly
|
[
"Abnormal spindle-like microcephaly-associated protein",
"ATR-interacting protein",
"CDK5 regulatory subunit-associated protein 2",
"Centromere protein J",
"Centrosomal protein of 135 kDa",
"Centrosomal protein of 152 kDa",
"Centrosomal protein of 63 kDa",
"Cyclin-dependent kinase 6",
"DNA endonuclease RBBP8",
"Kinetochore scaffold 1",
"Microcephalin",
"Ninein",
"Polyhomeotic-like protein 1",
"SCL-interrupting locus protein",
"Serine/threonine-protein kinase ATR",
"WD repeat-containing protein 62",
"ASPM",
"ATR",
"ATRIP",
"CDK5RAP2",
"CDK6",
"CENPJ",
"CEP135",
"CEP152",
"CEP63",
"KNL1",
"MCPH1",
"NIN",
"PHC1",
"RBBP8",
"STIL",
"WDR62",
"Primary Autosomal Recessive Microcephalies and Seckel Syndrome Spectrum Disorders"
] |
Primary Autosomal Recessive Microcephalies and Seckel Syndrome Spectrum Disorders – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Alain Verloes, Séverine Drunat, Pierre Gressens, Sandrine Passemard
|
Summary Primary autosomal recessive microcephalies (MCPH) and Seckel syndrome (SCKS) spectrum disorders are characterized by microcephaly and the absence of visceral malformations. Although MCHP and SCKS were previously distinguished by height (maximum height in SCKS was equivalent to the minimum height in MCPH), stature is no longer a discriminating feature, leading to the conclusion that these phenotypes constitute a spectrum rather than distinct entities. Microcephaly is characterized by: Onset during the second trimester of gestation; Occipito-frontal head circumference (OFC) at birth equal to or less than -2 SD below the mean for sex, age, and ethnicity; Slower than average increase in OFC after birth. Variable findings in the MCPH-SCKS spectrum disorders include: Brain structure (which is normal in the majority); Degree of cognitive impairment (usually mild to moderate without significant motor delay in the majority of persons with MCPH and more severe in those with SCKS and MCPH with brain malformations); Degree of short stature; Craniosynostosis (which may be secondary to poor brain growth). The diagnosis of MCPH-SCKS spectrum disorders is based on clinical findings, brain imaging that shows reduced brain volume with grossly normal architecture, family history consistent with autosomal recessive inheritance, and molecular genetic testing when available. The genes in which biallelic mutation is known to cause MCPH-SCKS spectrum disorders are separated into those that are currently known to be associated with: MCPH phenotype only: SCKS phenotype only: MCPH, SCKS, and/or intermediate phenotypes: Of note, roughly one half to three quarters of western Europeans or North Americans with MCPH have no identified gene defect; in contrast, the proportion of individuals with identified pathogenic variants appears higher in persons from the Indo-Pakistan area. MCPH-SCKS spectrum disorders are inherited in an autosomal recessive manner. At conception, each child of two carrier parents has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
|
## Diagnosis
The microcephaly is characterized by the following:
Onset during the second trimester of gestation
Occipito-frontal head circumference (OFC) at birth that is equal to or less than -2 SD (and often < -3 SD) below the mean for sex, age, and ethnicity. After birth, the OFC continues to increase, but at a slower rate than usual, so that microcephaly (expressed in SD) tends to worsen over time. After age six months OFC is at least -3 SD. In older individuals, OFC ranges between -4 and -12 SD (mean -8 SD). Note: “Mild microcephaly” refers to an OFC between -2 SD and -3 SD.
Small brain with small gyri. The volume of the cerebral hemispheres can be reduced to one third of normal, which is particularly evident in the cerebral cortex. The organization and topography of gyri are grossly normal; however, the pattern may be simplified.
Hindbrain and cerebellum that are evenly reduced in size and normally shaped
A significant correlation between the severity of microcephaly and both the degree of simplified gyration and the reduction of white matter volume
When microcephaly is severe, the gyri may be shallow and the gyration pattern may be simplified.
The corpus callosum tends to be thinner when microcephaly is more severe [
Some affected individuals show abnormalities of neuronal migration, such as heterotopias, or focal pachygyria or polymicrogyria [
Malformations are more common with mutation of certain genes, such as biallelic
See also Clinical Description,
Of note: roughly one half to three quarters of western Europeans or North Americans with MCPH have no identified gene defect; in contrast, the proportion of individuals with identified pathogenic variants appears higher in persons from the Indo-Pakistan area.
The following genes (followed by locus name in parentheses) in which biallelic pathogenic variants are known to cause MCPH-SCKS spectrum disorders are separated into those that are currently known to be associated with:
Note: No gene has yet been identified for the locus designated SCKL3.
Two approaches to molecular genetic testing can be considered:
In the European population, the genes in which pathogenic variants are most likely to be identified appear to be
Pathogenic variants in
For individuals from a consanguineous mating, SNP-array technology can identify regions of homozygosity (homozygosity mapping) that allow prioritization of the gene or genes to be tested.
Summary of Molecular Genetic Testing Used in MCPH-SCKS Spectrum Disorders
See
For the MCPH phenotype, few studies have addressed the relative importance of each locus or included all known genes. See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
Targeted pathogenic variants may vary by laboratory.
No exon deletions or duplications have been reported to date. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)
• Onset during the second trimester of gestation
• Occipito-frontal head circumference (OFC) at birth that is equal to or less than -2 SD (and often < -3 SD) below the mean for sex, age, and ethnicity. After birth, the OFC continues to increase, but at a slower rate than usual, so that microcephaly (expressed in SD) tends to worsen over time. After age six months OFC is at least -3 SD. In older individuals, OFC ranges between -4 and -12 SD (mean -8 SD). Note: “Mild microcephaly” refers to an OFC between -2 SD and -3 SD.
• Small brain with small gyri. The volume of the cerebral hemispheres can be reduced to one third of normal, which is particularly evident in the cerebral cortex. The organization and topography of gyri are grossly normal; however, the pattern may be simplified.
• Hindbrain and cerebellum that are evenly reduced in size and normally shaped
• A significant correlation between the severity of microcephaly and both the degree of simplified gyration and the reduction of white matter volume
• When microcephaly is severe, the gyri may be shallow and the gyration pattern may be simplified.
• The corpus callosum tends to be thinner when microcephaly is more severe [
• Some affected individuals show abnormalities of neuronal migration, such as heterotopias, or focal pachygyria or polymicrogyria [
• Malformations are more common with mutation of certain genes, such as biallelic
• See also Clinical Description,
• When microcephaly is severe, the gyri may be shallow and the gyration pattern may be simplified.
• The corpus callosum tends to be thinner when microcephaly is more severe [
• Some affected individuals show abnormalities of neuronal migration, such as heterotopias, or focal pachygyria or polymicrogyria [
• Malformations are more common with mutation of certain genes, such as biallelic
• When microcephaly is severe, the gyri may be shallow and the gyration pattern may be simplified.
• The corpus callosum tends to be thinner when microcephaly is more severe [
• Some affected individuals show abnormalities of neuronal migration, such as heterotopias, or focal pachygyria or polymicrogyria [
• Malformations are more common with mutation of certain genes, such as biallelic
• In the European population, the genes in which pathogenic variants are most likely to be identified appear to be
• Pathogenic variants in
• For individuals from a consanguineous mating, SNP-array technology can identify regions of homozygosity (homozygosity mapping) that allow prioritization of the gene or genes to be tested.
• In the European population, the genes in which pathogenic variants are most likely to be identified appear to be
• Pathogenic variants in
• For individuals from a consanguineous mating, SNP-array technology can identify regions of homozygosity (homozygosity mapping) that allow prioritization of the gene or genes to be tested.
• In the European population, the genes in which pathogenic variants are most likely to be identified appear to be
• Pathogenic variants in
• For individuals from a consanguineous mating, SNP-array technology can identify regions of homozygosity (homozygosity mapping) that allow prioritization of the gene or genes to be tested.
## Testing
Of note: roughly one half to three quarters of western Europeans or North Americans with MCPH have no identified gene defect; in contrast, the proportion of individuals with identified pathogenic variants appears higher in persons from the Indo-Pakistan area.
The following genes (followed by locus name in parentheses) in which biallelic pathogenic variants are known to cause MCPH-SCKS spectrum disorders are separated into those that are currently known to be associated with:
Note: No gene has yet been identified for the locus designated SCKL3.
Two approaches to molecular genetic testing can be considered:
In the European population, the genes in which pathogenic variants are most likely to be identified appear to be
Pathogenic variants in
For individuals from a consanguineous mating, SNP-array technology can identify regions of homozygosity (homozygosity mapping) that allow prioritization of the gene or genes to be tested.
Summary of Molecular Genetic Testing Used in MCPH-SCKS Spectrum Disorders
See
For the MCPH phenotype, few studies have addressed the relative importance of each locus or included all known genes. See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
Targeted pathogenic variants may vary by laboratory.
No exon deletions or duplications have been reported to date. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)
• In the European population, the genes in which pathogenic variants are most likely to be identified appear to be
• Pathogenic variants in
• For individuals from a consanguineous mating, SNP-array technology can identify regions of homozygosity (homozygosity mapping) that allow prioritization of the gene or genes to be tested.
• In the European population, the genes in which pathogenic variants are most likely to be identified appear to be
• Pathogenic variants in
• For individuals from a consanguineous mating, SNP-array technology can identify regions of homozygosity (homozygosity mapping) that allow prioritization of the gene or genes to be tested.
• In the European population, the genes in which pathogenic variants are most likely to be identified appear to be
• Pathogenic variants in
• For individuals from a consanguineous mating, SNP-array technology can identify regions of homozygosity (homozygosity mapping) that allow prioritization of the gene or genes to be tested.
## Clinical Characteristics
All individuals with the primary autosomal recessive microcephalies (MCPH) and Seckel syndrome (SCKS) spectrum disorders have (1) microcephaly and (2) no malformations in other organ systems. More variable are:
Brain structure (usually normal, but can be malformed at the severe end);
Cognitive function (ranging from low-normal intelligence to severe cognitive impairment); and
Linear growth (ranging from low-normal to extremely short).
Males and females are affected equally.
Historically SCKS has been distinguished from MCPH by intrauterine and postnatal growth retardation in the former; however, distinctions between MCPH and SCKS were blurred in 2010 when loss-of-function variants in
Furthermore, individuals with pathogenic variants in some genes (e.g.,
Because MCPH5 (caused by mutation of
In adults with molecularly confirmed MCPH5, OFC varies between -3 SD and -13 SD [
Most children with MCPH have speech delay; they acquire language between ages three and four years when there are no associated brain malformations.
The majority of individuals with MCPH have mild to moderate cognitive impairment; however, few data have been published on the cognitive function of individuals with molecularly confirmed MCPH. In individuals with MCPH5, full-scale IQ scores range from less than 40 to 70 and do not correlate well with OFC [
Individuals with MCPH have been described as cheerful, affable, and cooperative [
Infants and children with MCPH often have severe hyperactivity. Hyperactivity decreases in late childhood and is usually not a problem in adolescence.
No information on cancer risk in MCPH is available.
A simplified gyral pattern is frequently observed in MCPH5 [
A wide spectrum of severity (ranging from the “classic” small brain with simplified gyral pattern to severe brain disorganization) can be seen in individuals with pathogenic variants in
Neuropathologic findings in genetically characterized MCPH have not been reported to date.
SCKS was probably overdiagnosed in the past in individuals with microcephaly and short stature. Critical review of the literature prior to 2010 can be found in
Children with height between -3 SD and -4 SD persisting after age one year may be considered to have an intermediate phenotype between MCPH and SCKS.
Postnatal growth is severely restricted. The mean height is around -7 SD, but height as short as -13 SD has been observed.
See references cited in
Studies Related to MCPH/SCKS Types
The discovery of the genetic basis of the primary autosomal recessive microcephalies (MCPH) and Seckel syndrome (SCKS) has led to these two entities being considered part of a clinical spectrum, called the MCPH-SCKS spectrum disorders.
The gene products implicated in both phenotypes cooperate in the basic and universal cellular processes that regulate the cell cycle (monitoring of DNA damage, mitosis kinetics and checkpoint control, centrosome cycle, organization and function of the mitotic spindle). Not surprisingly, alteration of these proteins results in similar phenotypes. Nevertheless, gene-based analysis has shown more or less subtle differences in the manifestations of the phenotype associated with mutation of each gene. MCPH and SCKS remain rare disorders; only
Note: Some individuals with biallelic pathogenic variants in genes associated with MCPH-SCKS spectrum disorders have distinctive brain findings that could lead to their being considered separate entities (see
The abbreviation MCPH stands for
When
Primary microcephaly has an incidence of 1:30,000 to 1:250,000.
MCPH-SCKS spectrum disorders have been confirmed by molecular genetic testing and reported in fewer than 200 families.
Mutation of
Proportion of the Genes Most Likely to be Mutated in the Populations Studied
NA (not available) means that a gene was not investigated.
• Brain structure (usually normal, but can be malformed at the severe end);
• Cognitive function (ranging from low-normal intelligence to severe cognitive impairment); and
• Linear growth (ranging from low-normal to extremely short).
• A simplified gyral pattern is frequently observed in MCPH5 [
• A wide spectrum of severity (ranging from the “classic” small brain with simplified gyral pattern to severe brain disorganization) can be seen in individuals with pathogenic variants in
## Clinical Description
All individuals with the primary autosomal recessive microcephalies (MCPH) and Seckel syndrome (SCKS) spectrum disorders have (1) microcephaly and (2) no malformations in other organ systems. More variable are:
Brain structure (usually normal, but can be malformed at the severe end);
Cognitive function (ranging from low-normal intelligence to severe cognitive impairment); and
Linear growth (ranging from low-normal to extremely short).
Males and females are affected equally.
Historically SCKS has been distinguished from MCPH by intrauterine and postnatal growth retardation in the former; however, distinctions between MCPH and SCKS were blurred in 2010 when loss-of-function variants in
Furthermore, individuals with pathogenic variants in some genes (e.g.,
Because MCPH5 (caused by mutation of
In adults with molecularly confirmed MCPH5, OFC varies between -3 SD and -13 SD [
Most children with MCPH have speech delay; they acquire language between ages three and four years when there are no associated brain malformations.
The majority of individuals with MCPH have mild to moderate cognitive impairment; however, few data have been published on the cognitive function of individuals with molecularly confirmed MCPH. In individuals with MCPH5, full-scale IQ scores range from less than 40 to 70 and do not correlate well with OFC [
Individuals with MCPH have been described as cheerful, affable, and cooperative [
Infants and children with MCPH often have severe hyperactivity. Hyperactivity decreases in late childhood and is usually not a problem in adolescence.
No information on cancer risk in MCPH is available.
A simplified gyral pattern is frequently observed in MCPH5 [
A wide spectrum of severity (ranging from the “classic” small brain with simplified gyral pattern to severe brain disorganization) can be seen in individuals with pathogenic variants in
Neuropathologic findings in genetically characterized MCPH have not been reported to date.
SCKS was probably overdiagnosed in the past in individuals with microcephaly and short stature. Critical review of the literature prior to 2010 can be found in
Children with height between -3 SD and -4 SD persisting after age one year may be considered to have an intermediate phenotype between MCPH and SCKS.
Postnatal growth is severely restricted. The mean height is around -7 SD, but height as short as -13 SD has been observed.
See references cited in
Studies Related to MCPH/SCKS Types
• Brain structure (usually normal, but can be malformed at the severe end);
• Cognitive function (ranging from low-normal intelligence to severe cognitive impairment); and
• Linear growth (ranging from low-normal to extremely short).
• A simplified gyral pattern is frequently observed in MCPH5 [
• A wide spectrum of severity (ranging from the “classic” small brain with simplified gyral pattern to severe brain disorganization) can be seen in individuals with pathogenic variants in
## Autosomal Recessive Primary Microcephaly (MCPH)
Because MCPH5 (caused by mutation of
In adults with molecularly confirmed MCPH5, OFC varies between -3 SD and -13 SD [
Most children with MCPH have speech delay; they acquire language between ages three and four years when there are no associated brain malformations.
The majority of individuals with MCPH have mild to moderate cognitive impairment; however, few data have been published on the cognitive function of individuals with molecularly confirmed MCPH. In individuals with MCPH5, full-scale IQ scores range from less than 40 to 70 and do not correlate well with OFC [
Individuals with MCPH have been described as cheerful, affable, and cooperative [
Infants and children with MCPH often have severe hyperactivity. Hyperactivity decreases in late childhood and is usually not a problem in adolescence.
No information on cancer risk in MCPH is available.
A simplified gyral pattern is frequently observed in MCPH5 [
A wide spectrum of severity (ranging from the “classic” small brain with simplified gyral pattern to severe brain disorganization) can be seen in individuals with pathogenic variants in
Neuropathologic findings in genetically characterized MCPH have not been reported to date.
• A simplified gyral pattern is frequently observed in MCPH5 [
• A wide spectrum of severity (ranging from the “classic” small brain with simplified gyral pattern to severe brain disorganization) can be seen in individuals with pathogenic variants in
## Seckel Syndrome (SCKS)
SCKS was probably overdiagnosed in the past in individuals with microcephaly and short stature. Critical review of the literature prior to 2010 can be found in
Children with height between -3 SD and -4 SD persisting after age one year may be considered to have an intermediate phenotype between MCPH and SCKS.
Postnatal growth is severely restricted. The mean height is around -7 SD, but height as short as -13 SD has been observed.
## Details of the MCPH-SCKS Spectrum Disorders by Gene
See references cited in
Studies Related to MCPH/SCKS Types
## Genotype-Phenotype Correlations
The discovery of the genetic basis of the primary autosomal recessive microcephalies (MCPH) and Seckel syndrome (SCKS) has led to these two entities being considered part of a clinical spectrum, called the MCPH-SCKS spectrum disorders.
The gene products implicated in both phenotypes cooperate in the basic and universal cellular processes that regulate the cell cycle (monitoring of DNA damage, mitosis kinetics and checkpoint control, centrosome cycle, organization and function of the mitotic spindle). Not surprisingly, alteration of these proteins results in similar phenotypes. Nevertheless, gene-based analysis has shown more or less subtle differences in the manifestations of the phenotype associated with mutation of each gene. MCPH and SCKS remain rare disorders; only
Note: Some individuals with biallelic pathogenic variants in genes associated with MCPH-SCKS spectrum disorders have distinctive brain findings that could lead to their being considered separate entities (see
## Nomenclature
The abbreviation MCPH stands for
When
## Prevalence
Primary microcephaly has an incidence of 1:30,000 to 1:250,000.
MCPH-SCKS spectrum disorders have been confirmed by molecular genetic testing and reported in fewer than 200 families.
Mutation of
Proportion of the Genes Most Likely to be Mutated in the Populations Studied
NA (not available) means that a gene was not investigated.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Microcephaly can be considered primary (resulting from intrauterine reduced brain growth) or secondary (resulting from postnatal reduced brain growth caused by decreased cell proliferation and/or increased cell death). Although primary microcephaly and secondary microcephalies theoretically result from distinct pathogenic mechanisms, their etiologies can overlap. Moreover, processes that interfere with brain development prenatally may occasionally be insufficient to give rise to microcephaly prenatally (i.e., primary microcephaly) and thus result in what appears to be postnatal reduced brain growth (i.e., secondary microcephaly).
Both primary microcephaly and secondary microcephaly can be:
Associated with malformations of the central nervous system (CNS) or grossly normal CNS anatomy;
Syndromic (i.e., associated with malformations occurring in other parts of the body) or isolated (i.e., not associated with malformations in other organ systems);
Associated with disorders of DNA repair such as chromosome instability syndromes and syndromes with secondary onco-hematologic or immunologic disorders;
Common in genomic rearrangements. Deletion or duplication involving multiple genes results in copy number variations (CNVs) which are commonly associated with microcephaly and short stature.
Caused by teratogens. Well-known teratogens associated with microcephaly are alcohol and maternal hyperphenylalaninemia (usually the consequence of poor dietary control in a mother affected by PKU); see
Information useful for the differential diagnosis of microcephaly can be obtained through detailed past medical history (including history of the pregnancy and perinatal events), review of growth charts for head size and length, and physical examination (possibly with the help of someone trained in dysmorphology/clinical genetics).
Evaluation by a child neurologist
When MCPH seems likely:
When primary microcephaly is associated with short stature:
Microcephaly with a normal gyral pattern was distinguished from microcephaly with a simplified gyral pattern (MSG) by
MSG type 1 has a simplified gyral pattern, normal myelination, normal neonatal course, mild pyramidal signs, and no seizures, and is likely to correspond to the severe expression of the MCPH phenotype described in this
MSG types 2-5 (delineated based on the presence of white matter defect, the severity of the neurologic impairment, presence of seizure, and survival) are probably distinct disorders.
A new classification of severe microcephalies was proposed by
Group 1. Microcephaly with simplified gyri only (which includes individuals with MCPH and SCKS with a simplified gyral pattern)
Group 2. Severe congenital microcephaly, simplified gyral pattern, and pontocerebellar hypoplasia with thin pons. Cognitive development is usually similar to that seen in MCPH; however, some have more severe developmental and neurologic abnormalities. MCPH-associated genes appear not to be involved in this form, as cerebellar hypoplasia is not common in MCPH.
Group 3. Microcephaly with simplified gyri and enlarged extra-axial spaces
Group 4. Microcephaly with simplified gyri, enlarged extra-axial spaces, and cerebellar hypoplasia
Note: In this classification, groups 3 and 4 (in contrast to groups 1 and 2) have microcephaly of perinatal onset and severe neurologic involvement (severe to profound intellectual disability, spastic quadriparesis that prevents ambulation, and in some cases choreiform movements).
In the following section, a distinction is made between lissencephaly/pachygyria and polymicrogyria. It is important to note that mutation of the same genes may result in either phenotype or a combination of the two phenotypes; for example, pachygyria and polymicrogyria may be present in the same individual with biallelic pathogenic variants in
Classic lissencephaly is caused by mutation of one of several genes involved in neuronal migration. See
Types of Classic Lissencephaly and Associated Genes
Microcephaly (≤-5.5 SD) with agyria/pachygyria (more severe posteriorly) and/or subcortical band heterotopias has been reported in children heterozygous for a pathogenic variant in
Heterozygous pathogenic variants have been reported in
Eight of 30 individuals with lissencephaly/pachygyria spectrum born to consanguineous parents from Turkey had biallelic
Note: The term “microlissencephaly” was used in the literature prior to 2000 to designate both MLIS (with thick, disorganized cortex) and microcephaly with simplified gyral pattern (MSG).
Biallelic pathogenic variants in
Pathogenic variants in genes encoding tubulins are often associated with abnormalities of the corpus callosum, abnormal basal ganglia and internal capsule, and cerebellar hypoplasia. Heterozygous pathogenic variants in
Congenital microcephaly (-2.5 to -4 SD) is inconstant and does not always worsen after birth. Developmental delay ranges from mild to severe.
Heterozygous mutation of
Biallelic loss-of-function pathogenic variants in
Biallelic pathogenic variants in
Pathogenic variants that appear to be male lethal in the X-linked gene
Some form of microcephalies may show major involvement of the infratentorial structures (pons, brain stem, and cerebellum):
Brain MRI shows extreme microcephaly including hypoplastic cerebellum and brain stem, increased extra-axial space, enlarged ventricles, a simplified gyral pattern, absence of the corpus callosum, delayed myelinization, and probable progressive brain atrophy. Neuropathologic examination of one child showed thin cortex, reduced density of neurons with little apparent neuronal polarity or dendritic maturation, and disorganization of cortical layering. The cerebellum was also hypoplastic [
Biallelic pathogenic variants in
Pontocerebellar hypoplasia (PCH) describes a heterogeneous group of neurodegenerative disorders characterized by hypoplasia of the cerebellum and pons, severe delay in cognitive and motor development, and seizures. Primary microcephaly with simplified gyral pattern is present in some forms of PCH. Progressive cerebral atrophy (which does not occur in MCPH) is associated with worsening microcephaly, dyskinesia, seizures, and death in early childhood. Pathogenic variants are found in a dozen genes, many of them encoding subunits of the tRNA splicing endonuclease complex:
PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
PCH type 6 is caused by biallelic pathogenic variants in
PCH type 8 caused by biallelic pathogenic variants in
Mutation of the X-linked gene
Heterozygous mutation of
MGS is caused by heterozygous mutation of
Extreme microcephaly with structural brain malformations (abnormal gyration, pachygyria, heterotopias; agenesis of the cerebellar vermis and corpus callosum; and sometimes complex brain dysgenesis, sometimes associated with intractable seizures) [
Profound developmental delay
Distinctive facial findings (a prominent nose, bulging eyes, and a large, pointed nose)
Severe intrauterine growth retardation (IUGR)
Severe dwarfism (short neck; short limbs with relatively large hands but short fingers; platyspondyly with abnormal vertebral bodies; short, bowed and undermodeled long bones)
Distinctive skeletal findings (dislocation of the elbows and hips; long clavicles; wide metaphyses; delayed bone age; and hypoplastic pelvis with horizontal acetabulum)
Sparse scalp hair and dry skin
Taybi-Linder syndrome was described independently as three apparently distinct disorders: Taybi and Linder described the first cases in 1967 and Majewski in 1982 delineated two apparently “new” phenotypes, referred to as microcephalic osteodysplastic dwarfism, type I (MOPD1) [
Biallelic pathogenic variants in
These syndromes are characterized by either a stable retinal dysplasia or a progressive retinal degeneration. Because the chorioretinal dysplasia can be asymptomatic, fundus examination is necessary to establish this finding.
Some affected individuals have punched-out, hypopigmented retinal lesions that may resemble those caused by a TORCH syndrome agent (
The disorders include:
An autosomal recessive disorder, also called chorioretinal dysplasia-microcephaly-mental retardation (CDMM) syndrome (OMIM
An autosomal dominant disorder comprising microcephaly, chorioretinopathy and/or retinal folds, and/or lymphedema (OMIM
Microcephaly is a common feature of most DNA repair disorders [
• Associated with malformations of the central nervous system (CNS) or grossly normal CNS anatomy;
• Syndromic (i.e., associated with malformations occurring in other parts of the body) or isolated (i.e., not associated with malformations in other organ systems);
• Associated with disorders of DNA repair such as chromosome instability syndromes and syndromes with secondary onco-hematologic or immunologic disorders;
• Common in genomic rearrangements. Deletion or duplication involving multiple genes results in copy number variations (CNVs) which are commonly associated with microcephaly and short stature.
• Caused by teratogens. Well-known teratogens associated with microcephaly are alcohol and maternal hyperphenylalaninemia (usually the consequence of poor dietary control in a mother affected by PKU); see
• Evaluation by a child neurologist
•
•
• MSG type 1 has a simplified gyral pattern, normal myelination, normal neonatal course, mild pyramidal signs, and no seizures, and is likely to correspond to the severe expression of the MCPH phenotype described in this
• MSG types 2-5 (delineated based on the presence of white matter defect, the severity of the neurologic impairment, presence of seizure, and survival) are probably distinct disorders.
• Group 1. Microcephaly with simplified gyri only (which includes individuals with MCPH and SCKS with a simplified gyral pattern)
• Group 2. Severe congenital microcephaly, simplified gyral pattern, and pontocerebellar hypoplasia with thin pons. Cognitive development is usually similar to that seen in MCPH; however, some have more severe developmental and neurologic abnormalities. MCPH-associated genes appear not to be involved in this form, as cerebellar hypoplasia is not common in MCPH.
• Group 3. Microcephaly with simplified gyri and enlarged extra-axial spaces
• Group 4. Microcephaly with simplified gyri, enlarged extra-axial spaces, and cerebellar hypoplasia
• Biallelic pathogenic variants in
• Pathogenic variants in genes encoding tubulins are often associated with abnormalities of the corpus callosum, abnormal basal ganglia and internal capsule, and cerebellar hypoplasia. Heterozygous pathogenic variants in
• Congenital microcephaly (-2.5 to -4 SD) is inconstant and does not always worsen after birth. Developmental delay ranges from mild to severe.
• Heterozygous mutation of
• Biallelic loss-of-function pathogenic variants in
• Biallelic pathogenic variants in
• Pathogenic variants that appear to be male lethal in the X-linked gene
• Brain MRI shows extreme microcephaly including hypoplastic cerebellum and brain stem, increased extra-axial space, enlarged ventricles, a simplified gyral pattern, absence of the corpus callosum, delayed myelinization, and probable progressive brain atrophy. Neuropathologic examination of one child showed thin cortex, reduced density of neurons with little apparent neuronal polarity or dendritic maturation, and disorganization of cortical layering. The cerebellum was also hypoplastic [
• Biallelic pathogenic variants in
• Pontocerebellar hypoplasia (PCH) describes a heterogeneous group of neurodegenerative disorders characterized by hypoplasia of the cerebellum and pons, severe delay in cognitive and motor development, and seizures. Primary microcephaly with simplified gyral pattern is present in some forms of PCH. Progressive cerebral atrophy (which does not occur in MCPH) is associated with worsening microcephaly, dyskinesia, seizures, and death in early childhood. Pathogenic variants are found in a dozen genes, many of them encoding subunits of the tRNA splicing endonuclease complex:
• PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
• PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
• PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
• PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
• PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
• PCH type 6 is caused by biallelic pathogenic variants in
• PCH type 8 caused by biallelic pathogenic variants in
• PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
• PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
• PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
• PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
• PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
• PCH type 6 is caused by biallelic pathogenic variants in
• PCH type 8 caused by biallelic pathogenic variants in
• Mutation of the X-linked gene
• PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
• PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
• PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
• PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
• PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
• PCH type 6 is caused by biallelic pathogenic variants in
• PCH type 8 caused by biallelic pathogenic variants in
• Extreme microcephaly with structural brain malformations (abnormal gyration, pachygyria, heterotopias; agenesis of the cerebellar vermis and corpus callosum; and sometimes complex brain dysgenesis, sometimes associated with intractable seizures) [
• Profound developmental delay
• Distinctive facial findings (a prominent nose, bulging eyes, and a large, pointed nose)
• Severe intrauterine growth retardation (IUGR)
• Severe dwarfism (short neck; short limbs with relatively large hands but short fingers; platyspondyly with abnormal vertebral bodies; short, bowed and undermodeled long bones)
• Distinctive skeletal findings (dislocation of the elbows and hips; long clavicles; wide metaphyses; delayed bone age; and hypoplastic pelvis with horizontal acetabulum)
• Sparse scalp hair and dry skin
• An autosomal recessive disorder, also called chorioretinal dysplasia-microcephaly-mental retardation (CDMM) syndrome (OMIM
• An autosomal dominant disorder comprising microcephaly, chorioretinopathy and/or retinal folds, and/or lymphedema (OMIM
## Microcephaly with Brain Malformations
Microcephaly with a normal gyral pattern was distinguished from microcephaly with a simplified gyral pattern (MSG) by
MSG type 1 has a simplified gyral pattern, normal myelination, normal neonatal course, mild pyramidal signs, and no seizures, and is likely to correspond to the severe expression of the MCPH phenotype described in this
MSG types 2-5 (delineated based on the presence of white matter defect, the severity of the neurologic impairment, presence of seizure, and survival) are probably distinct disorders.
A new classification of severe microcephalies was proposed by
Group 1. Microcephaly with simplified gyri only (which includes individuals with MCPH and SCKS with a simplified gyral pattern)
Group 2. Severe congenital microcephaly, simplified gyral pattern, and pontocerebellar hypoplasia with thin pons. Cognitive development is usually similar to that seen in MCPH; however, some have more severe developmental and neurologic abnormalities. MCPH-associated genes appear not to be involved in this form, as cerebellar hypoplasia is not common in MCPH.
Group 3. Microcephaly with simplified gyri and enlarged extra-axial spaces
Group 4. Microcephaly with simplified gyri, enlarged extra-axial spaces, and cerebellar hypoplasia
Note: In this classification, groups 3 and 4 (in contrast to groups 1 and 2) have microcephaly of perinatal onset and severe neurologic involvement (severe to profound intellectual disability, spastic quadriparesis that prevents ambulation, and in some cases choreiform movements).
In the following section, a distinction is made between lissencephaly/pachygyria and polymicrogyria. It is important to note that mutation of the same genes may result in either phenotype or a combination of the two phenotypes; for example, pachygyria and polymicrogyria may be present in the same individual with biallelic pathogenic variants in
Classic lissencephaly is caused by mutation of one of several genes involved in neuronal migration. See
Types of Classic Lissencephaly and Associated Genes
Microcephaly (≤-5.5 SD) with agyria/pachygyria (more severe posteriorly) and/or subcortical band heterotopias has been reported in children heterozygous for a pathogenic variant in
Heterozygous pathogenic variants have been reported in
Eight of 30 individuals with lissencephaly/pachygyria spectrum born to consanguineous parents from Turkey had biallelic
Note: The term “microlissencephaly” was used in the literature prior to 2000 to designate both MLIS (with thick, disorganized cortex) and microcephaly with simplified gyral pattern (MSG).
Biallelic pathogenic variants in
Pathogenic variants in genes encoding tubulins are often associated with abnormalities of the corpus callosum, abnormal basal ganglia and internal capsule, and cerebellar hypoplasia. Heterozygous pathogenic variants in
Congenital microcephaly (-2.5 to -4 SD) is inconstant and does not always worsen after birth. Developmental delay ranges from mild to severe.
Heterozygous mutation of
Biallelic loss-of-function pathogenic variants in
Biallelic pathogenic variants in
Pathogenic variants that appear to be male lethal in the X-linked gene
Some form of microcephalies may show major involvement of the infratentorial structures (pons, brain stem, and cerebellum):
Brain MRI shows extreme microcephaly including hypoplastic cerebellum and brain stem, increased extra-axial space, enlarged ventricles, a simplified gyral pattern, absence of the corpus callosum, delayed myelinization, and probable progressive brain atrophy. Neuropathologic examination of one child showed thin cortex, reduced density of neurons with little apparent neuronal polarity or dendritic maturation, and disorganization of cortical layering. The cerebellum was also hypoplastic [
Biallelic pathogenic variants in
Pontocerebellar hypoplasia (PCH) describes a heterogeneous group of neurodegenerative disorders characterized by hypoplasia of the cerebellum and pons, severe delay in cognitive and motor development, and seizures. Primary microcephaly with simplified gyral pattern is present in some forms of PCH. Progressive cerebral atrophy (which does not occur in MCPH) is associated with worsening microcephaly, dyskinesia, seizures, and death in early childhood. Pathogenic variants are found in a dozen genes, many of them encoding subunits of the tRNA splicing endonuclease complex:
PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
PCH type 6 is caused by biallelic pathogenic variants in
PCH type 8 caused by biallelic pathogenic variants in
Mutation of the X-linked gene
Heterozygous mutation of
MGS is caused by heterozygous mutation of
Extreme microcephaly with structural brain malformations (abnormal gyration, pachygyria, heterotopias; agenesis of the cerebellar vermis and corpus callosum; and sometimes complex brain dysgenesis, sometimes associated with intractable seizures) [
Profound developmental delay
Distinctive facial findings (a prominent nose, bulging eyes, and a large, pointed nose)
Severe intrauterine growth retardation (IUGR)
Severe dwarfism (short neck; short limbs with relatively large hands but short fingers; platyspondyly with abnormal vertebral bodies; short, bowed and undermodeled long bones)
Distinctive skeletal findings (dislocation of the elbows and hips; long clavicles; wide metaphyses; delayed bone age; and hypoplastic pelvis with horizontal acetabulum)
Sparse scalp hair and dry skin
Taybi-Linder syndrome was described independently as three apparently distinct disorders: Taybi and Linder described the first cases in 1967 and Majewski in 1982 delineated two apparently “new” phenotypes, referred to as microcephalic osteodysplastic dwarfism, type I (MOPD1) [
Biallelic pathogenic variants in
These syndromes are characterized by either a stable retinal dysplasia or a progressive retinal degeneration. Because the chorioretinal dysplasia can be asymptomatic, fundus examination is necessary to establish this finding.
Some affected individuals have punched-out, hypopigmented retinal lesions that may resemble those caused by a TORCH syndrome agent (
The disorders include:
An autosomal recessive disorder, also called chorioretinal dysplasia-microcephaly-mental retardation (CDMM) syndrome (OMIM
An autosomal dominant disorder comprising microcephaly, chorioretinopathy and/or retinal folds, and/or lymphedema (OMIM
Microcephaly is a common feature of most DNA repair disorders [
• MSG type 1 has a simplified gyral pattern, normal myelination, normal neonatal course, mild pyramidal signs, and no seizures, and is likely to correspond to the severe expression of the MCPH phenotype described in this
• MSG types 2-5 (delineated based on the presence of white matter defect, the severity of the neurologic impairment, presence of seizure, and survival) are probably distinct disorders.
• Group 1. Microcephaly with simplified gyri only (which includes individuals with MCPH and SCKS with a simplified gyral pattern)
• Group 2. Severe congenital microcephaly, simplified gyral pattern, and pontocerebellar hypoplasia with thin pons. Cognitive development is usually similar to that seen in MCPH; however, some have more severe developmental and neurologic abnormalities. MCPH-associated genes appear not to be involved in this form, as cerebellar hypoplasia is not common in MCPH.
• Group 3. Microcephaly with simplified gyri and enlarged extra-axial spaces
• Group 4. Microcephaly with simplified gyri, enlarged extra-axial spaces, and cerebellar hypoplasia
• Biallelic pathogenic variants in
• Pathogenic variants in genes encoding tubulins are often associated with abnormalities of the corpus callosum, abnormal basal ganglia and internal capsule, and cerebellar hypoplasia. Heterozygous pathogenic variants in
• Congenital microcephaly (-2.5 to -4 SD) is inconstant and does not always worsen after birth. Developmental delay ranges from mild to severe.
• Heterozygous mutation of
• Biallelic loss-of-function pathogenic variants in
• Biallelic pathogenic variants in
• Pathogenic variants that appear to be male lethal in the X-linked gene
• Brain MRI shows extreme microcephaly including hypoplastic cerebellum and brain stem, increased extra-axial space, enlarged ventricles, a simplified gyral pattern, absence of the corpus callosum, delayed myelinization, and probable progressive brain atrophy. Neuropathologic examination of one child showed thin cortex, reduced density of neurons with little apparent neuronal polarity or dendritic maturation, and disorganization of cortical layering. The cerebellum was also hypoplastic [
• Biallelic pathogenic variants in
• Pontocerebellar hypoplasia (PCH) describes a heterogeneous group of neurodegenerative disorders characterized by hypoplasia of the cerebellum and pons, severe delay in cognitive and motor development, and seizures. Primary microcephaly with simplified gyral pattern is present in some forms of PCH. Progressive cerebral atrophy (which does not occur in MCPH) is associated with worsening microcephaly, dyskinesia, seizures, and death in early childhood. Pathogenic variants are found in a dozen genes, many of them encoding subunits of the tRNA splicing endonuclease complex:
• PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
• PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
• PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
• PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
• PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
• PCH type 6 is caused by biallelic pathogenic variants in
• PCH type 8 caused by biallelic pathogenic variants in
• PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
• PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
• PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
• PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
• PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
• PCH type 6 is caused by biallelic pathogenic variants in
• PCH type 8 caused by biallelic pathogenic variants in
• Mutation of the X-linked gene
• PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
• PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
• PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
• PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
• PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
• PCH type 6 is caused by biallelic pathogenic variants in
• PCH type 8 caused by biallelic pathogenic variants in
• Extreme microcephaly with structural brain malformations (abnormal gyration, pachygyria, heterotopias; agenesis of the cerebellar vermis and corpus callosum; and sometimes complex brain dysgenesis, sometimes associated with intractable seizures) [
• Profound developmental delay
• Distinctive facial findings (a prominent nose, bulging eyes, and a large, pointed nose)
• Severe intrauterine growth retardation (IUGR)
• Severe dwarfism (short neck; short limbs with relatively large hands but short fingers; platyspondyly with abnormal vertebral bodies; short, bowed and undermodeled long bones)
• Distinctive skeletal findings (dislocation of the elbows and hips; long clavicles; wide metaphyses; delayed bone age; and hypoplastic pelvis with horizontal acetabulum)
• Sparse scalp hair and dry skin
• An autosomal recessive disorder, also called chorioretinal dysplasia-microcephaly-mental retardation (CDMM) syndrome (OMIM
• An autosomal dominant disorder comprising microcephaly, chorioretinopathy and/or retinal folds, and/or lymphedema (OMIM
## Microcephaly with Cortical Migration or Organization Defects
Microcephaly with a normal gyral pattern was distinguished from microcephaly with a simplified gyral pattern (MSG) by
MSG type 1 has a simplified gyral pattern, normal myelination, normal neonatal course, mild pyramidal signs, and no seizures, and is likely to correspond to the severe expression of the MCPH phenotype described in this
MSG types 2-5 (delineated based on the presence of white matter defect, the severity of the neurologic impairment, presence of seizure, and survival) are probably distinct disorders.
A new classification of severe microcephalies was proposed by
Group 1. Microcephaly with simplified gyri only (which includes individuals with MCPH and SCKS with a simplified gyral pattern)
Group 2. Severe congenital microcephaly, simplified gyral pattern, and pontocerebellar hypoplasia with thin pons. Cognitive development is usually similar to that seen in MCPH; however, some have more severe developmental and neurologic abnormalities. MCPH-associated genes appear not to be involved in this form, as cerebellar hypoplasia is not common in MCPH.
Group 3. Microcephaly with simplified gyri and enlarged extra-axial spaces
Group 4. Microcephaly with simplified gyri, enlarged extra-axial spaces, and cerebellar hypoplasia
Note: In this classification, groups 3 and 4 (in contrast to groups 1 and 2) have microcephaly of perinatal onset and severe neurologic involvement (severe to profound intellectual disability, spastic quadriparesis that prevents ambulation, and in some cases choreiform movements).
In the following section, a distinction is made between lissencephaly/pachygyria and polymicrogyria. It is important to note that mutation of the same genes may result in either phenotype or a combination of the two phenotypes; for example, pachygyria and polymicrogyria may be present in the same individual with biallelic pathogenic variants in
Classic lissencephaly is caused by mutation of one of several genes involved in neuronal migration. See
Types of Classic Lissencephaly and Associated Genes
Microcephaly (≤-5.5 SD) with agyria/pachygyria (more severe posteriorly) and/or subcortical band heterotopias has been reported in children heterozygous for a pathogenic variant in
Heterozygous pathogenic variants have been reported in
Eight of 30 individuals with lissencephaly/pachygyria spectrum born to consanguineous parents from Turkey had biallelic
Note: The term “microlissencephaly” was used in the literature prior to 2000 to designate both MLIS (with thick, disorganized cortex) and microcephaly with simplified gyral pattern (MSG).
Biallelic pathogenic variants in
Pathogenic variants in genes encoding tubulins are often associated with abnormalities of the corpus callosum, abnormal basal ganglia and internal capsule, and cerebellar hypoplasia. Heterozygous pathogenic variants in
Congenital microcephaly (-2.5 to -4 SD) is inconstant and does not always worsen after birth. Developmental delay ranges from mild to severe.
Heterozygous mutation of
Biallelic loss-of-function pathogenic variants in
Biallelic pathogenic variants in
Pathogenic variants that appear to be male lethal in the X-linked gene
• MSG type 1 has a simplified gyral pattern, normal myelination, normal neonatal course, mild pyramidal signs, and no seizures, and is likely to correspond to the severe expression of the MCPH phenotype described in this
• MSG types 2-5 (delineated based on the presence of white matter defect, the severity of the neurologic impairment, presence of seizure, and survival) are probably distinct disorders.
• Group 1. Microcephaly with simplified gyri only (which includes individuals with MCPH and SCKS with a simplified gyral pattern)
• Group 2. Severe congenital microcephaly, simplified gyral pattern, and pontocerebellar hypoplasia with thin pons. Cognitive development is usually similar to that seen in MCPH; however, some have more severe developmental and neurologic abnormalities. MCPH-associated genes appear not to be involved in this form, as cerebellar hypoplasia is not common in MCPH.
• Group 3. Microcephaly with simplified gyri and enlarged extra-axial spaces
• Group 4. Microcephaly with simplified gyri, enlarged extra-axial spaces, and cerebellar hypoplasia
• Biallelic pathogenic variants in
• Pathogenic variants in genes encoding tubulins are often associated with abnormalities of the corpus callosum, abnormal basal ganglia and internal capsule, and cerebellar hypoplasia. Heterozygous pathogenic variants in
• Congenital microcephaly (-2.5 to -4 SD) is inconstant and does not always worsen after birth. Developmental delay ranges from mild to severe.
• Heterozygous mutation of
• Biallelic loss-of-function pathogenic variants in
• Biallelic pathogenic variants in
• Pathogenic variants that appear to be male lethal in the X-linked gene
## Microcephaly with Brain Stem and/or Cerebellar Malformation (Hypoplasia, Agenesis, or Segmentation Abnormalities)
Some form of microcephalies may show major involvement of the infratentorial structures (pons, brain stem, and cerebellum):
Brain MRI shows extreme microcephaly including hypoplastic cerebellum and brain stem, increased extra-axial space, enlarged ventricles, a simplified gyral pattern, absence of the corpus callosum, delayed myelinization, and probable progressive brain atrophy. Neuropathologic examination of one child showed thin cortex, reduced density of neurons with little apparent neuronal polarity or dendritic maturation, and disorganization of cortical layering. The cerebellum was also hypoplastic [
Biallelic pathogenic variants in
Pontocerebellar hypoplasia (PCH) describes a heterogeneous group of neurodegenerative disorders characterized by hypoplasia of the cerebellum and pons, severe delay in cognitive and motor development, and seizures. Primary microcephaly with simplified gyral pattern is present in some forms of PCH. Progressive cerebral atrophy (which does not occur in MCPH) is associated with worsening microcephaly, dyskinesia, seizures, and death in early childhood. Pathogenic variants are found in a dozen genes, many of them encoding subunits of the tRNA splicing endonuclease complex:
PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
PCH type 6 is caused by biallelic pathogenic variants in
PCH type 8 caused by biallelic pathogenic variants in
Mutation of the X-linked gene
• Brain MRI shows extreme microcephaly including hypoplastic cerebellum and brain stem, increased extra-axial space, enlarged ventricles, a simplified gyral pattern, absence of the corpus callosum, delayed myelinization, and probable progressive brain atrophy. Neuropathologic examination of one child showed thin cortex, reduced density of neurons with little apparent neuronal polarity or dendritic maturation, and disorganization of cortical layering. The cerebellum was also hypoplastic [
• Biallelic pathogenic variants in
• Pontocerebellar hypoplasia (PCH) describes a heterogeneous group of neurodegenerative disorders characterized by hypoplasia of the cerebellum and pons, severe delay in cognitive and motor development, and seizures. Primary microcephaly with simplified gyral pattern is present in some forms of PCH. Progressive cerebral atrophy (which does not occur in MCPH) is associated with worsening microcephaly, dyskinesia, seizures, and death in early childhood. Pathogenic variants are found in a dozen genes, many of them encoding subunits of the tRNA splicing endonuclease complex:
• PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
• PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
• PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
• PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
• PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
• PCH type 6 is caused by biallelic pathogenic variants in
• PCH type 8 caused by biallelic pathogenic variants in
• PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
• PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
• PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
• PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
• PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
• PCH type 6 is caused by biallelic pathogenic variants in
• PCH type 8 caused by biallelic pathogenic variants in
• Mutation of the X-linked gene
• PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration and early death. Biallelic pathogenic variants in
• PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH 2A is caused by biallelic pathogenic variants in
• PCH type 4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. It is caused by biallelic pathogenic variants in
• PCH type 3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. The associated gene is unknown.
• PCH type 5 shows cerebellar hypoplasia of prenatal onset and seizures. It is caused by biallelic pathogenic variants in
• PCH type 6 is caused by biallelic pathogenic variants in
• PCH type 8 caused by biallelic pathogenic variants in
## Syndromic Microcephaly
Heterozygous mutation of
## Syndromes with Severe Short Stature (previously termed Dwarfism)
MGS is caused by heterozygous mutation of
Extreme microcephaly with structural brain malformations (abnormal gyration, pachygyria, heterotopias; agenesis of the cerebellar vermis and corpus callosum; and sometimes complex brain dysgenesis, sometimes associated with intractable seizures) [
Profound developmental delay
Distinctive facial findings (a prominent nose, bulging eyes, and a large, pointed nose)
Severe intrauterine growth retardation (IUGR)
Severe dwarfism (short neck; short limbs with relatively large hands but short fingers; platyspondyly with abnormal vertebral bodies; short, bowed and undermodeled long bones)
Distinctive skeletal findings (dislocation of the elbows and hips; long clavicles; wide metaphyses; delayed bone age; and hypoplastic pelvis with horizontal acetabulum)
Sparse scalp hair and dry skin
Taybi-Linder syndrome was described independently as three apparently distinct disorders: Taybi and Linder described the first cases in 1967 and Majewski in 1982 delineated two apparently “new” phenotypes, referred to as microcephalic osteodysplastic dwarfism, type I (MOPD1) [
Biallelic pathogenic variants in
• Extreme microcephaly with structural brain malformations (abnormal gyration, pachygyria, heterotopias; agenesis of the cerebellar vermis and corpus callosum; and sometimes complex brain dysgenesis, sometimes associated with intractable seizures) [
• Profound developmental delay
• Distinctive facial findings (a prominent nose, bulging eyes, and a large, pointed nose)
• Severe intrauterine growth retardation (IUGR)
• Severe dwarfism (short neck; short limbs with relatively large hands but short fingers; platyspondyly with abnormal vertebral bodies; short, bowed and undermodeled long bones)
• Distinctive skeletal findings (dislocation of the elbows and hips; long clavicles; wide metaphyses; delayed bone age; and hypoplastic pelvis with horizontal acetabulum)
• Sparse scalp hair and dry skin
## Syndromes with Chorioretinal Dysplasia (Pseudotoxoplasmosis Syndrome)
These syndromes are characterized by either a stable retinal dysplasia or a progressive retinal degeneration. Because the chorioretinal dysplasia can be asymptomatic, fundus examination is necessary to establish this finding.
Some affected individuals have punched-out, hypopigmented retinal lesions that may resemble those caused by a TORCH syndrome agent (
The disorders include:
An autosomal recessive disorder, also called chorioretinal dysplasia-microcephaly-mental retardation (CDMM) syndrome (OMIM
An autosomal dominant disorder comprising microcephaly, chorioretinopathy and/or retinal folds, and/or lymphedema (OMIM
• An autosomal recessive disorder, also called chorioretinal dysplasia-microcephaly-mental retardation (CDMM) syndrome (OMIM
• An autosomal dominant disorder comprising microcephaly, chorioretinopathy and/or retinal folds, and/or lymphedema (OMIM
## Microcephaly in Disorders of DNA Repair (including syndromes with chromosome instability, photosensitivity, and hematologic or immunologic disorders)
Microcephaly is a common feature of most DNA repair disorders [
## Microcephaly and Mitotic Instability
## Management
To establish the extent of disease in an individual diagnosed with the primary autosomal recessive microcephalies (MCPH) and Seckel syndrome (SCKS) spectrum disorders, the following evaluations are recommended:
Neurology consultation
Age-adapted psychomotor or neuropsychological evaluation
Electroencephalogram if seizures are suspected
Review of brain MRI performed at the time of diagnosis to evaluate for malformations which can have a prognostic value in young children
If short stature is present, skeletal survey (if not performed at the time of diagnosis)
Therapy is supportive and involves the following:
Special education programs tailored to the needs of the individual
Speech and language therapy
Behavioral therapy as needed
Occupational therapy as needed
Community services that provide support for families
Ritalin
Seizures are usually responsive to monotherapy with standard antiepileptic drugs (AEDs).
Growth hormone may be considered in individuals with mild growth retardation; objective efficiency of GH therapy has not been evaluated.
Intubation may be difficult in affected individuals with small chin [
The following are appropriate:
Monitoring of head circumference and stature using standard growth charts
Neurologic follow-up from birth to adulthood to detect behavioral difficulties, hyperactivity, attention disorder, and motor problems (spasticity), and to monitor for evidence of seizures which can be late onset
Periodic neuropsychologic evaluation in order to adapt interventions and schooling to the level of the individual's cognitive abilities
See
Search
• Neurology consultation
• Age-adapted psychomotor or neuropsychological evaluation
• Electroencephalogram if seizures are suspected
• Review of brain MRI performed at the time of diagnosis to evaluate for malformations which can have a prognostic value in young children
• If short stature is present, skeletal survey (if not performed at the time of diagnosis)
• Special education programs tailored to the needs of the individual
• Speech and language therapy
• Behavioral therapy as needed
• Occupational therapy as needed
• Community services that provide support for families
• Monitoring of head circumference and stature using standard growth charts
• Neurologic follow-up from birth to adulthood to detect behavioral difficulties, hyperactivity, attention disorder, and motor problems (spasticity), and to monitor for evidence of seizures which can be late onset
• Periodic neuropsychologic evaluation in order to adapt interventions and schooling to the level of the individual's cognitive abilities
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with the primary autosomal recessive microcephalies (MCPH) and Seckel syndrome (SCKS) spectrum disorders, the following evaluations are recommended:
Neurology consultation
Age-adapted psychomotor or neuropsychological evaluation
Electroencephalogram if seizures are suspected
Review of brain MRI performed at the time of diagnosis to evaluate for malformations which can have a prognostic value in young children
If short stature is present, skeletal survey (if not performed at the time of diagnosis)
• Neurology consultation
• Age-adapted psychomotor or neuropsychological evaluation
• Electroencephalogram if seizures are suspected
• Review of brain MRI performed at the time of diagnosis to evaluate for malformations which can have a prognostic value in young children
• If short stature is present, skeletal survey (if not performed at the time of diagnosis)
## Treatment of Manifestations
Therapy is supportive and involves the following:
Special education programs tailored to the needs of the individual
Speech and language therapy
Behavioral therapy as needed
Occupational therapy as needed
Community services that provide support for families
Ritalin
Seizures are usually responsive to monotherapy with standard antiepileptic drugs (AEDs).
Growth hormone may be considered in individuals with mild growth retardation; objective efficiency of GH therapy has not been evaluated.
Intubation may be difficult in affected individuals with small chin [
• Special education programs tailored to the needs of the individual
• Speech and language therapy
• Behavioral therapy as needed
• Occupational therapy as needed
• Community services that provide support for families
## Surveillance
The following are appropriate:
Monitoring of head circumference and stature using standard growth charts
Neurologic follow-up from birth to adulthood to detect behavioral difficulties, hyperactivity, attention disorder, and motor problems (spasticity), and to monitor for evidence of seizures which can be late onset
Periodic neuropsychologic evaluation in order to adapt interventions and schooling to the level of the individual's cognitive abilities
• Monitoring of head circumference and stature using standard growth charts
• Neurologic follow-up from birth to adulthood to detect behavioral difficulties, hyperactivity, attention disorder, and motor problems (spasticity), and to monitor for evidence of seizures which can be late onset
• Periodic neuropsychologic evaluation in order to adapt interventions and schooling to the level of the individual's cognitive abilities
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The primary autosomal recessive microcephalies (MCPH) and Seckel syndrome (SCKS) spectrum disorders discussed in this
The parents of an affected child are obligate carriers and therefore carry one heterozygous pathogenic variant.
Heterozygous individuals (carriers) are asymptomatic.
At conception, each sib of one affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier if the parents are heterozygous.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygous individuals (carriers) are asymptomatic.
Note: Carriers are heterozygotes for these autosomal recessive disorders and are not at risk of developing the disorder. No health problem has been associated with carrier status.
The optimal time for determination of the genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The parents of an affected child are obligate carriers and therefore carry one heterozygous pathogenic variant.
• Heterozygous individuals (carriers) are asymptomatic.
• At conception, each sib of one affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier if the parents are heterozygous.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygous individuals (carriers) are asymptomatic.
• The optimal time for determination of the genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
•
## Mode of Inheritance
The primary autosomal recessive microcephalies (MCPH) and Seckel syndrome (SCKS) spectrum disorders discussed in this
## Risk to Family Members
The parents of an affected child are obligate carriers and therefore carry one heterozygous pathogenic variant.
Heterozygous individuals (carriers) are asymptomatic.
At conception, each sib of one affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier if the parents are heterozygous.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygous individuals (carriers) are asymptomatic.
• The parents of an affected child are obligate carriers and therefore carry one heterozygous pathogenic variant.
• Heterozygous individuals (carriers) are asymptomatic.
• At conception, each sib of one affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier if the parents are heterozygous.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygous individuals (carriers) are asymptomatic.
## Carrier (Heterozygote) Detection
Note: Carriers are heterozygotes for these autosomal recessive disorders and are not at risk of developing the disorder. No health problem has been associated with carrier status.
## Related Genetic Counseling Issues
The optimal time for determination of the genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of the genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Diagnosis
•
## Resources
No specific resources for Primary Autosomal Recessive Microcephalies and Seckel Syndrome Spectrum Disorders have been identified by
## Molecular Genetics
Primary Autosomal Recessive Microcephalies and Seckel Syndrome Spectrum Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Primary Autosomal Recessive Microcephalies and Seckel Syndrome Spectrum Disorders (
The genes in which mutation causes MCPH-SCKS spectrum disorders are involved in basic, intricate cell processes. Not surprisingly, loss of function of these genes results in overlapping phenotypes. The cell processes involved can include:
Control of DNA integrity (double-strand breaks)
Control of initiation of mitosis at cell cycle checkpoints 1 and 2
Control of the metaphase-anaphase checkpoint
Regulation of centrosome duplication
Regulation of mitotic spindle organization and kinetics
Two distinct pathogenic mechanisms give rise to MCPH-SCKS spectrum disorders.
For a detailed summary of gene and protein information for the genes listed below, see
Missense and nonsense variants and small and gross deletions have been reported; see
A homozygous 1-bp duplication in exon 5 of
See
The physiology of MCPH1 is complex. It has been implicated in various cellular processes including DNA damage checkpoint (ATM-and ATR-mediated DNA-damage response), control of intra-S and G2-M mitotic checkpoints, DNA repair, repression of the human telomerase reverse transcriptase (hTERT), and transcription. Interaction of MCPH1 with condensin II may explain the premature chromatin condensation that occurs in microcephalin-deficient microcephalies.
Chromosome preparations of patients with MCPH1 exhibit an elevated fraction of prophase-like cells and show poor metaphase resolution. Increased frequency of spontaneous chromosome breakage, endomitosis, and hypersensitivity to clastogenic agents was reported in one case [
See
Experimental depletion of WDR62 by siRNA results in spindle orientation defects, decreased integrity of centrosomes which are displaced from the spindle pole, and delayed mitotic progression [
A pathogenic variant, originally described as p.Ser81Ter in one family [
In one family the c.4186-15A>G variant was originally considered to result in the insertion of a new splice acceptor site, leading to a subsequent frameshift and a premature stop codon [
See
See
CASC protein functions as a molecular scaffold to dock other proteins (notably BUB1 and BUB1B) to kinetochores at the equatorial plate. It has two major roles during mitosis: proper attachment of the kinetochores of chromosome centromeres to the microtubule apparatus and spindle-assembly checkpoint (SAC) signaling. It is weakly expressed in interphase nuclei. Expression increases from prophase to anaphase, and declines during the exit of mitosis.
Even in consanguineous families, compound pathogenic variants have been reported [
Even in consanguineous families, compound heterozygosity of pathogenic variants has been reported [
Only one missense variant has been reported in
A balanced familial chromosome translocation t(1;4)(q31;p15.3) was reported in an infant with primary microcephaly [
An apparently balanced familial chromosome translocation t(1;4)(q31;p15.3) – in which the translocation breakpoint was situated within intron 17 of
See
ASPM localizes to centrosomes and is recruited in a microtubule-dependent manner to the pericentriolar matrix (PCM) at the spindle poles during mitosis, where it binds to the microtubule minus end. It colocalizes with the centrosomal marker γ-tubulin. It is concentrated at the midbody ring during cytokinesis [
In mice, truncating
One homozygous transition in the last nucleotide of intron 11 (c.3302-1G>C) was reported in a consanguineous Saudi family with SCKL [
See
CENPJ is present in the cytoplasm of proliferating cells. During centriole biogenesis, it is concentrated within the proximal lumen of both parental centrioles and procentrioles, and in the pericentriolar matrix.
CENPJ and Polo-like kinase PLK4 are recruited to the centrosome by CEP152 [
See
STIL is a cytoplasmic protein that localizes to the pericentriolar region surrounding parental centrioles. It is implicated in regulation of the mitotic spindle checkpoint by increasing phosphorylation of CDK1, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. STIL is recruited by PLK4 and is necessary for SAS6 recruitment to centrioles. It interacts with the centromere proteins CENPJ and SAS4 [
See
See
See
See
See
ATR forms a stable complex with ATRIP [
Once activated, ATR phosphorylates and activates several downstream effector kinases (BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1, and TP53) which collectively inhibit DNA replication and mitosis, promote DNA repair, and phosphorylate histone H2AX at sites of DNA damage. Activated ATR and Chk1 coordinate DNA replication, DNA repair, and cell-cycle transitions. Action of ATR requires its interaction with the FANCD2 complex (one of the complexes formed by genes associated with
A 2-bp deletion in exon 11 [
A homozygous T>G transversion 53 bp within intron 15 [
See
See
See
See
ATRIP mediates the accumulation of ATR on damaged chromatin via an interaction with the RPA complex (which recognizes and coats single-stranded DNA), resulting in accumulation of the ATR kinase at intranuclear foci induced by DNA damage.
See
• Control of DNA integrity (double-strand breaks)
• Control of initiation of mitosis at cell cycle checkpoints 1 and 2
• Control of the metaphase-anaphase checkpoint
• Regulation of centrosome duplication
• Regulation of mitotic spindle organization and kinetics
• Missense and nonsense variants and small and gross deletions have been reported; see
• A homozygous 1-bp duplication in exon 5 of
• A pathogenic variant, originally described as p.Ser81Ter in one family [
• In one family the c.4186-15A>G variant was originally considered to result in the insertion of a new splice acceptor site, leading to a subsequent frameshift and a premature stop codon [
• A 2-bp deletion in exon 11 [
• A homozygous T>G transversion 53 bp within intron 15 [
## Molecular Genetic Pathogenesis
The genes in which mutation causes MCPH-SCKS spectrum disorders are involved in basic, intricate cell processes. Not surprisingly, loss of function of these genes results in overlapping phenotypes. The cell processes involved can include:
Control of DNA integrity (double-strand breaks)
Control of initiation of mitosis at cell cycle checkpoints 1 and 2
Control of the metaphase-anaphase checkpoint
Regulation of centrosome duplication
Regulation of mitotic spindle organization and kinetics
Two distinct pathogenic mechanisms give rise to MCPH-SCKS spectrum disorders.
For a detailed summary of gene and protein information for the genes listed below, see
Missense and nonsense variants and small and gross deletions have been reported; see
A homozygous 1-bp duplication in exon 5 of
See
The physiology of MCPH1 is complex. It has been implicated in various cellular processes including DNA damage checkpoint (ATM-and ATR-mediated DNA-damage response), control of intra-S and G2-M mitotic checkpoints, DNA repair, repression of the human telomerase reverse transcriptase (hTERT), and transcription. Interaction of MCPH1 with condensin II may explain the premature chromatin condensation that occurs in microcephalin-deficient microcephalies.
Chromosome preparations of patients with MCPH1 exhibit an elevated fraction of prophase-like cells and show poor metaphase resolution. Increased frequency of spontaneous chromosome breakage, endomitosis, and hypersensitivity to clastogenic agents was reported in one case [
See
Experimental depletion of WDR62 by siRNA results in spindle orientation defects, decreased integrity of centrosomes which are displaced from the spindle pole, and delayed mitotic progression [
A pathogenic variant, originally described as p.Ser81Ter in one family [
In one family the c.4186-15A>G variant was originally considered to result in the insertion of a new splice acceptor site, leading to a subsequent frameshift and a premature stop codon [
See
See
CASC protein functions as a molecular scaffold to dock other proteins (notably BUB1 and BUB1B) to kinetochores at the equatorial plate. It has two major roles during mitosis: proper attachment of the kinetochores of chromosome centromeres to the microtubule apparatus and spindle-assembly checkpoint (SAC) signaling. It is weakly expressed in interphase nuclei. Expression increases from prophase to anaphase, and declines during the exit of mitosis.
Even in consanguineous families, compound pathogenic variants have been reported [
Even in consanguineous families, compound heterozygosity of pathogenic variants has been reported [
Only one missense variant has been reported in
A balanced familial chromosome translocation t(1;4)(q31;p15.3) was reported in an infant with primary microcephaly [
An apparently balanced familial chromosome translocation t(1;4)(q31;p15.3) – in which the translocation breakpoint was situated within intron 17 of
See
ASPM localizes to centrosomes and is recruited in a microtubule-dependent manner to the pericentriolar matrix (PCM) at the spindle poles during mitosis, where it binds to the microtubule minus end. It colocalizes with the centrosomal marker γ-tubulin. It is concentrated at the midbody ring during cytokinesis [
In mice, truncating
One homozygous transition in the last nucleotide of intron 11 (c.3302-1G>C) was reported in a consanguineous Saudi family with SCKL [
See
CENPJ is present in the cytoplasm of proliferating cells. During centriole biogenesis, it is concentrated within the proximal lumen of both parental centrioles and procentrioles, and in the pericentriolar matrix.
CENPJ and Polo-like kinase PLK4 are recruited to the centrosome by CEP152 [
See
STIL is a cytoplasmic protein that localizes to the pericentriolar region surrounding parental centrioles. It is implicated in regulation of the mitotic spindle checkpoint by increasing phosphorylation of CDK1, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. STIL is recruited by PLK4 and is necessary for SAS6 recruitment to centrioles. It interacts with the centromere proteins CENPJ and SAS4 [
See
See
See
See
See
ATR forms a stable complex with ATRIP [
Once activated, ATR phosphorylates and activates several downstream effector kinases (BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1, and TP53) which collectively inhibit DNA replication and mitosis, promote DNA repair, and phosphorylate histone H2AX at sites of DNA damage. Activated ATR and Chk1 coordinate DNA replication, DNA repair, and cell-cycle transitions. Action of ATR requires its interaction with the FANCD2 complex (one of the complexes formed by genes associated with
A 2-bp deletion in exon 11 [
A homozygous T>G transversion 53 bp within intron 15 [
See
See
See
See
ATRIP mediates the accumulation of ATR on damaged chromatin via an interaction with the RPA complex (which recognizes and coats single-stranded DNA), resulting in accumulation of the ATR kinase at intranuclear foci induced by DNA damage.
See
• Control of DNA integrity (double-strand breaks)
• Control of initiation of mitosis at cell cycle checkpoints 1 and 2
• Control of the metaphase-anaphase checkpoint
• Regulation of centrosome duplication
• Regulation of mitotic spindle organization and kinetics
• Missense and nonsense variants and small and gross deletions have been reported; see
• A homozygous 1-bp duplication in exon 5 of
• A pathogenic variant, originally described as p.Ser81Ter in one family [
• In one family the c.4186-15A>G variant was originally considered to result in the insertion of a new splice acceptor site, leading to a subsequent frameshift and a premature stop codon [
• A 2-bp deletion in exon 11 [
• A homozygous T>G transversion 53 bp within intron 15 [
Missense and nonsense variants and small and gross deletions have been reported; see
A homozygous 1-bp duplication in exon 5 of
See
The physiology of MCPH1 is complex. It has been implicated in various cellular processes including DNA damage checkpoint (ATM-and ATR-mediated DNA-damage response), control of intra-S and G2-M mitotic checkpoints, DNA repair, repression of the human telomerase reverse transcriptase (hTERT), and transcription. Interaction of MCPH1 with condensin II may explain the premature chromatin condensation that occurs in microcephalin-deficient microcephalies.
Chromosome preparations of patients with MCPH1 exhibit an elevated fraction of prophase-like cells and show poor metaphase resolution. Increased frequency of spontaneous chromosome breakage, endomitosis, and hypersensitivity to clastogenic agents was reported in one case [
• Missense and nonsense variants and small and gross deletions have been reported; see
• A homozygous 1-bp duplication in exon 5 of
See
Experimental depletion of WDR62 by siRNA results in spindle orientation defects, decreased integrity of centrosomes which are displaced from the spindle pole, and delayed mitotic progression [
A pathogenic variant, originally described as p.Ser81Ter in one family [
In one family the c.4186-15A>G variant was originally considered to result in the insertion of a new splice acceptor site, leading to a subsequent frameshift and a premature stop codon [
See
• A pathogenic variant, originally described as p.Ser81Ter in one family [
• In one family the c.4186-15A>G variant was originally considered to result in the insertion of a new splice acceptor site, leading to a subsequent frameshift and a premature stop codon [
See
CASC protein functions as a molecular scaffold to dock other proteins (notably BUB1 and BUB1B) to kinetochores at the equatorial plate. It has two major roles during mitosis: proper attachment of the kinetochores of chromosome centromeres to the microtubule apparatus and spindle-assembly checkpoint (SAC) signaling. It is weakly expressed in interphase nuclei. Expression increases from prophase to anaphase, and declines during the exit of mitosis.
Even in consanguineous families, compound pathogenic variants have been reported [
Even in consanguineous families, compound heterozygosity of pathogenic variants has been reported [
Only one missense variant has been reported in
A balanced familial chromosome translocation t(1;4)(q31;p15.3) was reported in an infant with primary microcephaly [
An apparently balanced familial chromosome translocation t(1;4)(q31;p15.3) – in which the translocation breakpoint was situated within intron 17 of
See
ASPM localizes to centrosomes and is recruited in a microtubule-dependent manner to the pericentriolar matrix (PCM) at the spindle poles during mitosis, where it binds to the microtubule minus end. It colocalizes with the centrosomal marker γ-tubulin. It is concentrated at the midbody ring during cytokinesis [
In mice, truncating
One homozygous transition in the last nucleotide of intron 11 (c.3302-1G>C) was reported in a consanguineous Saudi family with SCKL [
See
CENPJ is present in the cytoplasm of proliferating cells. During centriole biogenesis, it is concentrated within the proximal lumen of both parental centrioles and procentrioles, and in the pericentriolar matrix.
CENPJ and Polo-like kinase PLK4 are recruited to the centrosome by CEP152 [
See
STIL is a cytoplasmic protein that localizes to the pericentriolar region surrounding parental centrioles. It is implicated in regulation of the mitotic spindle checkpoint by increasing phosphorylation of CDK1, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. STIL is recruited by PLK4 and is necessary for SAS6 recruitment to centrioles. It interacts with the centromere proteins CENPJ and SAS4 [
See
See
See
See
See
ATR forms a stable complex with ATRIP [
Once activated, ATR phosphorylates and activates several downstream effector kinases (BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1, and TP53) which collectively inhibit DNA replication and mitosis, promote DNA repair, and phosphorylate histone H2AX at sites of DNA damage. Activated ATR and Chk1 coordinate DNA replication, DNA repair, and cell-cycle transitions. Action of ATR requires its interaction with the FANCD2 complex (one of the complexes formed by genes associated with
A 2-bp deletion in exon 11 [
A homozygous T>G transversion 53 bp within intron 15 [
See
• A 2-bp deletion in exon 11 [
• A homozygous T>G transversion 53 bp within intron 15 [
See
See
##
See
ATRIP mediates the accumulation of ATR on damaged chromatin via an interaction with the RPA complex (which recognizes and coats single-stranded DNA), resulting in accumulation of the ATR kinase at intranuclear foci induced by DNA damage.
See
## References
## Literature Cited
## Chapter Notes
This publication has been supported by the Fondation Jérome Lejeune and the Fondation pour la Recherche Médicale.
Séverine Drunat, PharmD, PhD (2013-present)Bénédicte Gérard, PharmD, PhD, GC; Hôpital Robert Debré (2009-2013)Pierre Gressens, MD, PhD (2009-present)Angela M Kaindl, MD, PhD; Charité Universitätsmedizin (2009-2013)Sandrine Passemard, MD (2009-present)Luigi Titomanlio, MD; Hôpital Robert Debré (2009-2013)Alain Verloes, MD, PhD (2009-present)
10 September 2018 (ma) Chapter retired: Chapter does not reflect current use of genetic testing.
31 October 2013 (me) Comprehensive update posted live
1 September 2009 (me) Review posted live
10 November 2008 (av) Original submission
• 10 September 2018 (ma) Chapter retired: Chapter does not reflect current use of genetic testing.
• 31 October 2013 (me) Comprehensive update posted live
• 1 September 2009 (me) Review posted live
• 10 November 2008 (av) Original submission
## Acknowledgments
This publication has been supported by the Fondation Jérome Lejeune and the Fondation pour la Recherche Médicale.
## Author History
Séverine Drunat, PharmD, PhD (2013-present)Bénédicte Gérard, PharmD, PhD, GC; Hôpital Robert Debré (2009-2013)Pierre Gressens, MD, PhD (2009-present)Angela M Kaindl, MD, PhD; Charité Universitätsmedizin (2009-2013)Sandrine Passemard, MD (2009-present)Luigi Titomanlio, MD; Hôpital Robert Debré (2009-2013)Alain Verloes, MD, PhD (2009-present)
## Revision History
10 September 2018 (ma) Chapter retired: Chapter does not reflect current use of genetic testing.
31 October 2013 (me) Comprehensive update posted live
1 September 2009 (me) Review posted live
10 November 2008 (av) Original submission
• 10 September 2018 (ma) Chapter retired: Chapter does not reflect current use of genetic testing.
• 31 October 2013 (me) Comprehensive update posted live
• 1 September 2009 (me) Review posted live
• 10 November 2008 (av) Original submission
|
[
"Y Adachi, A Poduri, A Kawaguch, G Yoon, MA Salih, F Yamashita, CA Walsh, AJ Barkovich. Congenital microcephaly with a simplified gyral pattern: associated findings and their significance.. AJNR Am J Neuroradiol. 2011;32:1123-9",
"MS Al-Dosari, R Shaheen, D Colak, FS Alkuraya. Novel CENPJ mutation causes Seckel syndrome.. J Med Genet. 2010;47:411-4",
"C Arquint, KF Sonnen, YD Stierhof, EA Nigg. Cell-cycle-regulated expression of STIL controls centriole number in human cells.. J Cell Sci. 2012;125:1342-52",
"S Awad, MS Al-Dosari, N Al-Yacoub, D Colak, MA Salih, FS Alkuraya, C Poizat. Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis.. Hum Mol Genet. 2013;22:2200-13",
"L Baala, S Briault, HC Etchevers, F Laumonnier, A Natiq, J Amiel, N Boddaert, C Picard, A Sbiti, A Asermouh, T Attié-Bitach, F Encha-Razavi, A Munnich, A Sefiani, S Lyonnet. Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis.. Nat Genet. 2007;39:454-6",
"CA Bacino, LA Arriola, J Wiszniewska, PE Bonnen. WDR62 missense mutation in a consanguineous family with primary microcephaly.. Am J Med Genet A. 2012;158A:622-5",
"AJ Barkovich, DM Ferriero, RM Barr, P Gressens, WB Dobyns, CL Truwit, P Evrard. Microlissencephaly: a heterogeneous malformation of cortical development.. Neuropediatrics. 1998;29:113-9",
"L Basel-Vanagaite, WB Dobyns. Clinical and brain imaging heterogeneity of severe microcephaly.. Pediatr Neurol. 2010;43:7-16",
"R Basto, J Lau, T Vinogradova, A Gardiol, CG Woods, A Khodjakov, JW Raff. Flies without centrioles.. Cell. 2006;125:1375-86",
"V Bhat, SC Girimaji, G Mohan, HR Arvinda, P Singhmar, MR Duvvari, A Kumar. Mutations in WDR62, encoding a centrosomal and nuclear protein, in Indian primary microcephaly families with cortical malformations.. Clin Genet. 2011;80:532-40",
"K Bilguvar, AK Oztürk, A Louvi, KY Kwan, M Choi, B Tatli, D Yalnizoğlu, B Tüysüz, AO Cağlayan, S Gökben, H Kaymakçalan, T Barak, M Bakircioğlu, K Yasuno, W Ho, S Sanders, Y Zhu, S Yilmaz, A Dinçer, MH Johnson, RA Bronen, N Koçer, H Per, S Mane, MN Pamir, C Yalçinkaya, S Kumandaş, M Topçu, M Ozmen, N Sestan, RP Lifton, MW State, M Günel. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.. Nature. 2010;467:207-10",
"MA Bogoyevitch, YY Yeap, Z Qu, KR Ngoei, YY Yip, TT Zhao, JI Heng, DC Ng. WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression.. J Cell Sci. 2012;125:5096-109",
"J Bond, E Roberts, GH Mochida, DJ Hampshire, S Scott, JM Askham, K Springell, M Mahadevan, YJ Crow, AF Markham, CA Walsh, CG Woods. ASPM is a major determinant of cerebral cortical size.. Nat Genet. 2002;32:316-20",
"J Bond, E Roberts, K Springell, SB Lizarraga, S Scott, J Higgins, DJ Hampshire, EE Morrison, GF Leal, EO Silva, SM Costa, D Baralle, M Raponi, G Karbani, Y Rashid, H Jafri, C Bennett, P Corry, CA Walsh, CG Woods. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size.. Nat Genet. 2005;37:353-5",
"J Bond, S Scott, DJ Hampshire, K Springell, P Corry, MJ Abramowicz, GH Mochida, RC Hennekam, ER Maher, JP Fryns, A Alswaid, H Jafri, Y Rashid, A Mubaidin, CA Walsh, E Roberts, CG Woods. Protein-truncating mutations in ASPM cause variable reduction in brain size.. Am J Hum Genet. 2003;73:1170-7",
"AD Borglum, T Balslev, A Haagerup, N Birkebaek, H Binderup, TA Kruse, JM Hertz. A new locus for Seckel syndrome on chromosome 18p11.31-q11.2.. Eur J Hum Genet. 2001;9:753-7",
"M Breuss, JI Heng, K Poirier, G Tian, XH Jaglin, Z Qu, A Braun, T Gstrein, L Ngo, M Haas, N Bahi-Buisson, ML Moutard, S Passemard, A Verloes, P Gressens, Y Xie, KJ Robson, DS Rani, K Thangaraj, T Clausen, J Chelly, NJ Cowan, DA Keays. Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities.. Cell Rep. 2012;2:1554-62",
"JJ Buchman, HC Tseng, Y Zhou, CL Frank, Z Xie, LH Tsai. Cdk5rap2 interacts with pericentrin to maintain the neural progenitor pool in the developing neocortex.. Neuron. 2010;66:386-402",
"D Buck, L Malivert, R de Chasseval, A Barraud, MC Fondanèche, O Sanal, A Plebani, JL Stéphan, M Hufnagel, F le Deist, A Fischer, A Durandy, JP de Villartay, P Revy. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly.. Cell. 2006;124:287-99",
"JM Capo-Chichi, SK Bharti, JA Sommers, T Yammine, E Chouery, L Patry, GA Rouleau, ME Samuels, FF Hamdan, JL Michaud, RM Brosh, A Mégarbane, Z Kibar. Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome.. Hum Mutat. 2013;34:103-7",
"J Chang, O Cizmecioglu, I Hoffmann, K. Rhee. PLK2 phosphorylation is critical for CPAP function in procentriole formation during the centrosome cycle.. EMBO J. 2010;29:2395-406",
"DA Chistiakov, NV Voronova, AP Chistiakov. Ligase IV syndrome.. Eur J Med Genet. 2009;52:373-8",
"O Cizmecioglu, M Arnold, R Bahtz, F Settele, L Ehret, U Haselmann-Weiss, C Antony, I. Hoffmann. Cep152 acts as a scaffold for recruitment of Plk4 and CPAP to the centrosome.. J Cell Biol. 2010;191:731-9",
"D Cortez, S Guntuku, J Qin, SJ Elledge. ATR and ATRIP: partners in checkpoint signaling.. Science. 2001;294:1713-6",
"J Cox, AP Jackson, J Bond, CG Woods. What primary microcephaly can tell us about brain growth.. Trends Mol Med. 2006;12:358-66",
"TD Cushion, WB Dobyns, JG Mullins, N Stoodley, SK Chung, AE Fry, U Hehr, R Gunny, AS Aylsworth, P Prabhakar, G Uyanik, J Rankin, MI Rees, DT Pilz. Overlapping cortical malformations and mutations in TUBB2B and TUBA1A.. Brain. 2013;136:536-48",
"H Darvish, S Esmaeeli-Nieh, GB Monajemi, M Mohseni, S Ghasemi-Firouzabadi, SS Abedini, I Bahman, P Jamali, S Azimi, F Mojahedi, A Dehghan, Y Shafeghati, A Jankhah, M Falah, MJ Soltani Banavandi, M Ghani-Kakhi, M Garshasbi, F Rakhshani, A Naghavi, A Tzschach, H Neitzel, HH Ropers, AW Kuss, F Behjati, K Kahrizi, H Najmabadi. A clinical and molecular genetic study of 112 Iranian families with primary microcephaly.. J Med Genet. 2010;47:823-8",
"A Dauber, SH Lafranchi, Z Maliga, JC Lui, JE Moon, C McDeed, K Henke, J Zonana, GA Kingman, TH Pers, J Baron, RG Rosenfeld, JN Hirschhorn, MP Harris, V Hwa. Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein.. J Clin Endocrinol Metab. 2012;97:E2140-51",
"SA de Munnik, LS Bicknell, S Aftimos, JY Al-Aama, Y van Bever, MB Bober, J Clayton-Smith, AY Edrees, M Feingold, A Fryer, JM van Hagen, RC Hennekam, MC Jansweijer, D Johnson, SG Kant, JM Opitz, AR Ramadevi, W Reardon, A Ross, P Sarda, CT Schrander-Stumpel, J Schoots, IK Temple, PA Terhal, A Toutain, CA Wise, M Wright, DL Skidmore, ME Samuels, LH Hoefsloot, NV Knoers, HG Brunner, AP Jackson, EM Bongers. Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis.. Eur J Hum Genet. 2012;20:598-606",
"L de Pontual, E Yao, P Callier, L Faivre, V Drouin, S Cariou, A Van Haeringen, D Geneviève, A Goldenberg, M Oufadem, S Manouvrier, A Munnich, JA Vidigal, M Vekemans, S Lyonnet, A Henrion-Caude, A Ventura, J Amiel. Germline deletion of the miR-17~92 cluster causes skeletal and growth defects in humans.. Nat Genet. 2011;43:1026-30",
"J Desir, M Cassart, P David, P Van Bogaert, M. Abramowicz. Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally.. Am J Med Genet A. 2008;146A:1439-43",
"P Edery, C Marcaillou, M Sahbatou, A Labalme, J Chastang, R Touraine, E Tubacher, F Senni, MB Bober, S Nampoothiri, PS Jouk, E Steichen, S Berland, A Toutain, CA Wise, D Sanlaville, F Rousseau, F Clerget-Darpoux, AL Leutenegger. Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA.. Science. 2011;332:240-3",
"M Farooq, S Baig, N Tommerup, KW Kjaer. Craniosynostosis-microcephaly with chromosomal breakage and other abnormalities is caused by a truncating MCPH1 mutation and is allelic to premature chromosomal condensation syndrome and primary autosomal recessive microcephaly type 1.. Am J Med Genet A. 2010;152A:495-7",
"M Garshasbi, MM Motazacker, K Kahrizi, F Behjati, SS Abedini, SE Nieh, SG Firouzabadi, C Becker, F Rüschendorf, P Nürnberg, A Tzschach, R Vazifehmand, F Erdogan, R Ullmann, S Lenzner, AW Kuss, HH Ropers, H Najmabadi. SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly.. Hum Genet. 2006;118:708-15",
"A Genin, J Desir, N Lambert, M Biervliet, N Van Der Aa, G Pierquin, A Killian, M Tosi, M Urbina, A Lefort, F Libert, I Pirson, M. Abramowicz. Kinetochore KMN network gene CASC5 mutated in primary microcephaly.. Hum Mol Genet. 2012;21:5306-17",
"D Germanaud, M Rossi, G Bussy, D Gérard, L Hertz-Pannier, P Blanchet, H Dollfus, F Giuliano, V Bennouna-Greene, P Sarda, S Sigaudy, A Curie, MC Vincent, R Touraine, V des Portes. The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males.. Clin Genet. 2011;79:225-35",
"M Ghani-Kakhki, PN Robinson, S Morlot, D Mitter, M Trimborn, B Albrecht, R Varon, K Sperling, H Neitzel. Two missense mutations in the primary autosomal recessive microcephaly gene MCPH1 disrupt the function of the highly conserved N-terminal BRCT domain of microcephalin.. Mol Syndromol. 2012;3:6-13",
"J Goodship, H Gill, J Carter, A Jackson, M Splitt, M Wright. Autozygosity mapping of a seckel syndrome locus to chromosome 3q22. 1-q24.. Am J Hum Genet. 2000;67:498-503",
"DL Guernsey, H Jiang, J Hussin, M Arnold, K Bouyakdan, S Perry, T Babineau-Sturk, J Beis, N Dumas, SC Evans, M Ferguson, M Matsuoka, C Macgillivray, M Nightingale, L Patry, AL Rideout, A Thomas, A Orr, I Hoffmann, JL Michaud, P Awadalla, DC Meek, M Ludman, ME Samuels. Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4.. Am J Hum Genet. 2010;87:40-51",
"A Gul, MJ Hassan, S Hussain, SI Raza, MS Chishti, W Ahmad. A novel deletion mutation in CENPJ gene in a Pakistani family with autosomal recessive primary microcephaly.. J Hum Genet. 2006a;51:760-4",
"A Gul, MJ Hassan, S Mahmood, W Chen, S Rahmani, MI Naseer, L Dellefave, N Muhammad, MA Rafiq, M Ansar, MS Chishti, G Ali, T Siddique, W Ahmad. Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: Novel sequence variants in ASPM gene.. Neurogenetics. 2006b;7:105-10",
"A Gul, M Tariq, MN Khan, MJ Hassan, G Ali, W Ahmad. Novel protein-truncating mutations in the ASPM gene in families with autosomal recessive primary microcephaly.. J Neurogenet. 2007;21:153-63",
"Y Gürkan, T Hosten, H Dayioglu, K Toker, M. Solak. Anesthesia for Seckel syndrome.. Paediatr Anaesth. 2006;16:359-60",
"MJ Hassan, MS Chishti, SM Jamal, M Tariq, W Ahmad. A syndromic form of autosomal recessive congenital microcephaly (Jawad syndrome) maps to chromosome 18p11.22-q11.2.. Hum Genet. 2008;123:77-82",
"MJ Hassan, M Khurshid, Z Azeem, P John, G Ali, MS Chishti, W Ahmad. Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly.. BMC Med Genet. 2007;8:58",
"A Hayani, CR Suarez, Z Molnar, M LeBeau, J Godwin. Acute myeloid leukaemia in a patient with Seckel syndrome.. J Med Genet. 1994;31:148-9",
"H He, S Liyanarachchi, K Akagi, R Nagy, J Li, RC Dietrich, W Li, N Sebastian, B Wen, B Xin, J Singh, P Yan, H Alder, E Haan, D Wieczorek, B Albrecht, E Puffenberger, H Wang, JA Westman, RA Padgett, DE Symer, A de la Chapelle. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I.. Science. 2011;332:238-40",
"J Higgins, C Midgley, AM Bergh, SM Bell, JM Askham, E Roberts, RK Binns, SM Sharif, C Bennett, DM Glover, CG Woods, EE Morrison, J Bond. Human ASPM participates in spindle organisation, spindle orientation and cytokinesis.. BMC Cell Biol. 2010;11:85",
"MS Hussain, SM Baig, S Neumann, G Nürnberg, M Farooq, I Ahmad, T Alef, HC Hennies, M Technau, J Altmüller, P Frommolt, H Thiele, AA Noegel, P Nürnberg. A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function.. Am J Hum Genet. 2012;90:871-8",
"MS Hussain, SM Baig, S Neumann, VS Peche, S Szczepanski, G Nürnberg, M Tariq, M Jameel, T Naeem, A Fatima, NA Malik, I Ahmad, J Altmüller, P Frommolt, H Thiele, W Höhne, G Yigit, B Wollnik, BA Neubauer, P Nürnberg, AA Noegel. CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.. Hum Mol Genet. 2013;22:5199-214",
"L Issa, K Mueller, K Seufert, N Kraemer, H Rosenkotter, O Ninnemann, M Buob, AM Kaindl, DJ Morris-Rosendahl. Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation.. Orphanet J Rare Dis. 2013;8:59",
"AP Jackson, H Eastwood, SM Bell, J Adu, C Toomes, IM Carr, E Roberts, DJ Hampshire, YJ Crow, AJ Mighell, G Karbani, H Jafri, Y Rashid, RF Mueller, AF Markham, CG Woods. Identification of microcephalin, a protein implicated in determining the size of the human brain.. Am J Hum Genet. 2002;71:136-42",
"XH Jaglin, K Poirier, Y Saillour, E Buhler, G Tian, N Bahi-Buisson, C Fallet-Bianco, F Phan-Dinh-Tuy, XP Kong, P Bomont, L Castelnau-Ptakhine, S Odent, P Loget, M Kossorotoff, I Snoeck, G Plessis, P Parent, C Beldjord, C Cardoso, A Represa, J Flint, DA Keays, NJ Cowan, J Chelly. Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria.. Nat Genet. 2009;41:746-52",
"CR Jamieson, C Govaerts, MJ Abramowicz. Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15.. Am J Hum Genet. 1999;65:1465-9",
"E Kalay, G Yigit, Y Aslan, KE Brown, E Pohl, LS Bicknell, H Kayserili, Y Li, B Tüysüz, G Nürnberg, W Kiess, M Koegl, I Baessmann, K Buruk, B Toraman, S Kayipmaz, S Kul, M Ikbal, DJ Turner, MS Taylor, J Aerts, C Scott, K Milstein, H Dollfus, D Wieczorek, HG Brunner, M Hurles, AP Jackson, A Rauch, P Nürnberg, A Karagüzel, B Wollnik. CEP152 is a genome maintenance protein disrupted in Seckel syndrome.. Nat Genet. 2011;43:23-6",
"S Katyal, PJ McKinnon. DNA repair deficiency and neurodegeneration.. Cell Cycle. 2007;6:2360-5",
"K Kim, S Lee, J Chang, K. Rhee. A novel function of CEP135 as a platform protein of C-NAP1 for its centriolar localization.. Exp Cell Res. 2008;314:3692-700",
"L Klinge, J Schaper, D Wieczorek, T Voit. Microlissencephaly in microcephalic osteodysplastic primordial dwarfism: a case report and review of the literature.. Neuropediatrics. 2002;33:309-13",
"N Kouprina, A Pavlicek, NK Collins, M Nakano, VN Noskov, J Ohzeki, GH Mochida, JI Risinger, P Goldsmith, M Gunsior, G Solomon, W Gersch, JH Kim, JC Barrett, CA Walsh, J Jurka, H Masumoto, V Larionov. The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein.. Hum Mol Genet. 2005;14:2155-65",
"R Kousar, MJ Hassan, B Khan, S Basit, S Mahmood, A Mir, W Ahmad, M Ansar. Mutations in WDR62 gene in Pakistani families with autosomal recessive primary microcephaly.. BMC Neurol. 2011;11:119",
"R Kousar, H Nawaz, M Khurshid, G Ali, SU Khan, H Mir, M Ayub, A Wali, N Ali, M Jelani, S Basit, W Ahmad, M Ansar. Mutation analysis of the ASPM gene in 18 Pakistani families with autosomal recessive primary microcephaly.. J Child Neurol. 2010;25:715-20",
"A Kumar, SH Blanton, M Babu, M Markandaya, SC Girimaji. Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.. Clin Genet. 2004;66:341-8",
"A Kumar, SC Girimaji, MR Duvvari, SH Blanton. Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly.. Am J Hum Genet. 2009;84:286-90",
"JW Leung, A Leitch, JL Wood, C Shaw-Smith, K Metcalfe, LS Bicknell, AP Jackson, J Chen. SET nuclear oncogene associates with microcephalin/MCPH1 and regulates chromosome condensation.. J Biol Chem. 2011;286:21393-400",
"H Loffler, A Fechter, M Matuszewska, R Saffrich, M Mistrik, J Marhold, C Hornung, F Westermann, J Bartek, A. Krämer. Cep63 recruits Cdk1 to the centrosome: implications for regulation of mitotic entry, centrosome amplification, and genome maintenance.. Cancer Res. 2011;71:2129-39",
"S Mahmood, W Ahmad, MJ Hassan. Autosomal Recessive Primary Microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum.. Orphanet J Rare Dis. 2011;6:39",
"F Majewski, T Goecke. Studies of microcephalic primordial dwarfism I: approach to a delineation of the Seckel syndrome.. Am J Med Genet. 1982;12:7-21",
"F Majewski, M Ranke, A Schinzel. Studies of microcephalic primordial dwarfism II: the osteodysplastic type II of primordial dwarfism.. Am J Med Genet. 1982a;12:23-35",
"F Majewski, M Stoeckenius, H Kemperdick. Studies of microcephalic primordial dwarfism III: an intrauterine dwarf with platyspondyly and anomalies of pelvis and clavicles--osteodysplastic primordial dwarfism type III.. Am J Med Genet. 1982b;12:37-42",
"MM Memon, SI Raza, S Basit, R Kousar, W Ahmad, M Ansar. A novel WDR62 mutation causes primary microcephaly in a Pakistani family.. Mol Biol Rep. 2013;40:591-5",
"GH Mochida, CA Walsh. Molecular genetics of human microcephaly.. Curr Opin Neurol. 2001;14:151-6",
"H Mokrani-Benhelli, L Gaillard, P Biasutto, T Le Guen, F Touzot, N Vasquez, J Komatsu, E Conseiller, C Pïcard, E Gluckman, C Francannet, A Fischer, A Durandy, J Soulier, JP de Villartay, M Cavazzana-Calvo, P Revy. Primary microcephaly, impaired DNA replication, and genomic instability caused by compound heterozygous ATR mutations.. Hum Mutat. 2013;34:374-84",
"F Muhammad, S Mahmood Baig, L Hansen, M Sajid Hussain, I Anjum Inayat, M Aslam, J Anver Qureshi, M Toilat, E Kirst, M Wajid, P Nürnberg, H Eiberg, N Tommerup, KW Kjaer. Compound heterozygous ASPM mutations in Pakistani MCPH families.. Am J Med Genet A. 2009;149A:926-30",
"DR Murdock, GD Clark, MN Bainbridge, I Newsham, YQ Wu, DM Muzny, SW Cheung, RA Gibbs, MB Ramocki. Whole-exome sequencing identifies compound heterozygous mutations in WDR62 in siblings with recurrent polymicrogyria.. Am J Med Genet A. 2011;155A:2071-7",
"J Najm, D Horn, I Wimplinger, JA Golden, VV Chizhikov, J Sudi, SL Christian, R Ullmann, A Kuechler, CA Haas, A Flubacher, LR Charnas, G Uyanik, U Frank, E Klopocki, WB Dobyns, K Kutsche. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum.. Nat Genet. 2008;40:1065-7",
"H Neitzel, LM Neumann, D Schindler, A Wirges, H Tönnies, M Trimborn, A Krebsova, R Richter, K Sperling. Premature chromosome condensation in humans associated with microcephaly and mental retardation: a novel autosomal recessive condition.. Am J Hum Genet. 2002;70:1015-22",
"AK Nicholas, M Khurshid, J Désir, OP Carvalho, JJ Cox, G Thornton, R Kausar, M Ansar, W Ahmad, A Verloes, S Passemard, JP Misson, S Lindsay, F Gergely, WB Dobyns, E Roberts, M Abramowicz, CG Woods. WDR62 is associated with the spindle pole and is mutated in human microcephaly.. Nat Genet. 2010;42:1010-4",
"AK Nicholas, EA Swanson, JJ Cox, G Karbani, S Malik, K Springell, D Hampshire, M Ahmed, J Bond, D Di Benedetto, M Fichera, C Romano, WB Dobyns, CG Woods. The molecular landscape of ASPM mutations in primary microcephaly.. J Med Genet. 2009;46:249-53",
"M O'Driscoll, PA Jeggo. The role of the DNA damage response pathways in brain development and microcephaly: insight from human disorders.. DNA Repair (Amst) 2008;7:1039-50",
"M O'Driscoll, VL Ruiz-Perez, CG Woods, PA Jeggo, JA Goodship. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome.. Nat Genet. 2003;33:497-501",
"T Ogi, S Walker, T Stiff, E Hobson, S Limsirichaikul, G Carpenter, K Prescott, M Suri, PJ Byrd, M Matsuse, N Mitsutake, Y Nakazawa, P Vasudevan, M Barrow, GS Stewart, AM Taylor, M O'Driscoll, PA Jeggo. Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome.. PLoS Genet. 2012;8",
"P Ostergaard, MA Simpson, A Mendola, P Vasudevan, FC Connell, A van Impel, AT Moore, BL Loeys, A Ghalamkarpour, A Onoufriadis, I Martinez-Corral, S Devery, JG Leroy, L van Laer, A Singer, MG Bialer, M McEntagart, O Quarrell, G Brice, RC Trembath, S Schulte-Merker, T Makinen, M Vikkula, PS Mortimer, S Mansour, S Jeffery. Mutations in KIF1 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy.. Am J Hum Genet. 2012;90:356-62",
"AT Pagnamenta, JE Murray, G Yoon, E Sadighi Akha, V Harrison, LS Bicknell, K Ajilogba, H Stewart, U Kini, JC Taylor, DA Keays, AP Jackson, SJ Knight. A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss.. Am J Med Genet A. 2012;158A:2577-82",
"E Papari, M Bastami, A Farhadi, SS Abedini, M Hosseini, I Bahman, M Mohseni, M Garshasbi, LA Moheb, F Behjati, K Kahrizi, HH Ropers, H Najmabadi. Investigation of primary microcephaly in Bushehr province of Iran: novel STIL and ASPM mutations.. Clin Genet. 2013;83:488-90",
"M Paramasivam, YJ Chang, JJ LoTurco. ASPM and citron kinase co-localize to the midbody ring during cytokinesis.. Cell Cycle. 2007;6:1605-12",
"JS Park, MK Lee, JL Rosales, KY Lee. Primary microcephaly 3 (MCPH3): revisiting two critical mutations.. Cell Cycle. 2011;10:1331-3",
"S Passemard, L Titomanlio, M Elmaleh, A Afenjar, JL Alessandri, G Andria, TB de Villemeur, O Boespflug-Tanguy, L Burglen, E Del Giudice, F Guimiot, C Hyon, B Isidor, A Mégarbané, U Moog, S Odent, K Hernandez, N Pouvreau, I Scala, M Schaer, P Gressens, B Gerard, A Verloes. Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations.. Neurology. 2009;73:962-9",
"L Pattison, YJ Crow, VJ Deeble, AP Jackson, H Jafri, Y Rashid, E Roberts, CG Woods. A fifth locus for primary autosomal recessive microcephaly maps to chromosome 1q31.. Am J Hum Genet. 2000;67:1578-80",
"X Piao, BS Chang, A Bodell, K Woods, B Benzeev, M Topcu, R Guerrini, H Goldberg-Stern, L Sztriha, WB Dobyns, AJ Barkovich, CA Walsh. Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes.. Ann Neurol. 2005;58:680-7",
"B Pichon, S Vankerckhove, G Bourrouillou, L Duprez, MJ Abramowicz. A translocation breakpoint disrupts the ASPM gene in a patient with primary microcephaly.. Eur J Hum Genet. 2004;12:419-21",
"MJ Pierce, RP Morse. The neurologic findings in Taybi-Linder syndrome (MOPD I/III): case report and review of the literature.. Am J Med Genet A. 2012;158A:606-10",
"K Poirier, DA Keays, F Francis, Y Saillour, N Bahi, S Manouvrier, C Fallet-Bianco, L Pasquier, A Toutain, FP Tuy, T Bienvenu, S Joriot, S Odent, D Ville, I Desguerre, A Goldenberg, ML Moutard, JP Fryns, H van Esch, RJ Harvey, C Siebold, J Flint, C Beldjord, J Chelly. Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).. Hum Mutat. 2007;28:1055-64",
"K Poirier, N Lebrun, L Broix, G Tian, Y Saillour, C Boscheron, E Parrini, S Valence, BS Pierre, M Oger, D Lacombe, D Geneviève, E Fontana, F Darra, C Cances, M Barth, D Bonneau, BD Bernadina, S N'guyen, C Gitiaux, P Parent, V des Portes, JM Pedespan, V Legrez, L Castelnau-Ptakine, P Nitschke, T Hieu, C Masson, D Zelenika, A Andrieux, F Francis, R Guerrini, NJ Cowan, N Bahi-Buisson, J Chelly. Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.. Nat Genet. 2013;45:639-47",
"K Poirier, Y Saillour, N Bahi-Buisson, XH Jaglin, C Fallet-Bianco, R Nabbout, L Castelnau-Ptakhine, A Roubertie, T Attie-Bitach, I Desguerre, D Genevieve, C Barnerias, B Keren, N Lebrun, N Boddaert, F Encha-Razavi, J Chelly. Mutations in the neuronal ß-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects.. Hum Mol Genet. 2010;19:4462-73",
"AK Poznanski, G Iannaccone, AM Pasquino, B Boscherini. Radiological findings in the hand in Seckel syndrome (bird-headed dwarfism).. Pediatr Radiol. 1983;13:19-24",
"EG Puffenberger, RN Jinks, C Sougnez, K Cibulskis, RA Willert, NP Achilly, RP Cassidy, CJ Fiorentini, KF Heiken, JJ Lawrence, MH Mahoney, CJ Miller, DT Nair, KA Politi, KN Worcester, RA Setton, R Dipiazza, EA Sherman, JT Eastman, C Francklyn, S Robey-Bond, NL Rider, S Gabriel, DH Morton, KA Strauss. Genetic mapping and exome sequencing identify variants associated with five novel diseases.. PLoS One. 2012;7",
"JN Pulvers, J Bryk, JL Fish, M Wilsch-Bräuninger, Y Arai, D Schreier, R Naumann, J Helppi, B Habermann, J Vogt, R Nitsch, A Tóth, W Enard, S Pääbo, WB Huttner. Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline.. Proc Natl Acad Sci U S A. 2010;107:16595-600",
"P Qvist, P Huertas, S Jimeno, M Nyegaard, MJ Hassan, SP Jackson, AD Børglum. CtIP Mutations Cause Seckel and Jawad Syndromes.. PLoS Genet. 2011;7",
"MJ Rosenberg, R Agarwala, G Bouffard, J Davis, G Fiermonte, MS Hilliard, T Koch, LM Kalikin, I Makalowska, DH Morton, EM Petty, JL Weber, F Palmieri, RI Kelley, AA Schäffer, LG Biesecker. Mutant deoxynucleotide carrier is associated with congenital microcephaly.. Nat Genet. 2002;32:175-9",
"A Saadi, G Borck, N Boddaert, MC Chekkour, B Imessaoudene, A Munnich, L Colleaux, M Chaouch. Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical gyration in a consanguineous Algerian family.. Eur J Med Genet. 2009;52:180-4",
"M Sajid Hussain, S Marriam Bakhtiar, M Farooq, I Anjum, E Janzen, M Reza Toliat, H Eiberg, KW Kjaer, N Tommerup, AA Noegel, P Nürnberg, SM Baig, L Hansen. Genetic heterogeneity in Pakistani microcephaly families.. Clin Genet. 2013;83:446-51",
"VL Sheen, VS Ganesh, M Topcu, G Sebire, A Bodell, RS Hill, PE Grant, YY Shugart, J Imitola, SJ Khoury, R Guerrini, CA Walsh. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex.. Nat Genet. 2004;36:69-76",
"J Shen, W Eyaid, GH Mochida, F Al-Moayyad, A Bodell, CG Woods, CA Walsh. ASPM mutations identified in patients with primary microcephaly and seizures.. J Med Genet. 2005;42:725-9",
"S Sigaudy, A Toutain, A Moncla, C Fredouille, B Bourlière, S Ayme, N Philip. Microcephalic osteodysplastic primordial dwarfism Taybi-Linder type: report of four cases and review of the literature.. Am J Med Genet. 1998;80:16-24",
"P Singhmar, A. Kumar. Angelman syndrome protein UBE3A interacts with primary microcephaly protein ASPM, localizes to centrosomes and regulates chromosome segregation.. PLoS One. 2011;6",
"JH Sir, AR Barr, AK Nicholas, OP Carvalho, M Khurshid, A Sossick, S Reichelt, C D'Santos, CG Woods, F Gergely. A primary microcephaly protein complex forms a ring around parental centrioles.. Nat Genet. 2011;43:1147-53",
"CA Tan, S Topper, C Ward Melver, J Stein, A Reeder, K Arndt, S Das. The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing.. Brain Dev. 2014;36:351-5",
"CJ Tang, SY Lin, WB Hsu, YN Lin, CT Wu, YC Lin, CW Chang, KS Wu, TK Tang. The human microcephaly protein STIL interacts with CPAP and is required for procentriole formation.. EMBO J. 2011;30:4790-804",
"N Tommerup, E Mortensen, MH Nielsen, RD Wegner, D Schindler, M Mikkelsen. Chromosomal breakage, endomitosis, endoreduplication, and hypersensitivity toward radiomimetric and alkylating agents: a possible new autosomal recessive mutation in a girl with craniosynostosis and microcephaly.. Hum Genet. 1993;92:339-46",
"M Trimborn, SM Bell, C Felix, Y Rashid, H Jafri, PD Griffiths, LM Neumann, A Krebs, A Reis, K Sperling, H Neitzel, AP Jackson. Mutations in microcephalin cause aberrant regulation of chromosome condensation.. Am J Hum Genet. 2004;75:261-6",
"M Trimborn, R Richter, N Sternberg, I Gavvovidis, D Schindler, AP Jackson, EC Prott, K Sperling, G Gillessen-Kaesbach, H Neitzel. The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype.. Hum Mutat. 2005;26:496",
"Y Tunca, S Vurucu, J Parma, R Akin, J Désir, I Baser, A Ergun, M Abramowicz. Prenatal diagnosis of primary microcephaly in two consanguineous families by confrontation of morphometry with DNA data.. Prenat Diagn. 2006;26:449-53",
"Y Uetake, Y Terada, J Matuliene, R. Kuriyama. Interaction of Cep135 with a p50 dynactin subunit in mammalian centrosomes.. Cell Motil Cytoskeleton. 2004;58:53-66",
"H van Bokhoven, J Celli, J van Reeuwijk, T Rinne, B Glaudemans, E van Beusekom, P Rieu, RA Newbury-Ecob, C Chiang, HG Brunner. MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.. Nat Genet. 2005;37:465-7",
"P van der Lelij, KH Chrzanowska, BC Godthelp, MA Rooimans, AB Oostra, M Stumm, MZ Zdzienicka, H Joenje, JP de Winter. Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1.. Am J Hum Genet. 2010;86:262-6",
"GF Vichi, G Currarino, RL Wasserman, PL Duvina, L Filippi. Cephaloskeletal dysplasia (Taybi-Linder syndrome: osteodysplastic primordial dwarfism type III): report of two cases and review of the literature.. Pediatr Radiol. 2000;30:644-52",
"MJ Walenkamp, JM Wit. Single gene mutations causing SGA.. Best Pract Res Clin Endocrinol Metab. 2008;22:433-46",
"JK Wang, Y Li, B Su. A common SNP of MCPH1 is associated with cranial volume variation in Chinese population.. Hum Mol Genet. 2008;17:1329-35",
"RM Winter, J Wigglesworth, BN Harding. Osteodysplastic primordial dwarfism: report of a further patient with manifestations similar to those seen in patients with types I and III.. Am J Med Genet. 1985;21:569-74",
"CG Woods, J Bond, W Enard. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings.. Am J Hum Genet. 2005;76:717-28",
"RP Woods, NB Freimer, JA De Young, SC Fears, NL Sicotte, SK Service, DJ Valentino, AW Toga, JC Mazziotta. Normal variants of Microcephalin and ASPM do not account for brain size variability.. Hum Mol Genet. 2006;15:2025-9",
"YJ Yang, AE Baltus, RS Mathew, EA Murphy, GD Evrony, DM Gonzalez, EP Wang, CA Marshall-Walker, BJ Barry, J Murn, A Tatarakis, MA Mahajan, HH Samuels, Y Shi, JA Golden, M Mahajnah, R Shenhav, CA Walsh. Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation.. Cell. 2012;151:1097-112",
"TW Yu, GH Mochida, DJ Tischfield, SK Sgaier, L Flores-Sarnat, CM Sergi, M Topçu, MT McDonald, BJ Barry, JM Felie, C Sunu, WB Dobyns, RD Folkerth, AJ Barkovich, CA Walsh. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture.. Nat Genet. 2010;42:1015-20",
"X Zhang, D Liu, S Lv, H Wang, X Zhong, B Liu, B Wang, J Liao, J Li, GP Pfeifer, X Xu. CDK5RAP2 is required for spindle checkpoint function.. Cell Cycle. 2009;8:1206-16",
"L Zhao, C Jin, Y Chu, C Varghese, S Hua, F Yan, Y Miao, J Liu, D Mann, X Ding, J Zhang, Z Wang, Z Dou, X. Yao. Dimerization of CPAP orchestrates centrosome cohesion plasticity.. J Biol Chem. 2010;285:2488-97"
] |
1/9/2009
|
31/10/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
microph-lsd
|
microph-lsd
|
[
"Microphthalmia, Dermal Aplasia, and Sclerocornea (MIDAS) Syndrome",
"MLS Syndrome",
"MLS Syndrome",
"Microphthalmia, Dermal Aplasia, and Sclerocornea Syndrome",
"Cytochrome c oxidase subunit 7B, mitochondrial",
"Holocytochrome c-type synthase",
"NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial",
"COX7B",
"HCCS",
"NDUFB11",
"Microphthalmia with Linear Skin Defects Syndrome"
] |
Microphthalmia with Linear Skin Defects Syndrome
|
Manuela Morleo, Brunella Franco
|
Summary Microphthalmia with linear skin defects (MLS) syndrome is characterized by unilateral or bilateral microphthalmia and/or anophthalmia and linear skin defects, usually involving the face and neck, which are present at birth and heal with age, leaving minimal residual scarring. Other findings can include a wide variety of other ocular abnormalities (e.g., corneal anomalies, orbital cysts, cataracts), central nervous system involvement (e.g., structural anomalies, developmental delay, infantile seizures), cardiac concerns (e.g., hypertrophic or oncocytic cardiomyopathy, atrial or ventricular septal defects, arrhythmias), short stature, diaphragmatic hernia, nail dystrophy, hearing impairment, and genitourinary malformations. Inter- and intrafamilial variability is described. The clinical diagnosis is established when the two major criteria (microphthalmia and/or anophthalmia MLS syndrome is inherited in an X-linked manner and is generally lethal in males. Most cases are simplex (i.e., a single occurrence in a family), but rare familial occurrences have been described. Women who are affected or have an MLS syndrome-associated pathogenic variant have a 50% chance of passing the genetic alteration to each offspring. Because male conceptuses with an MLS syndrome-associated pathogenic variant are typically nonviable, the likelihood of a live-born affected child is less than 50%. Molecular genetic testing of at-risk female relatives to determine their genetic status, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for MLS syndrome are possible if the disease-causing genetic alteration has been identified in an affected family member.
|
## Diagnosis
Microphthalmia with linear skin defects (MLS) syndrome
Microphthalmia and/or anophthalmia
Reported in 81% of affected individuals
Can be unilateral or bilateral (see
Linear skin defects
Reported in 75% of affected individuals
Present at birth
Usually involve the face and neck (see
Heal with age, leaving minimal residual scarring
The clinical signs observed in MLS syndrome are considered major if they are present in at least 70% of affected individuals and minor if they are less frequent (see Clinical Description,
The clinical diagnosis of MLS syndrome can be made when the two major criteria are present [
Molecular testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of MLS syndrome is broad, individuals with both
When the phenotypic and laboratory findings suggest the diagnosis of MLS syndrome, molecular genetic testing approaches can include chromosome microarray analysis or use of a multigene panel:
Note: (1) Deletions reported in the literature were most frequently detected by karyotype and FISH analysis; however, CMA is used more frequently than karyotyping in clinical practice for individuals with complex medical issues and has greater resolution and precision than a karyotype. Some complex karyotypes have been reported (e.g., 45,X[18]/46,X,der(X)(p22q21)[24]/46,X,del(X)(p22)[58] and 46,X,der(X)t(X;Y)); therefore, karyotype and/or FISH follow up may be necessary based on CMA results. (2) Apparently balanced translocations have been reported in affected individuals [
For an introduction to multigene panels click
When the diagnosis of MLS syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Note: Although not used for diagnosis, X-chromosome inactivation studies have been performed in females with MLS syndrome. Skewed X-chromosome inactivation has been detected in 21 of the 22 individuals with MLS syndrome analyzed to date [
Molecular Genetic Testing Used in MLS Syndrome
NA = not applicable
Genes are listed alphabetically.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
ClinGen:
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the Xp22.3 region.
Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
All large deletions reported to date are large deletions that encompass
Note: Deletions reported in the literature were most frequently detected by karyotype and FISH analysis; however, CMA is more commonly used than karyotyping in clinical practice for individuals with complex medical issues and has greater resolution and precision than a karyotype. Some complex karyotypes have been reported (e.g., 45,X[18]/46,X,der(X)(p22q21)[24]/46,X,del(X)(p22)[58] and 46,X,der(X)t(X;Y)), therefore, karyotype and/or FISH follow up may be necessary based on CMA results.
• Microphthalmia and/or anophthalmia
• Reported in 81% of affected individuals
• Can be unilateral or bilateral (see
• Reported in 81% of affected individuals
• Can be unilateral or bilateral (see
• Linear skin defects
• Reported in 75% of affected individuals
• Present at birth
• Usually involve the face and neck (see
• Heal with age, leaving minimal residual scarring
• Reported in 75% of affected individuals
• Present at birth
• Usually involve the face and neck (see
• Heal with age, leaving minimal residual scarring
• Reported in 81% of affected individuals
• Can be unilateral or bilateral (see
• Reported in 75% of affected individuals
• Present at birth
• Usually involve the face and neck (see
• Heal with age, leaving minimal residual scarring
• Note: (1) Deletions reported in the literature were most frequently detected by karyotype and FISH analysis; however, CMA is used more frequently than karyotyping in clinical practice for individuals with complex medical issues and has greater resolution and precision than a karyotype. Some complex karyotypes have been reported (e.g., 45,X[18]/46,X,der(X)(p22q21)[24]/46,X,del(X)(p22)[58] and 46,X,der(X)t(X;Y)); therefore, karyotype and/or FISH follow up may be necessary based on CMA results. (2) Apparently balanced translocations have been reported in affected individuals [
• For an introduction to multigene panels click
## Suggestive Findings
Microphthalmia with linear skin defects (MLS) syndrome
Microphthalmia and/or anophthalmia
Reported in 81% of affected individuals
Can be unilateral or bilateral (see
Linear skin defects
Reported in 75% of affected individuals
Present at birth
Usually involve the face and neck (see
Heal with age, leaving minimal residual scarring
• Microphthalmia and/or anophthalmia
• Reported in 81% of affected individuals
• Can be unilateral or bilateral (see
• Reported in 81% of affected individuals
• Can be unilateral or bilateral (see
• Linear skin defects
• Reported in 75% of affected individuals
• Present at birth
• Usually involve the face and neck (see
• Heal with age, leaving minimal residual scarring
• Reported in 75% of affected individuals
• Present at birth
• Usually involve the face and neck (see
• Heal with age, leaving minimal residual scarring
• Reported in 81% of affected individuals
• Can be unilateral or bilateral (see
• Reported in 75% of affected individuals
• Present at birth
• Usually involve the face and neck (see
• Heal with age, leaving minimal residual scarring
## Major Criteria
Microphthalmia and/or anophthalmia
Reported in 81% of affected individuals
Can be unilateral or bilateral (see
Linear skin defects
Reported in 75% of affected individuals
Present at birth
Usually involve the face and neck (see
Heal with age, leaving minimal residual scarring
• Microphthalmia and/or anophthalmia
• Reported in 81% of affected individuals
• Can be unilateral or bilateral (see
• Reported in 81% of affected individuals
• Can be unilateral or bilateral (see
• Linear skin defects
• Reported in 75% of affected individuals
• Present at birth
• Usually involve the face and neck (see
• Heal with age, leaving minimal residual scarring
• Reported in 75% of affected individuals
• Present at birth
• Usually involve the face and neck (see
• Heal with age, leaving minimal residual scarring
• Reported in 81% of affected individuals
• Can be unilateral or bilateral (see
• Reported in 75% of affected individuals
• Present at birth
• Usually involve the face and neck (see
• Heal with age, leaving minimal residual scarring
## Establishing the Diagnosis
The clinical signs observed in MLS syndrome are considered major if they are present in at least 70% of affected individuals and minor if they are less frequent (see Clinical Description,
The clinical diagnosis of MLS syndrome can be made when the two major criteria are present [
Molecular testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of MLS syndrome is broad, individuals with both
When the phenotypic and laboratory findings suggest the diagnosis of MLS syndrome, molecular genetic testing approaches can include chromosome microarray analysis or use of a multigene panel:
Note: (1) Deletions reported in the literature were most frequently detected by karyotype and FISH analysis; however, CMA is used more frequently than karyotyping in clinical practice for individuals with complex medical issues and has greater resolution and precision than a karyotype. Some complex karyotypes have been reported (e.g., 45,X[18]/46,X,der(X)(p22q21)[24]/46,X,del(X)(p22)[58] and 46,X,der(X)t(X;Y)); therefore, karyotype and/or FISH follow up may be necessary based on CMA results. (2) Apparently balanced translocations have been reported in affected individuals [
For an introduction to multigene panels click
When the diagnosis of MLS syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Note: Although not used for diagnosis, X-chromosome inactivation studies have been performed in females with MLS syndrome. Skewed X-chromosome inactivation has been detected in 21 of the 22 individuals with MLS syndrome analyzed to date [
Molecular Genetic Testing Used in MLS Syndrome
NA = not applicable
Genes are listed alphabetically.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
ClinGen:
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the Xp22.3 region.
Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
All large deletions reported to date are large deletions that encompass
Note: Deletions reported in the literature were most frequently detected by karyotype and FISH analysis; however, CMA is more commonly used than karyotyping in clinical practice for individuals with complex medical issues and has greater resolution and precision than a karyotype. Some complex karyotypes have been reported (e.g., 45,X[18]/46,X,der(X)(p22q21)[24]/46,X,del(X)(p22)[58] and 46,X,der(X)t(X;Y)), therefore, karyotype and/or FISH follow up may be necessary based on CMA results.
• Note: (1) Deletions reported in the literature were most frequently detected by karyotype and FISH analysis; however, CMA is used more frequently than karyotyping in clinical practice for individuals with complex medical issues and has greater resolution and precision than a karyotype. Some complex karyotypes have been reported (e.g., 45,X[18]/46,X,der(X)(p22q21)[24]/46,X,del(X)(p22)[58] and 46,X,der(X)t(X;Y)); therefore, karyotype and/or FISH follow up may be necessary based on CMA results. (2) Apparently balanced translocations have been reported in affected individuals [
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of MLS syndrome, molecular genetic testing approaches can include chromosome microarray analysis or use of a multigene panel:
Note: (1) Deletions reported in the literature were most frequently detected by karyotype and FISH analysis; however, CMA is used more frequently than karyotyping in clinical practice for individuals with complex medical issues and has greater resolution and precision than a karyotype. Some complex karyotypes have been reported (e.g., 45,X[18]/46,X,der(X)(p22q21)[24]/46,X,del(X)(p22)[58] and 46,X,der(X)t(X;Y)); therefore, karyotype and/or FISH follow up may be necessary based on CMA results. (2) Apparently balanced translocations have been reported in affected individuals [
For an introduction to multigene panels click
• Note: (1) Deletions reported in the literature were most frequently detected by karyotype and FISH analysis; however, CMA is used more frequently than karyotyping in clinical practice for individuals with complex medical issues and has greater resolution and precision than a karyotype. Some complex karyotypes have been reported (e.g., 45,X[18]/46,X,der(X)(p22q21)[24]/46,X,del(X)(p22)[58] and 46,X,der(X)t(X;Y)); therefore, karyotype and/or FISH follow up may be necessary based on CMA results. (2) Apparently balanced translocations have been reported in affected individuals [
• For an introduction to multigene panels click
## Option 2
When the diagnosis of MLS syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Note: Although not used for diagnosis, X-chromosome inactivation studies have been performed in females with MLS syndrome. Skewed X-chromosome inactivation has been detected in 21 of the 22 individuals with MLS syndrome analyzed to date [
Molecular Genetic Testing Used in MLS Syndrome
NA = not applicable
Genes are listed alphabetically.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
ClinGen:
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the Xp22.3 region.
Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
All large deletions reported to date are large deletions that encompass
Note: Deletions reported in the literature were most frequently detected by karyotype and FISH analysis; however, CMA is more commonly used than karyotyping in clinical practice for individuals with complex medical issues and has greater resolution and precision than a karyotype. Some complex karyotypes have been reported (e.g., 45,X[18]/46,X,der(X)(p22q21)[24]/46,X,del(X)(p22)[58] and 46,X,der(X)t(X;Y)), therefore, karyotype and/or FISH follow up may be necessary based on CMA results.
## Clinical Characteristics
Microphthalmia with linear skin defects (MLS) syndrome is characterized by unilateral or bilateral microphthalmia or anophthalmia (see
Note: Categories are in descending order of frequency.
Sclerocornea
Orbital cysts
Microcornea
Eyelid fissures
Corneal leukoma
Iridocorneal adhesion (Peters anomaly)
Congenital glaucoma with total/peripheral anterior synechiae
Aniridia
Cataracts
A remnant of the anterior hyaloid artery
Vitreous opacity
Hypopigmented areas of the retinal pigment epithelium
Agenesis of corpus callosum
Anencephaly
Microcephaly
Hydrocephalus
Developmental delay / intellectual disability
Infantile seizures
Cardiomyopathy (hypertrophic or oncocytic)
Atrial and ventricular septal defects
Arrhythmias such as supraventricular tachycardia and ventricular fibrillation
Short stature (18/42)
Genitourinary or lower intestinal malformations: bicornuate uterus, ambiguous genitalia, anterior or imperforate anus, penile hypospadias in rare males with a 46,XX karyotype (14/64)
Hearing impairment (5/64)
Nail dystrophy (3/55)
Diaphragmatic hernia (3/64)
Pseudotail [
No genotype-phenotype correlations have been observed.
MLS syndrome, first described by
MLS syndrome appears to be the most appropriate designation for this disorder.
The disorder is rare; 64 individuals with a clinical diagnosis of MLS syndrome have been reported to date.
• Sclerocornea
• Orbital cysts
• Microcornea
• Eyelid fissures
• Corneal leukoma
• Iridocorneal adhesion (Peters anomaly)
• Congenital glaucoma with total/peripheral anterior synechiae
• Aniridia
• Cataracts
• A remnant of the anterior hyaloid artery
• Vitreous opacity
• Hypopigmented areas of the retinal pigment epithelium
• Agenesis of corpus callosum
• Anencephaly
• Microcephaly
• Hydrocephalus
• Developmental delay / intellectual disability
• Infantile seizures
• Cardiomyopathy (hypertrophic or oncocytic)
• Atrial and ventricular septal defects
• Arrhythmias such as supraventricular tachycardia and ventricular fibrillation
• Short stature (18/42)
• Genitourinary or lower intestinal malformations: bicornuate uterus, ambiguous genitalia, anterior or imperforate anus, penile hypospadias in rare males with a 46,XX karyotype (14/64)
• Hearing impairment (5/64)
• Nail dystrophy (3/55)
• Diaphragmatic hernia (3/64)
• Pseudotail [
## Clinical Description
Microphthalmia with linear skin defects (MLS) syndrome is characterized by unilateral or bilateral microphthalmia or anophthalmia (see
Note: Categories are in descending order of frequency.
Sclerocornea
Orbital cysts
Microcornea
Eyelid fissures
Corneal leukoma
Iridocorneal adhesion (Peters anomaly)
Congenital glaucoma with total/peripheral anterior synechiae
Aniridia
Cataracts
A remnant of the anterior hyaloid artery
Vitreous opacity
Hypopigmented areas of the retinal pigment epithelium
Agenesis of corpus callosum
Anencephaly
Microcephaly
Hydrocephalus
Developmental delay / intellectual disability
Infantile seizures
Cardiomyopathy (hypertrophic or oncocytic)
Atrial and ventricular septal defects
Arrhythmias such as supraventricular tachycardia and ventricular fibrillation
Short stature (18/42)
Genitourinary or lower intestinal malformations: bicornuate uterus, ambiguous genitalia, anterior or imperforate anus, penile hypospadias in rare males with a 46,XX karyotype (14/64)
Hearing impairment (5/64)
Nail dystrophy (3/55)
Diaphragmatic hernia (3/64)
Pseudotail [
• Sclerocornea
• Orbital cysts
• Microcornea
• Eyelid fissures
• Corneal leukoma
• Iridocorneal adhesion (Peters anomaly)
• Congenital glaucoma with total/peripheral anterior synechiae
• Aniridia
• Cataracts
• A remnant of the anterior hyaloid artery
• Vitreous opacity
• Hypopigmented areas of the retinal pigment epithelium
• Agenesis of corpus callosum
• Anencephaly
• Microcephaly
• Hydrocephalus
• Developmental delay / intellectual disability
• Infantile seizures
• Cardiomyopathy (hypertrophic or oncocytic)
• Atrial and ventricular septal defects
• Arrhythmias such as supraventricular tachycardia and ventricular fibrillation
• Short stature (18/42)
• Genitourinary or lower intestinal malformations: bicornuate uterus, ambiguous genitalia, anterior or imperforate anus, penile hypospadias in rare males with a 46,XX karyotype (14/64)
• Hearing impairment (5/64)
• Nail dystrophy (3/55)
• Diaphragmatic hernia (3/64)
• Pseudotail [
## Major Criteria
## Minor Criteria (in <70% of affected individuals)
Note: Categories are in descending order of frequency.
Sclerocornea
Orbital cysts
Microcornea
Eyelid fissures
Corneal leukoma
Iridocorneal adhesion (Peters anomaly)
Congenital glaucoma with total/peripheral anterior synechiae
Aniridia
Cataracts
A remnant of the anterior hyaloid artery
Vitreous opacity
Hypopigmented areas of the retinal pigment epithelium
Agenesis of corpus callosum
Anencephaly
Microcephaly
Hydrocephalus
Developmental delay / intellectual disability
Infantile seizures
Cardiomyopathy (hypertrophic or oncocytic)
Atrial and ventricular septal defects
Arrhythmias such as supraventricular tachycardia and ventricular fibrillation
Short stature (18/42)
Genitourinary or lower intestinal malformations: bicornuate uterus, ambiguous genitalia, anterior or imperforate anus, penile hypospadias in rare males with a 46,XX karyotype (14/64)
Hearing impairment (5/64)
Nail dystrophy (3/55)
Diaphragmatic hernia (3/64)
Pseudotail [
• Sclerocornea
• Orbital cysts
• Microcornea
• Eyelid fissures
• Corneal leukoma
• Iridocorneal adhesion (Peters anomaly)
• Congenital glaucoma with total/peripheral anterior synechiae
• Aniridia
• Cataracts
• A remnant of the anterior hyaloid artery
• Vitreous opacity
• Hypopigmented areas of the retinal pigment epithelium
• Agenesis of corpus callosum
• Anencephaly
• Microcephaly
• Hydrocephalus
• Developmental delay / intellectual disability
• Infantile seizures
• Cardiomyopathy (hypertrophic or oncocytic)
• Atrial and ventricular septal defects
• Arrhythmias such as supraventricular tachycardia and ventricular fibrillation
• Short stature (18/42)
• Genitourinary or lower intestinal malformations: bicornuate uterus, ambiguous genitalia, anterior or imperforate anus, penile hypospadias in rare males with a 46,XX karyotype (14/64)
• Hearing impairment (5/64)
• Nail dystrophy (3/55)
• Diaphragmatic hernia (3/64)
• Pseudotail [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been observed.
## Nomenclature
MLS syndrome, first described by
MLS syndrome appears to be the most appropriate designation for this disorder.
## Prevalence
The disorder is rare; 64 individuals with a clinical diagnosis of MLS syndrome have been reported to date.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of MLS Syndrome
Distinctive skin findings (dermal hypoplasia)
Ophthalmologic manifestations
Skin lesions
Ocular abnormalities (present in 35% of those w/IP diagnosis)
Erythema followed by blisters (vesicles) anywhere on the body
Verrucous lesions
Focal skin defects
Anophthalmia / microphthalmia
Observed in males prevalently
Brain malformation
Psychomotor impairment & episodes of seizures
Microphthalmia
Pigmentary lesions of the skin
In Aicardi syndrome:
Agenesis of the corpus callosum
Distinctive chorioretinal lacunae
Infantile spasms
? = unknown; MOI = mode of inheritance; XL = X-linked
MLS syndrome is male lethal.
Polymicrogyria or periventricular heterotopia, agenesis of the corpus callosum, hypoplastic vermis of the cerebellum, hydrocephalus
Two of the three classic features (agenesis of the corpus callosum, distinctive chorioretinal lacunae, infantile spasms) are needed to make the diagnosis of Aicardi syndrome; these features are rarely found associated with microphthalmia in MLS syndrome.
• Distinctive skin findings (dermal hypoplasia)
• Ophthalmologic manifestations
• Skin lesions
• Ocular abnormalities (present in 35% of those w/IP diagnosis)
• Erythema followed by blisters (vesicles) anywhere on the body
• Verrucous lesions
• Focal skin defects
• Anophthalmia / microphthalmia
• Observed in males prevalently
• Brain malformation
• Psychomotor impairment & episodes of seizures
• Microphthalmia
• Pigmentary lesions of the skin
• Agenesis of the corpus callosum
• Distinctive chorioretinal lacunae
• Infantile spasms
## Management
To establish the extent of disease and needs in an individual diagnosed with microphthalmia with linear skin lesions (MLS) syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Ophthalmologic examination
Dermatologic evaluation for skin lesions
Brain MRI for corpus callosum dysgenesis and other neurologic abnormalities
Developmental assessment, with further evaluation if significant delays are identified
Cardiac evaluation
Hearing evaluation, as hearing loss is observed in 8% of cases
Consideration of abdominal MRI and standard protocols for management of diaphragmatic hernia
Consultation with a clinical geneticist and/or genetic counselor
The following are appropriate:
Under the guidance of an oculoplastics specialist, use of a prosthesis in severe microphthalmia and anophthalmia
Regular care by a dermatologist for individuals with significant skin lesions
Referral to a pediatric neurologist for evaluation and treatment if microcephaly, seizures, and/or other neurologic abnormalities are present
Appropriate developmental therapies and special education as indicated for developmental delay and intellectual disability
Standard care for cardiac concerns and other malformations, when present
Monitoring and follow up with ophthalmologist, dermatologist, pediatric neurologist, and other professionals as needed is appropriate.
Affected individuals with cardiac concerns should have regular complete evaluation at intervals determined by the cardiologist.
See
Search
• Ophthalmologic examination
• Dermatologic evaluation for skin lesions
• Brain MRI for corpus callosum dysgenesis and other neurologic abnormalities
• Developmental assessment, with further evaluation if significant delays are identified
• Cardiac evaluation
• Hearing evaluation, as hearing loss is observed in 8% of cases
• Consideration of abdominal MRI and standard protocols for management of diaphragmatic hernia
• Consultation with a clinical geneticist and/or genetic counselor
• Under the guidance of an oculoplastics specialist, use of a prosthesis in severe microphthalmia and anophthalmia
• Regular care by a dermatologist for individuals with significant skin lesions
• Referral to a pediatric neurologist for evaluation and treatment if microcephaly, seizures, and/or other neurologic abnormalities are present
• Appropriate developmental therapies and special education as indicated for developmental delay and intellectual disability
• Standard care for cardiac concerns and other malformations, when present
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with microphthalmia with linear skin lesions (MLS) syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Ophthalmologic examination
Dermatologic evaluation for skin lesions
Brain MRI for corpus callosum dysgenesis and other neurologic abnormalities
Developmental assessment, with further evaluation if significant delays are identified
Cardiac evaluation
Hearing evaluation, as hearing loss is observed in 8% of cases
Consideration of abdominal MRI and standard protocols for management of diaphragmatic hernia
Consultation with a clinical geneticist and/or genetic counselor
• Ophthalmologic examination
• Dermatologic evaluation for skin lesions
• Brain MRI for corpus callosum dysgenesis and other neurologic abnormalities
• Developmental assessment, with further evaluation if significant delays are identified
• Cardiac evaluation
• Hearing evaluation, as hearing loss is observed in 8% of cases
• Consideration of abdominal MRI and standard protocols for management of diaphragmatic hernia
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
The following are appropriate:
Under the guidance of an oculoplastics specialist, use of a prosthesis in severe microphthalmia and anophthalmia
Regular care by a dermatologist for individuals with significant skin lesions
Referral to a pediatric neurologist for evaluation and treatment if microcephaly, seizures, and/or other neurologic abnormalities are present
Appropriate developmental therapies and special education as indicated for developmental delay and intellectual disability
Standard care for cardiac concerns and other malformations, when present
• Under the guidance of an oculoplastics specialist, use of a prosthesis in severe microphthalmia and anophthalmia
• Regular care by a dermatologist for individuals with significant skin lesions
• Referral to a pediatric neurologist for evaluation and treatment if microcephaly, seizures, and/or other neurologic abnormalities are present
• Appropriate developmental therapies and special education as indicated for developmental delay and intellectual disability
• Standard care for cardiac concerns and other malformations, when present
## Surveillance
Monitoring and follow up with ophthalmologist, dermatologist, pediatric neurologist, and other professionals as needed is appropriate.
Affected individuals with cardiac concerns should have regular complete evaluation at intervals determined by the cardiologist.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Microphthalmia with linear skin lesions (MLS) syndrome is inherited in an X-linked manner and is generally lethal in males.
Most affected individuals represent simplex cases (i.e., a single occurrence in a family).
Most females with MLS syndrome have a
In rare cases, a female proband has inherited an MLS syndrome-related pathogenic variant from her mother, who may or may not be affected [
Detailed clinical evaluation of the mother and review of the extended family history may help distinguish probands with a
If the mother has clinical findings of MLS syndrome or if she has another affected relative, she is an obligate heterozygote for a pathogenic variant in
If a
Live-born affected males with MLS syndrome are rare and are the result of a new chromosomal aberration (46,XX karyotype and an X/Y translocation).
Affected males who do not survive pregnancy may have inherited the pathogenic variant from their mothers or may have a
If the mother of a proband is affected and/or is known to have a
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Males who inherit the pathogenic variant will be affected, often with lethality during gestation.
Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see
Note: If the proband is mosaic for a pathogenic variant, the risk to her offspring is as high as 50%, depending on the level of mosaicism in her germline.
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.
Note: (1) Females who are heterozygous for this X-linked disorder will have a range of clinical manifestations (see
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes or who are at increased risk of being heterozygotes or affected.
Once a
• Most females with MLS syndrome have a
• In rare cases, a female proband has inherited an MLS syndrome-related pathogenic variant from her mother, who may or may not be affected [
• Detailed clinical evaluation of the mother and review of the extended family history may help distinguish probands with a
• If the mother has clinical findings of MLS syndrome or if she has another affected relative, she is an obligate heterozygote for a pathogenic variant in
• If a
• If the mother has clinical findings of MLS syndrome or if she has another affected relative, she is an obligate heterozygote for a pathogenic variant in
• If a
• If the mother has clinical findings of MLS syndrome or if she has another affected relative, she is an obligate heterozygote for a pathogenic variant in
• If a
• Live-born affected males with MLS syndrome are rare and are the result of a new chromosomal aberration (46,XX karyotype and an X/Y translocation).
• Affected males who do not survive pregnancy may have inherited the pathogenic variant from their mothers or may have a
• If the mother of a proband is affected and/or is known to have a
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit the pathogenic variant will be affected, often with lethality during gestation.
• Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see
• Note: If the proband is mosaic for a pathogenic variant, the risk to her offspring is as high as 50%, depending on the level of mosaicism in her germline.
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes or who are at increased risk of being heterozygotes or affected.
## Mode of Inheritance
Microphthalmia with linear skin lesions (MLS) syndrome is inherited in an X-linked manner and is generally lethal in males.
Most affected individuals represent simplex cases (i.e., a single occurrence in a family).
## Risk to Family Members
Most females with MLS syndrome have a
In rare cases, a female proband has inherited an MLS syndrome-related pathogenic variant from her mother, who may or may not be affected [
Detailed clinical evaluation of the mother and review of the extended family history may help distinguish probands with a
If the mother has clinical findings of MLS syndrome or if she has another affected relative, she is an obligate heterozygote for a pathogenic variant in
If a
Live-born affected males with MLS syndrome are rare and are the result of a new chromosomal aberration (46,XX karyotype and an X/Y translocation).
Affected males who do not survive pregnancy may have inherited the pathogenic variant from their mothers or may have a
If the mother of a proband is affected and/or is known to have a
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Males who inherit the pathogenic variant will be affected, often with lethality during gestation.
Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see
Note: If the proband is mosaic for a pathogenic variant, the risk to her offspring is as high as 50%, depending on the level of mosaicism in her germline.
• Most females with MLS syndrome have a
• In rare cases, a female proband has inherited an MLS syndrome-related pathogenic variant from her mother, who may or may not be affected [
• Detailed clinical evaluation of the mother and review of the extended family history may help distinguish probands with a
• If the mother has clinical findings of MLS syndrome or if she has another affected relative, she is an obligate heterozygote for a pathogenic variant in
• If a
• If the mother has clinical findings of MLS syndrome or if she has another affected relative, she is an obligate heterozygote for a pathogenic variant in
• If a
• If the mother has clinical findings of MLS syndrome or if she has another affected relative, she is an obligate heterozygote for a pathogenic variant in
• If a
• Live-born affected males with MLS syndrome are rare and are the result of a new chromosomal aberration (46,XX karyotype and an X/Y translocation).
• Affected males who do not survive pregnancy may have inherited the pathogenic variant from their mothers or may have a
• If the mother of a proband is affected and/or is known to have a
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit the pathogenic variant will be affected, often with lethality during gestation.
• Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see
• Note: If the proband is mosaic for a pathogenic variant, the risk to her offspring is as high as 50%, depending on the level of mosaicism in her germline.
## Heterozygote Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.
Note: (1) Females who are heterozygous for this X-linked disorder will have a range of clinical manifestations (see
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes or who are at increased risk of being heterozygotes or affected.
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes or who are at increased risk of being heterozygotes or affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once a
## Resources
•
•
•
•
•
•
## Molecular Genetics
Microphthalmia with Linear Skin Defects Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Microphthalmia with Linear Skin Defects Syndrome (
The three genes associated with MLS syndrome are all X-linked. Females with MLS syndrome show high inter- and intrafamilial phenotypic variability. Individuals can show the full MLS syndrome phenotype, or they can show isolated ocular manifestations, or aplastic skin areas restricted to face and neck with no additional abnormalities. Females with MLS syndrome may also show no features at all. A possible explanation for this clinical variability is the degree of skewed X chromosome inactivation observed in different tissues [
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
The product of the HCCS-catalyzed reaction, cytochrome
Variants listed in the table have been provided by the authors.
A combined effect of MRC defects and enhanced cell death has been shown to underlie the brain and eye abnormalities observed in an hccs-deficient medaka fish model [
## Introduction
The three genes associated with MLS syndrome are all X-linked. Females with MLS syndrome show high inter- and intrafamilial phenotypic variability. Individuals can show the full MLS syndrome phenotype, or they can show isolated ocular manifestations, or aplastic skin areas restricted to face and neck with no additional abnormalities. Females with MLS syndrome may also show no features at all. A possible explanation for this clinical variability is the degree of skewed X chromosome inactivation observed in different tissues [
##
Variants listed in the table have been provided by the authors.
##
Variants listed in the table have been provided by the authors.
The product of the HCCS-catalyzed reaction, cytochrome
##
Variants listed in the table have been provided by the authors.
A combined effect of MRC defects and enhanced cell death has been shown to underlie the brain and eye abnormalities observed in an hccs-deficient medaka fish model [
## References
## Literature Cited
## Chapter Notes
Research by the authors is supported by the Italian Telethon Foundation. We thank the families and all individuals affected with MLS syndrome participating in our research programs.
26 July 2018 (ha) Comprehensive update posted live
18 August 2011 (me) Comprehensive update posted live
8 September 2009 (cd) Revision: sequence analysis available clinically; deletion/duplication analysis no longer available
18 June 2009 (et) Review posted live
16 January 2009 (mm) Original submission
• 26 July 2018 (ha) Comprehensive update posted live
• 18 August 2011 (me) Comprehensive update posted live
• 8 September 2009 (cd) Revision: sequence analysis available clinically; deletion/duplication analysis no longer available
• 18 June 2009 (et) Review posted live
• 16 January 2009 (mm) Original submission
## Acknowledgments
Research by the authors is supported by the Italian Telethon Foundation. We thank the families and all individuals affected with MLS syndrome participating in our research programs.
## Revision History
26 July 2018 (ha) Comprehensive update posted live
18 August 2011 (me) Comprehensive update posted live
8 September 2009 (cd) Revision: sequence analysis available clinically; deletion/duplication analysis no longer available
18 June 2009 (et) Review posted live
16 January 2009 (mm) Original submission
• 26 July 2018 (ha) Comprehensive update posted live
• 18 August 2011 (me) Comprehensive update posted live
• 8 September 2009 (cd) Revision: sequence analysis available clinically; deletion/duplication analysis no longer available
• 18 June 2009 (et) Review posted live
• 16 January 2009 (mm) Original submission
Reticulolinear scar lesions on the neck of a female age 36 years with an otherwise normal phenotype.
Cytogenetic analysis revealed 46,X,del(X)(p22.3 pter) [
Bilateral microphthalmia and irregular linear skin areas involving the face and neck in a female infant with MLS syndrome who has a single-nucleotide variant in exon 6 of
Typical linear skin lesions on the face and neck of a newborn female with MLS syndrome who has a deletion of exons 1-3 of
|
[
"MS Alberry, G Juvanic, J Crolla, P Soothill, R Newbury-Ecob. Pseudotail as a feature of microphthalmia with linear skin defects syndrome.. Clin Dysmorphol. 2011;20:111-3",
"LI al-Gazali, RF Mueller, A Caine, A Antoniou, A McCartney, M Fitchett, NR Dennis. Two 46,XX,t(X;Y) females with linear skin defects and congenital microphthalmia: a new syndrome at Xp22.3.. J Med Genet 1990;27:59-63",
"J Allanson, S Richter. Linear skin defects and congenital microphthalmia: a new syndrome at Xp22.2.. J Med Genet 1991;28:143-4",
"A Anguiano, X Yang, JK Felix, JJ Hoo. Twin brothers with MIDAS syndrome and XX karyotype.. Am J Med Genet A 2003;119A:47-9",
"DG Bernard, ST Gabilly, G Dujardin, S Merchant, PP Hamel. Overlapping specificities of the mitochondrial cytochrome c and c1 heme lyases.. J Biol Chem 2003;278:49732-42",
"LM Bird, HF Krous, LF Eichenfield, CI Swalwell, MC Jones. Female infant with oncocytic cardiomyopathy and microphthalmia with linear skin defects (MLS): a clue to the pathogenesis of oncocytic cardiomyopathy?. Am J Med Genet. 1994;53:141-8",
"CC Cain, D Saul, L Attanasio, E Oehler, A Hamosh, K Blakemore, G Stetten. Microphthalmia with linear skin defects (MLS) syndrome evaluated by prenatal karyotyping, FISH and array comparative genomic hybridization.. Prenat Diagn 2007;27:373-9",
"CJ Cape, GW Zaidman, AD Beck, AH Kaufman. Phenotypic variation in ophthalmic manifestations of MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea).. Arch Ophthalmol 2004;122:1070-4",
"KB Carman, A Yakut, I Sabuncu, C Yarar. MIDAS (microphthalmia, dermal aplasia, sclerocornea) syndrome with central nervous system abnormalities.. Clin Dysmorphol 2009;18:234-5",
"A Eng, RR Lebel, BR Elejalde, C Anderson, L Bennett. Linear facial skin defects associated with microphthalmia and other malformations, with chromosome deletion Xp22.1.. J Am Acad Dermatol 1994;31:680-2",
"F Enright, P Campbell, RL Stallings, K Hall, AJ Green, E Sweeney, L Barnes, R Watson. Xp22.3 microdeletion in a 19-year-old girl with clinical features of MLS syndrome.. Pediatr Dermatol 2003;20:153-7",
"A García-Rabasco, B De-Unamuno, F Martínez, I Febrer-Bosch, V Alegre-de-Miquel. Microphtalmia with linear skin defects syndrome.. Pediatr Dermatol 2013;30:e230-31",
"R Happle, O Daniëls, RJ Koopman. MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea): an X-linked phenotype distinct from Goltz syndrome.. Am J Med Genet. 1993;47:710-3",
"MC Herwig, KU Loeffler, U Gembruch, K Kuchelmeister, AM Müller. Anterior Segment Developmental Anomalies in a 33-Week-Old Fetus with MIDAS Syndrome.. Pediatr Dev Pathol 2014;17:491-5",
"GM Hobson, CW Gibson, M Aragon, ZA Yuan, A Davis-Williams, L Banser, J Kirkham, AH Brook. A large X-chromosomal deletion is associated with microphthalmia with linear skin defects (MLS) and amelogenesis imperfecta (XAI).. Am J Med Genet A. 2009;149A:1698-705",
"A Indrieri, VA van Rahden, V Tiranti, M Morleo, D Iaconis, R Tammaro, I D'Amato, I Conte, I Maystadt, S Demuth, A Zvulunov, K Kutsche, M Zeviani, B Franco. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease.. Am J Hum Genet 2012;91:942-49",
"A Indrieri, I Conte, G Chesi, A Romano, J Quartararo, R Tate, D Ghezzi, M Zeviani, P Goffrini, I Ferrero, P Bovolenta, B Franco. The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.. EMBO Mol Med 2013;5:280-93",
"X Jiang, X Wang. Cytochrome C-mediated apoptosis.. Annu Rev Biochem 2004;73:87-106",
"R Kapur, EY Tu, S Toyran, P Shah, S Vangveeravong, WC Lloyd, DP Edward. Corneal pathology in microphthalmia with linear skin defects syndrome.. Cornea 2008;27:734-8",
"L Kherbaoui-Redouani, C Eschard, N Bednarek, P Morville, N Bednare. Cutaneous aplasia, non compaction of the left ventricle and severe cardiac arrhythmia: a new case of MLS syndrome (microphtalmia with linear skin defects).. Arch Pediatr 2003;10:224-6",
"N Kluger, A Bouissou, L Tauzin, J Puechberty, O Dereure. Congenital linear streaks on the face and neck and microphthalmia in an infant girl.. Acta Derm Venereol. 2014;94:342-3",
"M Kobayashi, M Kiyosawa, T Toyoura, T Tokoro. An XX male with microphthalmos and sclerocornea.. J Pediatr Ophthalmol Strabismus 1998;35:122-4",
"T Kono, T Migita, S Koyama, I Seki. Another observation of microphthalmia in an XX male: microphthalmia with linear skin defects syndrome without linear skin lesions.. J Hum Genet 1999;44:63-8",
"EA Lindsay, A Grillo, GB Ferrero, EJ Roth, E Magenis, M Grompe, M Hultén, C Gould, A Baldini, HY Zoghbi, A Ballabio. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic and molecular characterization.. Am J Med Genet 1994;49:229-34",
"M Morleo, B Franco. Dosage compensation of the mammalian X chromosome influences the phenotypic variability of X-linked dominant male-lethal disorders.. J Med Genet 2008;45:401-8",
"M Morleo, T Pramparo, L Perone, G Gregato, C Le Caignec, RF Mueller, T Ogata, A Raas-Rothschild, MC de Blois, LC Wilson, G Zaidman, O Zuffardi, A Ballabio, B Franco. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization of 11 cases.. Am J Med Genet A 2005;137:190-8",
"J Mücke, W Hoepffner, B Thamm, H Theile. MIDAS syndrome (microphthalmia, dermal aplasia and sclerocornea): an autonomous entity with linear skin defects within the spectrum of focal hypoplasias.. Eur J Dermatol 1995;5:197-203",
"BR Paulger, EW Kraus, DR Pulitzer, CM Moore. Xp microdeletion syndrome characterized by pathognomonic linear skin defects on the head and neck.. Pediatr Dermatol 1997;14:26-30",
"V Petruzzella, A Tessa, A Torraco, F Fattori, MT Dotti, C Bruno, E Cardaioli, S Papa, A Federico, FM Santorelli. The NDUFB11 gene is not a modifier in Leber hereditary optic neuropathy.. Biochem Biophys Res Commun. 2007;355:181-7",
"G Rea, T Homfray, J Till, F Roses-Noguer, RJ Buchan, S Wilkinson, A Wilk, R Walsh, S John, S McKee, FJ Stewart, V Murday, RW Taylor, M Ashworth, AJ Baksi, P Daubeney, S Prasad, PJR Barton, SA Cook, JS Ware. Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in. Cold Spring Harb Mol Case Stud 2017;3",
"C Schluth, M Cossee, F Girard-Lemaire, N Carelle, H Dollfus, E Jeandidier, E Flori. Phenotype in X chromosome rearrangements: pitfalls of X inactivation study.. Pathol Biol (Paris) 2007;55:29-36",
"VM Sharma, AM Ruiz de Luzuriaga, D Waggoner, M Greenwald, SL Stein. Microphthalmia with linear skin defects: a case report and review.. Pediatr Dermatol 2008;25:548-52",
"BM Shehata, CA Cundiff, K Lee, A Sabharwal, MK Lalwani, AK Davis, V Agrawal, S Sivasubbu, GJ Iannucci, G Gibson. Exome sequencing of patients with histiocytoid cardiomyopathy reveals a de novo NDUFB11 mutation that plays a role in the pathogenesis of histiocytoid cardiomyopathy.. Am J Med Genet A. 2015;167A:2114-21",
"E Steichen-Gersdorf, E Griesmaier, FK Pientka, D Kotzot, K Kutsche. A severe form of the X-linked microphthalmia with linear skin defects syndrome in a female newborn.. Clin Dysmorphol. 2010;19:82-4",
"RF Stratton, CA Walter, BR Paulgar, ME Price, CM Moore. Second 46,XX males with MLS syndrome.. Am J Med Genet 1998;76:37-41",
"A Torraco, M Bianchi, D Verrigni, V Gelmetti, L Riley, M Niceta, D Martinelli, A Montanari, Y Guo, T Rizza, D Diodato, M Di Nottia, B Lucarelli, F Sorrentino, F Piemonte, S Francisci, M Tartaglia, EM Valente, C Dionisi-Vici, J Christodoulou, E Bertini, R Carrozzo. A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia.. Clin Genet 2017;91:441-47",
"VA van Rahden, I Rau, S Fuchs, FK Kosyna, H Larangeira de Almeida, F Fryssira, B Isidor, A Jauch, M Joubert, AMA Lachmeijer, C Zweier, U Moog, K Kutsche. Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome.. Orphanet J Rare Dis 2014;9:53",
"VA van Rahden, E Fernandez-Vizarra, M Alawi, K Brand, F Florence Fellmann, D Horn, Z Massimo Zeviani, K Kutsche. Mutations in NDUFB11, Encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome.. Am J Hum Genet 2015;96:640-50",
"S Vergult, B Leroy, I Claerhout, B Menten. Familial cases of a submicroscopic Xp22.2 deletion: genotype-phenotype correlation in microphthalmia with linear skin defects syndrome.. Mol Vis 2013;19:311-8",
"I Wimplinger, M Morleo, G Rosenberger, D Iaconis, U Orth, P Meinecke, I Lerer, A Ballabio, A Gal, B Franco, K Kutsche. Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.. Am J Hum Genet 2006;79:878-89",
"I Wimplinger, A Rauch, U Orth, U Schwarzer, U Trautmann, K Kutsche. Mother and daughter with a terminal Xp deletion: implication of chromosomal mosaicism and X-inactivation in the high clinical variability of the microphthalmia with linear skin defects (MLS) syndrome.. Eur J Med Genet 2007a;50:421-31",
"I Wimplinger, GM Shaw, K Kutsche. HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations?. Mol Vis 2007b;13:1475-82",
"A Zvulunov, L Kachko, E Manor, E Shinwell, R Carmi. Reticulolinear aplasia cutis congenita of the face and neck: a distinctiv cutaneous manifestation in several syndromes linked to Xp22.. Br J Dermatol 1998;138:1046-52"
] |
18/6/2009
|
26/7/2018
|
8/9/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
milroy
|
milroy
|
[
"Hereditary Lymphedema Type I",
"Hereditary Lymphedema Type I",
"Vascular endothelial growth factor receptor 3",
"FLT4",
"Milroy Disease"
] |
Milroy Disease
|
Malou Van Zanten, Sahar Mansour, Pia Ostergaard, Peter Mortimer, Kristiana Gordon
|
Summary Milroy disease is characterized by lower-limb lymphedema, present as pedal edema at (or before) birth or developing soon after. Occasionally it presents later in life. The severity of edema shows both inter- and intrafamilial variability. Swelling is usually bilateral but can be asymmetric. The degree of edema can progress but, in some instances, can improve, particularly in the early years. Other features sometimes associated with Milroy disease include hydrocele (37% of males), prominent veins below the knees (23%), upslanting toenails (14%), papillomatosis (10%), and urethral abnormalities in males (4%). Cellulitis, which can damage the lymphatic vessels, occurs in approximately 20% of affected individuals, with infection significantly more likely in males than females. The diagnosis of Milroy disease is established in a proband with congenital or infantile-onset lower-limb lymphedema accompanied by lack of uptake of radioactive colloid in the ilioinguinal lymph nodes on lymphoscintigraphy and/or by identification of a heterozygous pathogenic variant in Milroy disease is inherited in an autosomal dominant manner. Most individuals diagnosed with Milroy disease have an affected parent. If a parent of the proband is affected and/or has an
|
## Diagnosis
Milroy disease
Lower-limb swelling that is:
Usually (not always) bilateral
Present at birth or develops soon after
Note: In neonates the swelling predominantly affects the dorsum of the feet; with age, the swelling may improve or progress to affect the below-knee region (rarely extending above the knees).
Large-caliber veins below the knees
Upslanting and small, dysplastic toenails
Deep interphalangeal creases of the feet
Hydroceles in males
No internal clinically significant lymphatic issues (e.g., intestinal lymphangiectasia, pleural or pericardial effusions)
Note: The lymphoscintigraphic findings are characteristic and useful for diagnosis, but this test is not absolutely required (see
Note: Absence of a known family history of Milroy disease does not preclude the diagnosis.
The diagnosis of Milroy disease
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Milroy is broad, individuals with the distinctive findings described in
When the phenotypic and radiographic findings suggest the diagnosis of Milroy disease, molecular genetic testing approaches can include
Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. However, such variants would not be anticipated to lead to Milroy disease.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by lymphedema,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Milroy Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants detected may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Gene-targeted deletion/duplication analysis has not identified any deletions or duplications of
No other loci have been identified, but reports suggest that Milroy disease is genetically heterogeneous [
• Lower-limb swelling that is:
• Usually (not always) bilateral
• Present at birth or develops soon after
• Note: In neonates the swelling predominantly affects the dorsum of the feet; with age, the swelling may improve or progress to affect the below-knee region (rarely extending above the knees).
• Usually (not always) bilateral
• Present at birth or develops soon after
• Note: In neonates the swelling predominantly affects the dorsum of the feet; with age, the swelling may improve or progress to affect the below-knee region (rarely extending above the knees).
• Large-caliber veins below the knees
• Upslanting and small, dysplastic toenails
• Deep interphalangeal creases of the feet
• Hydroceles in males
• No internal clinically significant lymphatic issues (e.g., intestinal lymphangiectasia, pleural or pericardial effusions)
• Usually (not always) bilateral
• Present at birth or develops soon after
• Note: In neonates the swelling predominantly affects the dorsum of the feet; with age, the swelling may improve or progress to affect the below-knee region (rarely extending above the knees).
• Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. However, such variants would not be anticipated to lead to Milroy disease.
• For an introduction to multigene panels click
## Suggestive Findings
Milroy disease
Lower-limb swelling that is:
Usually (not always) bilateral
Present at birth or develops soon after
Note: In neonates the swelling predominantly affects the dorsum of the feet; with age, the swelling may improve or progress to affect the below-knee region (rarely extending above the knees).
Large-caliber veins below the knees
Upslanting and small, dysplastic toenails
Deep interphalangeal creases of the feet
Hydroceles in males
No internal clinically significant lymphatic issues (e.g., intestinal lymphangiectasia, pleural or pericardial effusions)
Note: The lymphoscintigraphic findings are characteristic and useful for diagnosis, but this test is not absolutely required (see
Note: Absence of a known family history of Milroy disease does not preclude the diagnosis.
• Lower-limb swelling that is:
• Usually (not always) bilateral
• Present at birth or develops soon after
• Note: In neonates the swelling predominantly affects the dorsum of the feet; with age, the swelling may improve or progress to affect the below-knee region (rarely extending above the knees).
• Usually (not always) bilateral
• Present at birth or develops soon after
• Note: In neonates the swelling predominantly affects the dorsum of the feet; with age, the swelling may improve or progress to affect the below-knee region (rarely extending above the knees).
• Large-caliber veins below the knees
• Upslanting and small, dysplastic toenails
• Deep interphalangeal creases of the feet
• Hydroceles in males
• No internal clinically significant lymphatic issues (e.g., intestinal lymphangiectasia, pleural or pericardial effusions)
• Usually (not always) bilateral
• Present at birth or develops soon after
• Note: In neonates the swelling predominantly affects the dorsum of the feet; with age, the swelling may improve or progress to affect the below-knee region (rarely extending above the knees).
## Establishing the Diagnosis
The diagnosis of Milroy disease
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Milroy is broad, individuals with the distinctive findings described in
When the phenotypic and radiographic findings suggest the diagnosis of Milroy disease, molecular genetic testing approaches can include
Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. However, such variants would not be anticipated to lead to Milroy disease.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by lymphedema,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Milroy Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants detected may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Gene-targeted deletion/duplication analysis has not identified any deletions or duplications of
No other loci have been identified, but reports suggest that Milroy disease is genetically heterogeneous [
• Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. However, such variants would not be anticipated to lead to Milroy disease.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and radiographic findings suggest the diagnosis of Milroy disease, molecular genetic testing approaches can include
Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. However, such variants would not be anticipated to lead to Milroy disease.
For an introduction to multigene panels click
• Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. However, such variants would not be anticipated to lead to Milroy disease.
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by lymphedema,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Milroy Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants detected may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Gene-targeted deletion/duplication analysis has not identified any deletions or duplications of
No other loci have been identified, but reports suggest that Milroy disease is genetically heterogeneous [
## Clinical Characteristics
The most common finding in Milroy disease is congenital bilateral, lower-limb lymphedema. The edema is usually present from (or before) birth. Rarely, prenatal pleural effusion and fetal hydrops have been reported [
The amount of edema varies both within and among families. Swelling is often bilateral but can be asymmetric.
The degree of edema sometimes progresses but in some instances can improve, particularly in early years.
Other features sometimes associated with Milroy disease:
Hydrocele (37% of males)
Prominent veins (23%) below the knees (with or without venous reflux seen on duplex imaging) [
Upslanting (spoon-shaped and/or dysplastic) toenails (14%)
Papillomatosis located on the toes and/or forefoot (10%)
Urethral abnormalities, such as hypospadias or urethral stricture, in males (4%)
Cellulitis occurs in approximately 20% of affected individuals, with infection significantly more likely in males than females [
No genotype-phenotype correlation for Milroy disease has been reported. Most pathogenic variants are missense variants that occur in the tyrosine kinase domain of
Approximately 85%-90% of individuals who have a pathogenic variant in
Milroy disease is named after William Milroy, who described 97 members of a family, of whom 26 had leg edema [
Hereditary lymphedema of the legs was also described by
Milroy disease may also be referred to as Milroy congenital lymphedema.
The prevalence of Milroy disease is not known but it appears to be one of the more common causes of primary lymphedema, occurring in all ethnic groups.
• Hydrocele (37% of males)
• Prominent veins (23%) below the knees (with or without venous reflux seen on duplex imaging) [
• Upslanting (spoon-shaped and/or dysplastic) toenails (14%)
• Papillomatosis located on the toes and/or forefoot (10%)
• Urethral abnormalities, such as hypospadias or urethral stricture, in males (4%)
## Clinical Description
The most common finding in Milroy disease is congenital bilateral, lower-limb lymphedema. The edema is usually present from (or before) birth. Rarely, prenatal pleural effusion and fetal hydrops have been reported [
The amount of edema varies both within and among families. Swelling is often bilateral but can be asymmetric.
The degree of edema sometimes progresses but in some instances can improve, particularly in early years.
Other features sometimes associated with Milroy disease:
Hydrocele (37% of males)
Prominent veins (23%) below the knees (with or without venous reflux seen on duplex imaging) [
Upslanting (spoon-shaped and/or dysplastic) toenails (14%)
Papillomatosis located on the toes and/or forefoot (10%)
Urethral abnormalities, such as hypospadias or urethral stricture, in males (4%)
Cellulitis occurs in approximately 20% of affected individuals, with infection significantly more likely in males than females [
• Hydrocele (37% of males)
• Prominent veins (23%) below the knees (with or without venous reflux seen on duplex imaging) [
• Upslanting (spoon-shaped and/or dysplastic) toenails (14%)
• Papillomatosis located on the toes and/or forefoot (10%)
• Urethral abnormalities, such as hypospadias or urethral stricture, in males (4%)
## Genotype-Phenotype Correlations
No genotype-phenotype correlation for Milroy disease has been reported. Most pathogenic variants are missense variants that occur in the tyrosine kinase domain of
## Penetrance
Approximately 85%-90% of individuals who have a pathogenic variant in
## Nomenclature
Milroy disease is named after William Milroy, who described 97 members of a family, of whom 26 had leg edema [
Hereditary lymphedema of the legs was also described by
Milroy disease may also be referred to as Milroy congenital lymphedema.
## Prevalence
The prevalence of Milroy disease is not known but it appears to be one of the more common causes of primary lymphedema, occurring in all ethnic groups.
## Genetically Related (Allelic) Disorders
Germline heterozygous loss-of-function pathogenic variants in
## Differential Diagnosis
A list of differential diagnoses can be found in
Genes of Interest in the Differential Diagnosis of Milroy Disease
AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart defect; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance
Noonan syndrome is most often inherited in an autosomal dominant manner; Noonan syndrome caused by pathogenic variants in
The cognitive impairment with dysmorphic features was originally emphasized as a cardinal clinical sign of
Two families with a phenotype resembling Milroy disease have been shown to have pathogenic variants in
## Chromosomal Disorders and Hereditary Disorders of Unknown Genetic Cause
## Management
To establish the extent of disease and needs in an individual diagnosed with Milroy disease, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Milroy Disease
Treatment of Manifestations in Individuals with Milroy Disease
Fitting compression hosiery &/or bandaging
Massage
Supportive shoes
Toe gloves may be of benefit.
Good skin care
Although the edema cannot be cured, some improvement is usually possible with the supportive measures listed in the table. Such treatment measures may improve the cosmetic appearance of the limb, decrease the size of the limb, and reduce the risk of complications.
Secondary cellulitis is prevented through the following measures:
Prevention of foot infections, particularly athlete's foot or infected ingrown toenails
Prompt treatment for early cellulitis with appropriate antibiotics. It may be necessary to give the first few doses intravenously.
Prophylactic antibiotics in recurrent cases (e.g., penicillin V 250 mg 2x daily for 1-2 years). The dose may need to be adjusted for pediatric or obese individuals [
Routine follow up in a clinic specializing in the care of lymphedema is appropriate.
The following should be avoided:
Wounds to the swollen limbs, because of a reduced resistance to infection
Long periods of immobility with the legs in a dependent position (e.g., on a long airplane flight)
Medications that can cause increased leg swelling in some individuals (particularly calcium channel-blocking drugs)
It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment early in the course of the disease. The use of properly fitted compression hosiery and advice to reduce the risk of cellulitis of the legs and feet can be beneficial.
Evaluations can include:
Molecular genetic testing if the causative pathogenic variant in the family is known;
Physical examination if the causative pathogenic variant in the family is not known.
See
Ultrasound scanning during pregnancy may indicate if a fetus is affected if swelling of the dorsum of the feet is noted in the second or third trimester. The fetus may have mild pleural effusions which frequently resolve before birth [
If the mother is affected by Milroy disease there may be an increase in the mother's swelling during the pregnancy.
Attempts at overexpressing VEGF-C, the ligand for
Search
Treatment with diuretics is of no proven benefit.
• Fitting compression hosiery &/or bandaging
• Massage
• Supportive shoes
• Toe gloves may be of benefit.
• Good skin care
• Prevention of foot infections, particularly athlete's foot or infected ingrown toenails
• Prompt treatment for early cellulitis with appropriate antibiotics. It may be necessary to give the first few doses intravenously.
• Prophylactic antibiotics in recurrent cases (e.g., penicillin V 250 mg 2x daily for 1-2 years). The dose may need to be adjusted for pediatric or obese individuals [
• Wounds to the swollen limbs, because of a reduced resistance to infection
• Long periods of immobility with the legs in a dependent position (e.g., on a long airplane flight)
• Medications that can cause increased leg swelling in some individuals (particularly calcium channel-blocking drugs)
• Molecular genetic testing if the causative pathogenic variant in the family is known;
• Physical examination if the causative pathogenic variant in the family is not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Milroy disease, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Milroy Disease
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Milroy Disease
Fitting compression hosiery &/or bandaging
Massage
Supportive shoes
Toe gloves may be of benefit.
Good skin care
Although the edema cannot be cured, some improvement is usually possible with the supportive measures listed in the table. Such treatment measures may improve the cosmetic appearance of the limb, decrease the size of the limb, and reduce the risk of complications.
• Fitting compression hosiery &/or bandaging
• Massage
• Supportive shoes
• Toe gloves may be of benefit.
• Good skin care
## Prevention of Secondary Complications
Secondary cellulitis is prevented through the following measures:
Prevention of foot infections, particularly athlete's foot or infected ingrown toenails
Prompt treatment for early cellulitis with appropriate antibiotics. It may be necessary to give the first few doses intravenously.
Prophylactic antibiotics in recurrent cases (e.g., penicillin V 250 mg 2x daily for 1-2 years). The dose may need to be adjusted for pediatric or obese individuals [
• Prevention of foot infections, particularly athlete's foot or infected ingrown toenails
• Prompt treatment for early cellulitis with appropriate antibiotics. It may be necessary to give the first few doses intravenously.
• Prophylactic antibiotics in recurrent cases (e.g., penicillin V 250 mg 2x daily for 1-2 years). The dose may need to be adjusted for pediatric or obese individuals [
## Surveillance
Routine follow up in a clinic specializing in the care of lymphedema is appropriate.
## Agents/Circumstances to Avoid
The following should be avoided:
Wounds to the swollen limbs, because of a reduced resistance to infection
Long periods of immobility with the legs in a dependent position (e.g., on a long airplane flight)
Medications that can cause increased leg swelling in some individuals (particularly calcium channel-blocking drugs)
• Wounds to the swollen limbs, because of a reduced resistance to infection
• Long periods of immobility with the legs in a dependent position (e.g., on a long airplane flight)
• Medications that can cause increased leg swelling in some individuals (particularly calcium channel-blocking drugs)
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment early in the course of the disease. The use of properly fitted compression hosiery and advice to reduce the risk of cellulitis of the legs and feet can be beneficial.
Evaluations can include:
Molecular genetic testing if the causative pathogenic variant in the family is known;
Physical examination if the causative pathogenic variant in the family is not known.
See
• Molecular genetic testing if the causative pathogenic variant in the family is known;
• Physical examination if the causative pathogenic variant in the family is not known.
## Pregnancy Management
Ultrasound scanning during pregnancy may indicate if a fetus is affected if swelling of the dorsum of the feet is noted in the second or third trimester. The fetus may have mild pleural effusions which frequently resolve before birth [
If the mother is affected by Milroy disease there may be an increase in the mother's swelling during the pregnancy.
## Therapies Under Investigation
Attempts at overexpressing VEGF-C, the ligand for
Search
## Other
Treatment with diuretics is of no proven benefit.
## Genetic Counseling
Milroy disease is inherited in an autosomal dominant manner.
Most individuals diagnosed with Milroy disease have an affected parent.
An individual diagnosed with Milroy disease may have the disorder as the result of a
If a molecular diagnosis has been established in the proband, molecular genetic testing for the
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells.
The family history of some individuals diagnosed with Milroy disease may appear to be negative because of failure to recognize the disorder in family members as a result of variable expression or reduced penetrance.
If a parent of the proband is affected and/or has an
If the proband has an
If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with Milroy disease have an affected parent.
• An individual diagnosed with Milroy disease may have the disorder as the result of a
• If a molecular diagnosis has been established in the proband, molecular genetic testing for the
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells.
• The family history of some individuals diagnosed with Milroy disease may appear to be negative because of failure to recognize the disorder in family members as a result of variable expression or reduced penetrance.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells.
• If a parent of the proband is affected and/or has an
• If the proband has an
• If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Milroy disease is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with Milroy disease have an affected parent.
An individual diagnosed with Milroy disease may have the disorder as the result of a
If a molecular diagnosis has been established in the proband, molecular genetic testing for the
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells.
The family history of some individuals diagnosed with Milroy disease may appear to be negative because of failure to recognize the disorder in family members as a result of variable expression or reduced penetrance.
If a parent of the proband is affected and/or has an
If the proband has an
If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
• Most individuals diagnosed with Milroy disease have an affected parent.
• An individual diagnosed with Milroy disease may have the disorder as the result of a
• If a molecular diagnosis has been established in the proband, molecular genetic testing for the
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells.
• The family history of some individuals diagnosed with Milroy disease may appear to be negative because of failure to recognize the disorder in family members as a result of variable expression or reduced penetrance.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells.
• If a parent of the proband is affected and/or has an
• If the proband has an
• If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
St. Luke's Crypt
Sydney Street
London SW3 6NH
United Kingdom
116 New Montgomery Street
Suite 235
San Francisco CA 94105
Lymphatic Education and Research Network
261 Madison Avenue
9th Floor
New York NY 10016
VASCERN - European Reference Network (ERN)
•
• St. Luke's Crypt
• Sydney Street
• London SW3 6NH
• United Kingdom
•
•
• 116 New Montgomery Street
• Suite 235
• San Francisco CA 94105
•
•
• Lymphatic Education and Research Network
• 261 Madison Avenue
• 9th Floor
• New York NY 10016
•
•
•
•
• VASCERN - European Reference Network (ERN)
•
•
•
## Molecular Genetics
Milroy Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Milroy Disease (
The normal gene product of
VEGFR-3 is a lymphatic endothelial cell-specific receptor and, when stimulated by the VEGFC ligand, is the key regulator of lymphatic vessel growth and function. The abnormal gene products will form either mutant/mutant type homodimers showing no tyrosine kinase activity or mutant/wild type heterodimers showing some TK activity, leading to an overall decrease in downstream signaling [
## Molecular Pathogenesis
The normal gene product of
VEGFR-3 is a lymphatic endothelial cell-specific receptor and, when stimulated by the VEGFC ligand, is the key regulator of lymphatic vessel growth and function. The abnormal gene products will form either mutant/mutant type homodimers showing no tyrosine kinase activity or mutant/wild type heterodimers showing some TK activity, leading to an overall decrease in downstream signaling [
## Chapter Notes
We provide consultations and multidisciplinary approaches for the following medical conditions:
Primary lymphoedema (genetic/inherited types, and lymphovascular malformations)
Secondary lymphoedema
Rapid access appointments for patients with cancer-related lymphoedema
Complications of lymphoedema, e.g., recurrent cellulitis
Lipoedema & lipodystrophy
We have a range of diagnostic tools available within our service to aid our phenotyping and assessment process:
Lymphoscintigraphy
Genetic screening
MR lymphography
Our research interest and focus is gene discovery in primary lymphoedema / lymphovascular disease and understanding the mechanism of disease in primary lymphoedema through imaging (e.g., MR lymphography, ICG lymphography), histology, and blood immunophenotyping.
Please check our website for more information about our services:
Information about our research:
The VASCERN European Reference Network is a European platform where health care professionals and patient representatives share expertise and develop consensus and guidelines for rare vascular diseases. The Primary and Pediatric Lymphoedema Working Group is built upon Multidisciplinary Centres of Excellence collaborating and have a long-standing expertise in the diagnosis and management of adults and children with lymphatic problems.
For health care professionals, the VASCERN
The authors would like to thank the following organizations: the Medical Research Council, the British Heart Foundation, and the National Institute for Health Research.
Glen W Brice, RGN BSc (Hons); St George's, University of London (2005-2021)Fiona Connell, MBChB, MRCPCH, MD; Guy's Hospital (2009-2021)Kristiana Gordon, MD, FRCP (2021-present)Steve Jeffery, PhD; St George's, University of London (2005-2021)Sahar Mansour, FRCP (2005-present)Peter Mortimer, MD, FRCP (2005-present)Pia Ostergaard, PhD (2009-present)Carolyn Sholto-Douglas-Vernon, PhD; University of London (2005-2009)Malou Van Zanten, PhD (2021-present)
18 February 2021 (ma) Comprehensive update posted live
25 September 2014 (me) Comprehensive update posted live
23 July 2009 (me) Comprehensive update posted live
6 April 2007 (gb) Revision: sequence analysis and prenatal testing clinically available
27 April 2006 (me) Review posted live
19 July 2005 (gb) Original submission
• Primary lymphoedema (genetic/inherited types, and lymphovascular malformations)
• Secondary lymphoedema
• Rapid access appointments for patients with cancer-related lymphoedema
• Complications of lymphoedema, e.g., recurrent cellulitis
• Lipoedema & lipodystrophy
• Lymphoscintigraphy
• Genetic screening
• MR lymphography
• 18 February 2021 (ma) Comprehensive update posted live
• 25 September 2014 (me) Comprehensive update posted live
• 23 July 2009 (me) Comprehensive update posted live
• 6 April 2007 (gb) Revision: sequence analysis and prenatal testing clinically available
• 27 April 2006 (me) Review posted live
• 19 July 2005 (gb) Original submission
## Author Notes
We provide consultations and multidisciplinary approaches for the following medical conditions:
Primary lymphoedema (genetic/inherited types, and lymphovascular malformations)
Secondary lymphoedema
Rapid access appointments for patients with cancer-related lymphoedema
Complications of lymphoedema, e.g., recurrent cellulitis
Lipoedema & lipodystrophy
We have a range of diagnostic tools available within our service to aid our phenotyping and assessment process:
Lymphoscintigraphy
Genetic screening
MR lymphography
Our research interest and focus is gene discovery in primary lymphoedema / lymphovascular disease and understanding the mechanism of disease in primary lymphoedema through imaging (e.g., MR lymphography, ICG lymphography), histology, and blood immunophenotyping.
Please check our website for more information about our services:
Information about our research:
The VASCERN European Reference Network is a European platform where health care professionals and patient representatives share expertise and develop consensus and guidelines for rare vascular diseases. The Primary and Pediatric Lymphoedema Working Group is built upon Multidisciplinary Centres of Excellence collaborating and have a long-standing expertise in the diagnosis and management of adults and children with lymphatic problems.
For health care professionals, the VASCERN
• Primary lymphoedema (genetic/inherited types, and lymphovascular malformations)
• Secondary lymphoedema
• Rapid access appointments for patients with cancer-related lymphoedema
• Complications of lymphoedema, e.g., recurrent cellulitis
• Lipoedema & lipodystrophy
• Lymphoscintigraphy
• Genetic screening
• MR lymphography
## St George's University Hospitals
We provide consultations and multidisciplinary approaches for the following medical conditions:
Primary lymphoedema (genetic/inherited types, and lymphovascular malformations)
Secondary lymphoedema
Rapid access appointments for patients with cancer-related lymphoedema
Complications of lymphoedema, e.g., recurrent cellulitis
Lipoedema & lipodystrophy
We have a range of diagnostic tools available within our service to aid our phenotyping and assessment process:
Lymphoscintigraphy
Genetic screening
MR lymphography
Our research interest and focus is gene discovery in primary lymphoedema / lymphovascular disease and understanding the mechanism of disease in primary lymphoedema through imaging (e.g., MR lymphography, ICG lymphography), histology, and blood immunophenotyping.
Please check our website for more information about our services:
Information about our research:
• Primary lymphoedema (genetic/inherited types, and lymphovascular malformations)
• Secondary lymphoedema
• Rapid access appointments for patients with cancer-related lymphoedema
• Complications of lymphoedema, e.g., recurrent cellulitis
• Lipoedema & lipodystrophy
• Lymphoscintigraphy
• Genetic screening
• MR lymphography
## VASCERN European Reference Network
The VASCERN European Reference Network is a European platform where health care professionals and patient representatives share expertise and develop consensus and guidelines for rare vascular diseases. The Primary and Pediatric Lymphoedema Working Group is built upon Multidisciplinary Centres of Excellence collaborating and have a long-standing expertise in the diagnosis and management of adults and children with lymphatic problems.
For health care professionals, the VASCERN
## Acknowledgments
The authors would like to thank the following organizations: the Medical Research Council, the British Heart Foundation, and the National Institute for Health Research.
## Author History
Glen W Brice, RGN BSc (Hons); St George's, University of London (2005-2021)Fiona Connell, MBChB, MRCPCH, MD; Guy's Hospital (2009-2021)Kristiana Gordon, MD, FRCP (2021-present)Steve Jeffery, PhD; St George's, University of London (2005-2021)Sahar Mansour, FRCP (2005-present)Peter Mortimer, MD, FRCP (2005-present)Pia Ostergaard, PhD (2009-present)Carolyn Sholto-Douglas-Vernon, PhD; University of London (2005-2009)Malou Van Zanten, PhD (2021-present)
## Revision History
18 February 2021 (ma) Comprehensive update posted live
25 September 2014 (me) Comprehensive update posted live
23 July 2009 (me) Comprehensive update posted live
6 April 2007 (gb) Revision: sequence analysis and prenatal testing clinically available
27 April 2006 (me) Review posted live
19 July 2005 (gb) Original submission
• 18 February 2021 (ma) Comprehensive update posted live
• 25 September 2014 (me) Comprehensive update posted live
• 23 July 2009 (me) Comprehensive update posted live
• 6 April 2007 (gb) Revision: sequence analysis and prenatal testing clinically available
• 27 April 2006 (me) Review posted live
• 19 July 2005 (gb) Original submission
## References
## Published Guidelines / Consensus Statements
## Literature Cited
|
[] |
27/4/2006
|
18/2/2021
|
6/4/2007
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mirage
|
mirage
|
[
"Myelodysplasia, Infection, Restriction of Growth, Adrenal Hypoplasia, Genital Phenotypes, and Enteropathy",
"Myelodysplasia, Infection, Restriction of Growth, Adrenal Hypoplasia, Genital Phenotypes, and Enteropathy",
"Sterile alpha motif domain-containing protein 9",
"SAMD9",
"MIRAGE Syndrome"
] |
MIRAGE Syndrome
|
Kanako Tanase-Nakao, Timothy S Olson, Satoshi Narumi
|
Summary MIRAGE syndrome is an acronym for the major findings of The diagnosis of MIRAGE syndrome is established in a proband with suggestive findings and a heterozygous germline gain-of-function pathogenic variant in MIRAGE syndrome is an autosomal dominant disorder typically caused by a
|
## Diagnosis
Formal diagnostic criteria for MIRAGE syndrome have not been established.
MIRAGE syndrome
Easy bruising, mucocutaneous bleeding, oral ulcers, fatigue, pallor
Recurrent bacterial infections including pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. The most common organisms associated with these infections are enteric pathogens such as
Growth deficiency (intrauterine growth restriction with premature birth; persistent failure to thrive)
Diffuse skin hyperpigmentation, severe dehydration, and hypotension (due to primary adrenal insufficiency) which may be life threatening
Atypical external genitalia in 46,XY individuals (e.g., hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia)
Chronic intractable diarrhea
Dysphagia, recurrent aspiration pneumonia, gastroesophageal reflux
Mono- or multilineage cytopenia, either transient or persistent
Bone marrow aspirate and biopsy may show hypocellularity/aplasia with absent megakaryocytes, or it may show myelodysplastic syndrome and/or acute myelogenous leukemia (AML) with monosomy 7. Monosomy 7 may be transient if the clone is small, or it may persist for years before transformation to AML. Additional somatic pathogenic variants may correlate with transformation to AML.
Laboratory features of primary adrenal insufficiency: hyponatremia, hyperkalemia, hypoglycemia, low cortisol, and markedly elevated corticotropin (ACTH). Impaired cortisol response to cosyntropin stimulation is a confirmatory finding of primary adrenal insufficiency.
Adrenal aplasia or hypoplasia on ultrasound
Microcephaly, hydrocephalus, and white matter abnormalities on brain MRI
The diagnosis of MIRAGE syndrome
Note: Identification of a heterozygous
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: (1) A germline
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by growth restriction, myelodysplasia, and/or adrenal hypoplasia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in MIRAGE Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Somatically acquired loss of heterozygosity – for example, due to monosomy 7, del(7q), or uniparental disomy 7 – often occurs in hematopoietic tissue of individuals with a pathogenic
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available. In theory, deletion of
• Easy bruising, mucocutaneous bleeding, oral ulcers, fatigue, pallor
• Recurrent bacterial infections including pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. The most common organisms associated with these infections are enteric pathogens such as
• Growth deficiency (intrauterine growth restriction with premature birth; persistent failure to thrive)
• Diffuse skin hyperpigmentation, severe dehydration, and hypotension (due to primary adrenal insufficiency) which may be life threatening
• Atypical external genitalia in 46,XY individuals (e.g., hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia)
• Chronic intractable diarrhea
• Dysphagia, recurrent aspiration pneumonia, gastroesophageal reflux
• Mono- or multilineage cytopenia, either transient or persistent
• Bone marrow aspirate and biopsy may show hypocellularity/aplasia with absent megakaryocytes, or it may show myelodysplastic syndrome and/or acute myelogenous leukemia (AML) with monosomy 7. Monosomy 7 may be transient if the clone is small, or it may persist for years before transformation to AML. Additional somatic pathogenic variants may correlate with transformation to AML.
• Laboratory features of primary adrenal insufficiency: hyponatremia, hyperkalemia, hypoglycemia, low cortisol, and markedly elevated corticotropin (ACTH). Impaired cortisol response to cosyntropin stimulation is a confirmatory finding of primary adrenal insufficiency.
• Adrenal aplasia or hypoplasia on ultrasound
• Microcephaly, hydrocephalus, and white matter abnormalities on brain MRI
## Suggestive Findings
MIRAGE syndrome
Easy bruising, mucocutaneous bleeding, oral ulcers, fatigue, pallor
Recurrent bacterial infections including pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. The most common organisms associated with these infections are enteric pathogens such as
Growth deficiency (intrauterine growth restriction with premature birth; persistent failure to thrive)
Diffuse skin hyperpigmentation, severe dehydration, and hypotension (due to primary adrenal insufficiency) which may be life threatening
Atypical external genitalia in 46,XY individuals (e.g., hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia)
Chronic intractable diarrhea
Dysphagia, recurrent aspiration pneumonia, gastroesophageal reflux
Mono- or multilineage cytopenia, either transient or persistent
Bone marrow aspirate and biopsy may show hypocellularity/aplasia with absent megakaryocytes, or it may show myelodysplastic syndrome and/or acute myelogenous leukemia (AML) with monosomy 7. Monosomy 7 may be transient if the clone is small, or it may persist for years before transformation to AML. Additional somatic pathogenic variants may correlate with transformation to AML.
Laboratory features of primary adrenal insufficiency: hyponatremia, hyperkalemia, hypoglycemia, low cortisol, and markedly elevated corticotropin (ACTH). Impaired cortisol response to cosyntropin stimulation is a confirmatory finding of primary adrenal insufficiency.
Adrenal aplasia or hypoplasia on ultrasound
Microcephaly, hydrocephalus, and white matter abnormalities on brain MRI
• Easy bruising, mucocutaneous bleeding, oral ulcers, fatigue, pallor
• Recurrent bacterial infections including pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. The most common organisms associated with these infections are enteric pathogens such as
• Growth deficiency (intrauterine growth restriction with premature birth; persistent failure to thrive)
• Diffuse skin hyperpigmentation, severe dehydration, and hypotension (due to primary adrenal insufficiency) which may be life threatening
• Atypical external genitalia in 46,XY individuals (e.g., hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia)
• Chronic intractable diarrhea
• Dysphagia, recurrent aspiration pneumonia, gastroesophageal reflux
• Mono- or multilineage cytopenia, either transient or persistent
• Bone marrow aspirate and biopsy may show hypocellularity/aplasia with absent megakaryocytes, or it may show myelodysplastic syndrome and/or acute myelogenous leukemia (AML) with monosomy 7. Monosomy 7 may be transient if the clone is small, or it may persist for years before transformation to AML. Additional somatic pathogenic variants may correlate with transformation to AML.
• Laboratory features of primary adrenal insufficiency: hyponatremia, hyperkalemia, hypoglycemia, low cortisol, and markedly elevated corticotropin (ACTH). Impaired cortisol response to cosyntropin stimulation is a confirmatory finding of primary adrenal insufficiency.
• Adrenal aplasia or hypoplasia on ultrasound
• Microcephaly, hydrocephalus, and white matter abnormalities on brain MRI
## Establishing the Diagnosis
The diagnosis of MIRAGE syndrome
Note: Identification of a heterozygous
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: (1) A germline
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by growth restriction, myelodysplasia, and/or adrenal hypoplasia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in MIRAGE Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Somatically acquired loss of heterozygosity – for example, due to monosomy 7, del(7q), or uniparental disomy 7 – often occurs in hematopoietic tissue of individuals with a pathogenic
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available. In theory, deletion of
## Option 1
Note: (1) A germline
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by growth restriction, myelodysplasia, and/or adrenal hypoplasia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in MIRAGE Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Somatically acquired loss of heterozygosity – for example, due to monosomy 7, del(7q), or uniparental disomy 7 – often occurs in hematopoietic tissue of individuals with a pathogenic
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available. In theory, deletion of
## Clinical Characteristics
MIRAGE syndrome is a rare disorder characterized by six core features:
To date, no consensus clinical diagnostic criteria for MIRAGE syndrome are available. In this review, a diagnosis of MIRAGE syndrome is defined as:
46,XY individuals with four or more of the core features; or
46,XX individuals with three or more of the core features.
Using these diagnostic criteria, 44 individuals with features of MIRAGE syndrome and a pathogenic variant in
MIRAGE Syndrome: Frequency of Select Features
Evolution to myelodysplastic syndrome (MDS) is defined by acquisition of monosomy 7 or del(7q) in the setting of multilineage bone marrow dysplasia. Although myelodysplasia is included as a core feature of MIRAGE syndrome, myelodysplasia in these individuals appears to be due to an acquired deletion of
Individuals with a germline gain-of-function
No external genital anomalies were reported in individuals with 46,XX karyotype, but four were found to have hypoplastic or dysgenetic ovaries [
No genotype-phenotype correlations have been identified.
Penetrance is unknown. Of note, one asymptomatic female with a germline gain-of-function
To date, 44 affected individuals have been reported.
• 46,XY individuals with four or more of the core features; or
• 46,XX individuals with three or more of the core features.
## Clinical Description
MIRAGE syndrome is a rare disorder characterized by six core features:
To date, no consensus clinical diagnostic criteria for MIRAGE syndrome are available. In this review, a diagnosis of MIRAGE syndrome is defined as:
46,XY individuals with four or more of the core features; or
46,XX individuals with three or more of the core features.
Using these diagnostic criteria, 44 individuals with features of MIRAGE syndrome and a pathogenic variant in
MIRAGE Syndrome: Frequency of Select Features
Evolution to myelodysplastic syndrome (MDS) is defined by acquisition of monosomy 7 or del(7q) in the setting of multilineage bone marrow dysplasia. Although myelodysplasia is included as a core feature of MIRAGE syndrome, myelodysplasia in these individuals appears to be due to an acquired deletion of
Individuals with a germline gain-of-function
No external genital anomalies were reported in individuals with 46,XX karyotype, but four were found to have hypoplastic or dysgenetic ovaries [
• 46,XY individuals with four or more of the core features; or
• 46,XX individuals with three or more of the core features.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
Penetrance is unknown. Of note, one asymptomatic female with a germline gain-of-function
## Prevalence
To date, 44 affected individuals have been reported.
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of MIRAGE Syndrome
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; IMAGe-I =
A
See also
## Management
To establish the extent of disease and needs in an individual diagnosed with MIRAGE syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with MIRAGE Syndrome
Referral to hematologist
CBC w/differential
Bone marrow aspirate & biopsy
Obtain history of infections incl pathogens.
Eval of lymphocyte subsets & IgG levels
Assess for vaccine responses.
To assess for primary adrenal insufficiency
Consider consultation w/endocrinologist.
To incl eval of aspiration risk & nutritional status
Consider eval for duodenal tube placement in those w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Serum creatinine & blood urea nitrogen
Urinalysis
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
CBC = complete blood count; MDS = myelodysplastic syndrome; MOI = mode of inheritance
See
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with MIRAGE Syndrome
Transfusion support for severe anemia & thrombocytopenia
Bacterial infection prevention strategies incl antibiotic prophylaxis & fever precautions in those w/severe neutropenia
HSCT is curative treatment for myelodysplasia, chronic severe neutropenia, or chronic transfusion dependence.
Treatment w/antibiotics, antivirals, & antifungals as needed
Prophylactic IV Ig if endogenous Ig levels are ↓
Use of artificial tear solutions & treatment per ophthalmologist
Mgmt of ambient temperature for those w/temperature instability
HRT = hormone replacement therapy; HSCT = hematopoietic stem cell transplantation; Ig = immunoglobulin; IV = intravenous
Presence of adrenal hypoplasia may complicate transplantation, requiring extreme care.
Monosomy 7 greatly increases the risk for treatment-resistant leukemia.
No formal surveillance guidelines are available. The recommendations in
Recommended Surveillance for Individuals with MIRAGE Syndrome
Physical exam for features of adrenal hypoplasia
Serum sodium, potassium, glucose, cortisol, ACTH
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early evaluation for myelodysplasia. (See
See
Search
• Referral to hematologist
• CBC w/differential
• Bone marrow aspirate & biopsy
• Obtain history of infections incl pathogens.
• Eval of lymphocyte subsets & IgG levels
• Assess for vaccine responses.
• To assess for primary adrenal insufficiency
• Consider consultation w/endocrinologist.
• To incl eval of aspiration risk & nutritional status
• Consider eval for duodenal tube placement in those w/dysphagia &/or aspiration risk.
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Serum creatinine & blood urea nitrogen
• Urinalysis
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
• Transfusion support for severe anemia & thrombocytopenia
• Bacterial infection prevention strategies incl antibiotic prophylaxis & fever precautions in those w/severe neutropenia
• HSCT is curative treatment for myelodysplasia, chronic severe neutropenia, or chronic transfusion dependence.
• Treatment w/antibiotics, antivirals, & antifungals as needed
• Prophylactic IV Ig if endogenous Ig levels are ↓
• Use of artificial tear solutions & treatment per ophthalmologist
• Mgmt of ambient temperature for those w/temperature instability
• Physical exam for features of adrenal hypoplasia
• Serum sodium, potassium, glucose, cortisol, ACTH
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MIRAGE syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with MIRAGE Syndrome
Referral to hematologist
CBC w/differential
Bone marrow aspirate & biopsy
Obtain history of infections incl pathogens.
Eval of lymphocyte subsets & IgG levels
Assess for vaccine responses.
To assess for primary adrenal insufficiency
Consider consultation w/endocrinologist.
To incl eval of aspiration risk & nutritional status
Consider eval for duodenal tube placement in those w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Serum creatinine & blood urea nitrogen
Urinalysis
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
CBC = complete blood count; MDS = myelodysplastic syndrome; MOI = mode of inheritance
See
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Referral to hematologist
• CBC w/differential
• Bone marrow aspirate & biopsy
• Obtain history of infections incl pathogens.
• Eval of lymphocyte subsets & IgG levels
• Assess for vaccine responses.
• To assess for primary adrenal insufficiency
• Consider consultation w/endocrinologist.
• To incl eval of aspiration risk & nutritional status
• Consider eval for duodenal tube placement in those w/dysphagia &/or aspiration risk.
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Serum creatinine & blood urea nitrogen
• Urinalysis
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with MIRAGE Syndrome
Transfusion support for severe anemia & thrombocytopenia
Bacterial infection prevention strategies incl antibiotic prophylaxis & fever precautions in those w/severe neutropenia
HSCT is curative treatment for myelodysplasia, chronic severe neutropenia, or chronic transfusion dependence.
Treatment w/antibiotics, antivirals, & antifungals as needed
Prophylactic IV Ig if endogenous Ig levels are ↓
Use of artificial tear solutions & treatment per ophthalmologist
Mgmt of ambient temperature for those w/temperature instability
HRT = hormone replacement therapy; HSCT = hematopoietic stem cell transplantation; Ig = immunoglobulin; IV = intravenous
Presence of adrenal hypoplasia may complicate transplantation, requiring extreme care.
Monosomy 7 greatly increases the risk for treatment-resistant leukemia.
• Transfusion support for severe anemia & thrombocytopenia
• Bacterial infection prevention strategies incl antibiotic prophylaxis & fever precautions in those w/severe neutropenia
• HSCT is curative treatment for myelodysplasia, chronic severe neutropenia, or chronic transfusion dependence.
• Treatment w/antibiotics, antivirals, & antifungals as needed
• Prophylactic IV Ig if endogenous Ig levels are ↓
• Use of artificial tear solutions & treatment per ophthalmologist
• Mgmt of ambient temperature for those w/temperature instability
## Surveillance
No formal surveillance guidelines are available. The recommendations in
Recommended Surveillance for Individuals with MIRAGE Syndrome
Physical exam for features of adrenal hypoplasia
Serum sodium, potassium, glucose, cortisol, ACTH
• Physical exam for features of adrenal hypoplasia
• Serum sodium, potassium, glucose, cortisol, ACTH
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early evaluation for myelodysplasia. (See
See
## Therapies Under Investigation
Search
## Genetic Counseling
MIRAGE syndrome is an autosomal dominant disorder typically caused by a
Most individuals diagnosed with MIRAGE syndrome have the disorder as the result of a
Rarely, individuals diagnosed with MIRAGE syndrome have the disorder as the result of an
Molecular genetic testing is recommended for the parents of the proband. If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline mosaicism. Presumed parental germline mosaicism has been reported for MIRAGE syndrome; however, parental identity testing was not performed in the reported family [
The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with a pathogenic
Although rarely reported, the clinical family history of some individuals diagnosed with MIRAGE syndrome may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or phenotypic modification resulting from a natural protective second genetic event (see
If a parent of the proband has the
If the proband has a known
If the parents have not been tested for the
Each child of an individual with a heterozygous
To date, individuals with the typical MIRAGE syndrome phenotype are not known to reproduce, likely owing to the severity of the condition and/or primary gonadal dysfunction.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with MIRAGE syndrome.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with MIRAGE syndrome have the disorder as the result of a
• Rarely, individuals diagnosed with MIRAGE syndrome have the disorder as the result of an
• Molecular genetic testing is recommended for the parents of the proband. If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Presumed parental germline mosaicism has been reported for MIRAGE syndrome; however, parental identity testing was not performed in the reported family [
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with a pathogenic
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Presumed parental germline mosaicism has been reported for MIRAGE syndrome; however, parental identity testing was not performed in the reported family [
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with a pathogenic
• Although rarely reported, the clinical family history of some individuals diagnosed with MIRAGE syndrome may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or phenotypic modification resulting from a natural protective second genetic event (see
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Presumed parental germline mosaicism has been reported for MIRAGE syndrome; however, parental identity testing was not performed in the reported family [
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with a pathogenic
• If a parent of the proband has the
• If the proband has a known
• If the parents have not been tested for the
• Each child of an individual with a heterozygous
• To date, individuals with the typical MIRAGE syndrome phenotype are not known to reproduce, likely owing to the severity of the condition and/or primary gonadal dysfunction.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with MIRAGE syndrome.
## Mode of Inheritance
MIRAGE syndrome is an autosomal dominant disorder typically caused by a
## Risk to Family Members
Most individuals diagnosed with MIRAGE syndrome have the disorder as the result of a
Rarely, individuals diagnosed with MIRAGE syndrome have the disorder as the result of an
Molecular genetic testing is recommended for the parents of the proband. If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline mosaicism. Presumed parental germline mosaicism has been reported for MIRAGE syndrome; however, parental identity testing was not performed in the reported family [
The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with a pathogenic
Although rarely reported, the clinical family history of some individuals diagnosed with MIRAGE syndrome may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or phenotypic modification resulting from a natural protective second genetic event (see
If a parent of the proband has the
If the proband has a known
If the parents have not been tested for the
Each child of an individual with a heterozygous
To date, individuals with the typical MIRAGE syndrome phenotype are not known to reproduce, likely owing to the severity of the condition and/or primary gonadal dysfunction.
• Most individuals diagnosed with MIRAGE syndrome have the disorder as the result of a
• Rarely, individuals diagnosed with MIRAGE syndrome have the disorder as the result of an
• Molecular genetic testing is recommended for the parents of the proband. If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Presumed parental germline mosaicism has been reported for MIRAGE syndrome; however, parental identity testing was not performed in the reported family [
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with a pathogenic
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Presumed parental germline mosaicism has been reported for MIRAGE syndrome; however, parental identity testing was not performed in the reported family [
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with a pathogenic
• Although rarely reported, the clinical family history of some individuals diagnosed with MIRAGE syndrome may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or phenotypic modification resulting from a natural protective second genetic event (see
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Presumed parental germline mosaicism has been reported for MIRAGE syndrome; however, parental identity testing was not performed in the reported family [
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with a pathogenic
• If a parent of the proband has the
• If the proband has a known
• If the parents have not been tested for the
• Each child of an individual with a heterozygous
• To date, individuals with the typical MIRAGE syndrome phenotype are not known to reproduce, likely owing to the severity of the condition and/or primary gonadal dysfunction.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with MIRAGE syndrome.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with MIRAGE syndrome.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 8126
Gaithersburg MD 20898-8126
•
• PO Box 8126
• Gaithersburg MD 20898-8126
•
## Molecular Genetics
MIRAGE Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MIRAGE Syndrome (
This somatic change results in a decreased proportion of hematopoietic cells with the variant and may cause a false negative molecular result when testing leukocyte DNA. Therefore, evaluation of genomic abnormalities with SNP array and/or evaluation of low-abundance variants with deep sequencing (>1000X read depth) should be considered in individuals clinically suspected for MIRAGE syndrome who have a negative genetic test result. If feasible, use of DNA derived from non-hematopoietic tissues (e.g., skin fibroblasts, hair roots) may be considered.
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
This somatic change results in a decreased proportion of hematopoietic cells with the variant and may cause a false negative molecular result when testing leukocyte DNA. Therefore, evaluation of genomic abnormalities with SNP array and/or evaluation of low-abundance variants with deep sequencing (>1000X read depth) should be considered in individuals clinically suspected for MIRAGE syndrome who have a negative genetic test result. If feasible, use of DNA derived from non-hematopoietic tissues (e.g., skin fibroblasts, hair roots) may be considered.
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
25 November 2020 (sw) Review posted live
6 April 2020 (sn) Original submission
• 25 November 2020 (sw) Review posted live
• 6 April 2020 (sn) Original submission
## Author Notes
## Revision History
25 November 2020 (sw) Review posted live
6 April 2020 (sn) Original submission
• 25 November 2020 (sw) Review posted live
• 6 April 2020 (sn) Original submission
## References
## Literature Cited
|
[] |
25/11/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mirror
|
mirror
|
[
"Congenital Mirror Movement Disorder",
"Congenital Mirror Movement Disorder",
"DNA repair protein RAD51 homolog 1",
"Netrin receptor DCC",
"Netrin-1",
"DCC",
"NTN1",
"RAD51",
"Congenital Mirror Movements"
] |
Congenital Mirror Movements
|
Aurélie Méneret, Oriane Trouillard, Margaux Dunoyer, Christel Depienne, Emmanuel Roze
|
Summary The disorder of congenital mirror movements (CMM) is characterized by early-onset, obvious mirror movements (involuntary movements of one side of the body that mirror intentional movements on the opposite side) in individuals who typically have no other clinical signs or symptoms. Although mirror movements vary in severity, most affected individuals have strong and sustained mirror movements of a lesser amplitude than the corresponding voluntary movements. Mirror movements usually persist throughout life, without deterioration or improvement, and are not usually associated with subsequent onset of additional neurologic manifestations. However, a subset of affected individuals with a heterozygous pathogenic variant in The diagnosis of CMM is established in a proband with suggestive clinical findings and occasionally by identification of a heterozygous pathogenic variant in CMM is generally inherited in an autosomal dominant (AD) manner. (Autosomal recessive inheritance has been suggested in one family.) For AD inheritance: most individuals with CMM resulting from a pathogenic variant in
|
## Diagnosis
The diagnosis of the disorder of congenital mirror movements (CMM) is established by clinical findings and, in some instances, molecular genetic testing.
CMM
Onset of mirror movements (defined as involuntary movements of one side of the body that mirror intentional movements on the opposite side) in infancy or early childhood
Predominant involvement of the upper limbs, with more severe distal involvement, especially in the muscles controlling the fingers and hands, which are always involved
Persistence of mirror movements throughout adulthood and
Evidence of other clinical findings that would suggest an underlying syndrome [
Subsequent development of additional neurologic findings
The diagnosis of CMM
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of CMM, molecular genetic testing approaches include use of a
For an introduction to multigene panels click
When the diagnosis of CMM has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing may be pursued.
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Mirror Movements
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Significant locus heterogeneity is hypothesized
• Onset of mirror movements (defined as involuntary movements of one side of the body that mirror intentional movements on the opposite side) in infancy or early childhood
• Predominant involvement of the upper limbs, with more severe distal involvement, especially in the muscles controlling the fingers and hands, which are always involved
• Persistence of mirror movements throughout adulthood and
• Evidence of other clinical findings that would suggest an underlying syndrome [
• Subsequent development of additional neurologic findings
• Evidence of other clinical findings that would suggest an underlying syndrome [
• Subsequent development of additional neurologic findings
• Evidence of other clinical findings that would suggest an underlying syndrome [
• Subsequent development of additional neurologic findings
## Suggestive Findings
CMM
Onset of mirror movements (defined as involuntary movements of one side of the body that mirror intentional movements on the opposite side) in infancy or early childhood
Predominant involvement of the upper limbs, with more severe distal involvement, especially in the muscles controlling the fingers and hands, which are always involved
Persistence of mirror movements throughout adulthood and
Evidence of other clinical findings that would suggest an underlying syndrome [
Subsequent development of additional neurologic findings
• Onset of mirror movements (defined as involuntary movements of one side of the body that mirror intentional movements on the opposite side) in infancy or early childhood
• Predominant involvement of the upper limbs, with more severe distal involvement, especially in the muscles controlling the fingers and hands, which are always involved
• Persistence of mirror movements throughout adulthood and
• Evidence of other clinical findings that would suggest an underlying syndrome [
• Subsequent development of additional neurologic findings
• Evidence of other clinical findings that would suggest an underlying syndrome [
• Subsequent development of additional neurologic findings
• Evidence of other clinical findings that would suggest an underlying syndrome [
• Subsequent development of additional neurologic findings
## Establishing the Diagnosis
The diagnosis of CMM
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of CMM, molecular genetic testing approaches include use of a
For an introduction to multigene panels click
When the diagnosis of CMM has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing may be pursued.
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Mirror Movements
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Significant locus heterogeneity is hypothesized
## Option 1
When the phenotypic findings suggest the diagnosis of CMM, molecular genetic testing approaches include use of a
For an introduction to multigene panels click
## Option 2
When the diagnosis of CMM has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing may be pursued.
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Mirror Movements
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Significant locus heterogeneity is hypothesized
## Clinical Characteristics
Physiologic mild mirror movements may be seen in young children, but their persistence after age seven years is pathologic [
Although mirror movements vary in severity, most affected individuals have strong and sustained mirror movements of a lesser amplitude than the corresponding voluntary movements.
The severity of the mirror movements is defined according to the Woods and Teuber scale [
No MM
Barely discernible but repetitive MM
Slight but sustained MM or stronger but briefer MM
Strong and sustained repetitive MM
MM equal to that observed in the intended hand
Affected individuals have moderate difficulties with activities of daily living, including inability to perform pure unimanual movements, difficulty with tasks requiring skilled bimanual coordination, and occasional pain in the upper limbs during sustained manual activities [
There are no clear and validated genotype-phenotype correlations for
Pathogenic variants in the NTN1 binding interface may predispose to abnormalities in the development of the corpus callosum with or without CMM [
Males with truncating
Penetrance is reduced regardless of whether the causative pathogenic variant is in
The term "synkinesis" may be appropriate, although it is more often used to describe mirror movements acquired later in life, as a result of either neurodegenerative diseases or acute brain lesions [
The term "bimanual synergia" is mentioned in OMIM as having been used by William Bateson (1861-1926) in a family with CMM of apparent autosomal dominant inheritance and reduced penetrance (OMIM
Congenital mirror movements is a very rare disorder, with an estimated prevalence of <1:1,000,000 (Orphanet
• No MM
• Barely discernible but repetitive MM
• Slight but sustained MM or stronger but briefer MM
• Strong and sustained repetitive MM
• MM equal to that observed in the intended hand
• Pathogenic variants in the NTN1 binding interface may predispose to abnormalities in the development of the corpus callosum with or without CMM [
• Males with truncating
## Clinical Description
Physiologic mild mirror movements may be seen in young children, but their persistence after age seven years is pathologic [
Although mirror movements vary in severity, most affected individuals have strong and sustained mirror movements of a lesser amplitude than the corresponding voluntary movements.
The severity of the mirror movements is defined according to the Woods and Teuber scale [
No MM
Barely discernible but repetitive MM
Slight but sustained MM or stronger but briefer MM
Strong and sustained repetitive MM
MM equal to that observed in the intended hand
Affected individuals have moderate difficulties with activities of daily living, including inability to perform pure unimanual movements, difficulty with tasks requiring skilled bimanual coordination, and occasional pain in the upper limbs during sustained manual activities [
• No MM
• Barely discernible but repetitive MM
• Slight but sustained MM or stronger but briefer MM
• Strong and sustained repetitive MM
• MM equal to that observed in the intended hand
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
There are no clear and validated genotype-phenotype correlations for
Pathogenic variants in the NTN1 binding interface may predispose to abnormalities in the development of the corpus callosum with or without CMM [
Males with truncating
• Pathogenic variants in the NTN1 binding interface may predispose to abnormalities in the development of the corpus callosum with or without CMM [
• Males with truncating
## Penetrance
Penetrance is reduced regardless of whether the causative pathogenic variant is in
## Nomenclature
The term "synkinesis" may be appropriate, although it is more often used to describe mirror movements acquired later in life, as a result of either neurodegenerative diseases or acute brain lesions [
The term "bimanual synergia" is mentioned in OMIM as having been used by William Bateson (1861-1926) in a family with CMM of apparent autosomal dominant inheritance and reduced penetrance (OMIM
## Prevalence
Congenital mirror movements is a very rare disorder, with an estimated prevalence of <1:1,000,000 (Orphanet
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
The differential diagnosis of congenital mirror movements (CMM) from mirror movements of other causes is mainly theoretic, as the findings in CMM are distinctive, isolated, and easily recognized.
Syndromes with Early-Onset Mirror Movements
MM in persons w/KS is almost always linked to
Prevalence of MM in
Congenital fusion of cervical vertebrae
Typical phenotype incl low posterior hairline, short neck, & ↓ amplitude of neck movements
Klippel-Feil syndrome w/congenital perceptive deafness & Duane syndrome
Affected persons are almost exclusively female.
AD = autosomal dominant; AR = autosomal recessive; CMM = congenital mirror movements; GnRH = gonadotropin-releasing hormone; MM = mirror movements; MOI = mode of inheritance; XL = X-linked
Digenic inheritance has been reported.
Occasional variants in
Duane syndrome = abducens palsy with narrowing of the palpebral fissure
• MM in persons w/KS is almost always linked to
• Prevalence of MM in
• Congenital fusion of cervical vertebrae
• Typical phenotype incl low posterior hairline, short neck, & ↓ amplitude of neck movements
• Klippel-Feil syndrome w/congenital perceptive deafness & Duane syndrome
• Affected persons are almost exclusively female.
## Management
To establish the extent of disease and needs in an individual diagnosed with congenital mirror movements (CMM), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital Mirror Movements
Use of community or
Need for social work involvement for parental support.
ADL = activities of daily living; CC = corpus callosum; CMM = congenital mirror movements; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations in Individuals with Congenital Mirror Movements
Complex bimanual movements or sustained/repetitive hand activity should be limited in order to reduce the occurrence of pain or discomfort in the upper limbs.
See
Botulinum toxin injections have been successfully tried in one affected individual [
Noninvasive modulation of brain interhemispheric communication may be a possibility in the future [
Search
• Use of community or
• Need for social work involvement for parental support.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with congenital mirror movements (CMM), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital Mirror Movements
Use of community or
Need for social work involvement for parental support.
ADL = activities of daily living; CC = corpus callosum; CMM = congenital mirror movements; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Use of community or
• Need for social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Congenital Mirror Movements
## Agents/Circumstances to Avoid
Complex bimanual movements or sustained/repetitive hand activity should be limited in order to reduce the occurrence of pain or discomfort in the upper limbs.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Botulinum toxin injections have been successfully tried in one affected individual [
Noninvasive modulation of brain interhemispheric communication may be a possibility in the future [
Search
## Genetic Counseling
The disorder of congenital mirror movements (CMM) is generally inherited in an autosomal dominant manner.
Possible autosomal recessive inheritance of CMM was reported in one family [
Most individuals with CMM resulting from a pathogenic variant in
A proband with CMM may have the disorder as the result of a
If the causative pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband. If the pathogenic variant identified in the proband is not identified in either parent, several possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.
The family history of some individuals diagnosed with CMM may appear to be negative because of reduced penetrance or failure to recognize the disorder in family members. Therefore, when the molecular basis of CMM is known, molecular genetic testing is the most accurate means of determining the genetic status of at-risk individuals.
If a parent of the proband is affected and/or has a
If the proband has a known
If the parents of the proband are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for CMM because of the significant possibility of reduced penetrance in a parent and the theoretic possibility of parental germline mosaicism.
Each child of an individual with CMM caused by a pathogenic variant in
Because of reduced penetrance in CMM, offspring who inherit a
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring) to young adults who are affected or at risk of having the
Once the CMM-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for CMM are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals with CMM resulting from a pathogenic variant in
• A proband with CMM may have the disorder as the result of a
• If the causative pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband. If the pathogenic variant identified in the proband is not identified in either parent, several possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.
• The family history of some individuals diagnosed with CMM may appear to be negative because of reduced penetrance or failure to recognize the disorder in family members. Therefore, when the molecular basis of CMM is known, molecular genetic testing is the most accurate means of determining the genetic status of at-risk individuals.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.
• If a parent of the proband is affected and/or has a
• If the proband has a known
• If the parents of the proband are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for CMM because of the significant possibility of reduced penetrance in a parent and the theoretic possibility of parental germline mosaicism.
• Each child of an individual with CMM caused by a pathogenic variant in
• Because of reduced penetrance in CMM, offspring who inherit a
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring) to young adults who are affected or at risk of having the
## Mode of Inheritance
The disorder of congenital mirror movements (CMM) is generally inherited in an autosomal dominant manner.
Possible autosomal recessive inheritance of CMM was reported in one family [
## Risk to Family Members (Autosomal Dominant Inheritance)
Most individuals with CMM resulting from a pathogenic variant in
A proband with CMM may have the disorder as the result of a
If the causative pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband. If the pathogenic variant identified in the proband is not identified in either parent, several possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.
The family history of some individuals diagnosed with CMM may appear to be negative because of reduced penetrance or failure to recognize the disorder in family members. Therefore, when the molecular basis of CMM is known, molecular genetic testing is the most accurate means of determining the genetic status of at-risk individuals.
If a parent of the proband is affected and/or has a
If the proband has a known
If the parents of the proband are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for CMM because of the significant possibility of reduced penetrance in a parent and the theoretic possibility of parental germline mosaicism.
Each child of an individual with CMM caused by a pathogenic variant in
Because of reduced penetrance in CMM, offspring who inherit a
• Most individuals with CMM resulting from a pathogenic variant in
• A proband with CMM may have the disorder as the result of a
• If the causative pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband. If the pathogenic variant identified in the proband is not identified in either parent, several possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.
• The family history of some individuals diagnosed with CMM may appear to be negative because of reduced penetrance or failure to recognize the disorder in family members. Therefore, when the molecular basis of CMM is known, molecular genetic testing is the most accurate means of determining the genetic status of at-risk individuals.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.
• If a parent of the proband is affected and/or has a
• If the proband has a known
• If the parents of the proband are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for CMM because of the significant possibility of reduced penetrance in a parent and the theoretic possibility of parental germline mosaicism.
• Each child of an individual with CMM caused by a pathogenic variant in
• Because of reduced penetrance in CMM, offspring who inherit a
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring) to young adults who are affected or at risk of having the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring) to young adults who are affected or at risk of having the
## Prenatal Testing and Preimplantation Genetic Testing
Once the CMM-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for CMM are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Congenital Mirror Movements: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Congenital Mirror Movements (
Two of the genes (
Genes associated with CMM have also been associated with tumors or genomic integrity in individuals who do not have CMM.
## Molecular Pathogenesis
Two of the genes (
## Cancer and Benign Tumors
Genes associated with CMM have also been associated with tumors or genomic integrity in individuals who do not have CMM.
## Chapter Notes
24 September 2020 (ma) Comprehensive update posted live
12 March 2015 (me) Review posted live
5 November 2014 (am) Original submission
• 24 September 2020 (ma) Comprehensive update posted live
• 12 March 2015 (me) Review posted live
• 5 November 2014 (am) Original submission
## Revision History
24 September 2020 (ma) Comprehensive update posted live
12 March 2015 (me) Review posted live
5 November 2014 (am) Original submission
• 24 September 2020 (ma) Comprehensive update posted live
• 12 March 2015 (me) Review posted live
• 5 November 2014 (am) Original submission
## References
## Literature Cited
|
[] |
12/3/2015
|
24/9/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
miyoshi
|
miyoshi
|
[
"Miyoshi Muscular Dystrophy (Miyoshi Myopathy)",
"Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B)",
"DYSF-Related Asymptomatic HyperCKemia",
"DYSF-Related Distal Myopathy with Anterior Tibial Onset",
"Dysferlin",
"DYSF",
"Dysferlinopathy"
] |
Dysferlinopathy
|
Masashi Aoki, Toshiaki Takahashi
|
Summary Dysferlinopathy includes a spectrum of muscle disease characterized by two major phenotypes: Miyoshi muscular dystrophy (MMD) and limb-girdle muscular dystrophy type 2B (LGMD2B); and two minor phenotypes: asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT). The diagnosis of dysferlinopathy is established in a proband with suggestive findings and biallelic pathogenic variants in Dysferlinopathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
Miyoshi muscular dystrophy (Miyoshi myopathy)
Limb-girdle muscular dystrophy type 2B
Asymptomatic hyperCKemia
Distal myopathy with anterior tibial onset
For synonyms and outdated names see
• Miyoshi muscular dystrophy (Miyoshi myopathy)
• Limb-girdle muscular dystrophy type 2B
• Asymptomatic hyperCKemia
• Distal myopathy with anterior tibial onset
## Diagnosis
No consensus clinical diagnostic criteria for dysferlinopathy have been published.
Dysferlinopathy should be suspected in those with suggestive findings of
Dysferlinopathy
Mid- to late-childhood or early-adult onset; mean age at onset 19.0 years
Early and predominant distal muscle weakness affecting the upper and lower limbs, particularly the calf muscles (i.e., gastrocnemius and soleus muscles)
Slow progression
Elevation of serum CK concentration, often 10-100 times normal; mean CK: 8,940 IU/L
Primarily myogenic pattern on EMG
Predominant early weakness and atrophy of the pelvic and shoulder girdle muscles
Onset in the proximal lower-limb musculature in the late teens or later
Slow progression
Massive elevation of serum CK concentration
Subclinical involvement of distal muscles, identified by careful examination or ancillary investigations such as muscle CT scan and MRI
Dysferlinopathy
A family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity) should inform the consideration of dysferlinopathy in individuals with suggestive findings of the above major and minor phenotypes. Absence of a known family history does not preclude the diagnosis.
The diagnosis of dysferlinopathy
Note: Identification of biallelic
Molecular genetic testing approaches can include a combination of
Individuals with the distinctive findings described in
Note: RNA analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Dysferlinopathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Includes pathogenic variants deep within
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Mid- to late-childhood or early-adult onset; mean age at onset 19.0 years
• Early and predominant distal muscle weakness affecting the upper and lower limbs, particularly the calf muscles (i.e., gastrocnemius and soleus muscles)
• Slow progression
• Elevation of serum CK concentration, often 10-100 times normal; mean CK: 8,940 IU/L
• Primarily myogenic pattern on EMG
• Predominant early weakness and atrophy of the pelvic and shoulder girdle muscles
• Onset in the proximal lower-limb musculature in the late teens or later
• Slow progression
• Massive elevation of serum CK concentration
• Subclinical involvement of distal muscles, identified by careful examination or ancillary investigations such as muscle CT scan and MRI
## Suggestive Findings
Dysferlinopathy should be suspected in those with suggestive findings of
Dysferlinopathy
Mid- to late-childhood or early-adult onset; mean age at onset 19.0 years
Early and predominant distal muscle weakness affecting the upper and lower limbs, particularly the calf muscles (i.e., gastrocnemius and soleus muscles)
Slow progression
Elevation of serum CK concentration, often 10-100 times normal; mean CK: 8,940 IU/L
Primarily myogenic pattern on EMG
Predominant early weakness and atrophy of the pelvic and shoulder girdle muscles
Onset in the proximal lower-limb musculature in the late teens or later
Slow progression
Massive elevation of serum CK concentration
Subclinical involvement of distal muscles, identified by careful examination or ancillary investigations such as muscle CT scan and MRI
Dysferlinopathy
A family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity) should inform the consideration of dysferlinopathy in individuals with suggestive findings of the above major and minor phenotypes. Absence of a known family history does not preclude the diagnosis.
• Mid- to late-childhood or early-adult onset; mean age at onset 19.0 years
• Early and predominant distal muscle weakness affecting the upper and lower limbs, particularly the calf muscles (i.e., gastrocnemius and soleus muscles)
• Slow progression
• Elevation of serum CK concentration, often 10-100 times normal; mean CK: 8,940 IU/L
• Primarily myogenic pattern on EMG
• Predominant early weakness and atrophy of the pelvic and shoulder girdle muscles
• Onset in the proximal lower-limb musculature in the late teens or later
• Slow progression
• Massive elevation of serum CK concentration
• Subclinical involvement of distal muscles, identified by careful examination or ancillary investigations such as muscle CT scan and MRI
## Major Phenotypes
Dysferlinopathy
Mid- to late-childhood or early-adult onset; mean age at onset 19.0 years
Early and predominant distal muscle weakness affecting the upper and lower limbs, particularly the calf muscles (i.e., gastrocnemius and soleus muscles)
Slow progression
Elevation of serum CK concentration, often 10-100 times normal; mean CK: 8,940 IU/L
Primarily myogenic pattern on EMG
Predominant early weakness and atrophy of the pelvic and shoulder girdle muscles
Onset in the proximal lower-limb musculature in the late teens or later
Slow progression
Massive elevation of serum CK concentration
Subclinical involvement of distal muscles, identified by careful examination or ancillary investigations such as muscle CT scan and MRI
• Mid- to late-childhood or early-adult onset; mean age at onset 19.0 years
• Early and predominant distal muscle weakness affecting the upper and lower limbs, particularly the calf muscles (i.e., gastrocnemius and soleus muscles)
• Slow progression
• Elevation of serum CK concentration, often 10-100 times normal; mean CK: 8,940 IU/L
• Primarily myogenic pattern on EMG
• Predominant early weakness and atrophy of the pelvic and shoulder girdle muscles
• Onset in the proximal lower-limb musculature in the late teens or later
• Slow progression
• Massive elevation of serum CK concentration
• Subclinical involvement of distal muscles, identified by careful examination or ancillary investigations such as muscle CT scan and MRI
## Minor Phenotypes
Dysferlinopathy
## Family History
A family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity) should inform the consideration of dysferlinopathy in individuals with suggestive findings of the above major and minor phenotypes. Absence of a known family history does not preclude the diagnosis.
## Establishing the Diagnosis
The diagnosis of dysferlinopathy
Note: Identification of biallelic
Molecular genetic testing approaches can include a combination of
Individuals with the distinctive findings described in
Note: RNA analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Dysferlinopathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Includes pathogenic variants deep within
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
Note: RNA analysis of
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Dysferlinopathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Includes pathogenic variants deep within
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Dysferlinopathy includes a spectrum of muscle disease characterized by two major phenotypes (Miyoshi muscular dystrophy [MMD] and limb-girdle muscular dystrophy type 2B [LGMD2B]) and two minor phenotypes (asymptomatic hyperCKemia and distal myopathy with anterior tibial onset [DMAT]) [
The weakness and atrophy may be asymmetric with any of these presentations.
Dysferlinopathy: Comparison of Phenotypes by Select Features
DMAT = distal myopathy with anterior tibial onset; LGMD2B = limb-girdle muscular dystrophy type 2B; MMD = Miyoshi muscular dystrophy
Studies have reported genotype-phenotype correlates with the following two pathogenic variants [
Dysferlinopathy was originally called LGMD2B because at the time that it was mapped to 2p13 it was the second form (2) of autosomal recessive (B) limb-girdle muscular dystrophy (LGMD) to be mapped. The gene for Miyoshi muscular dystrophy and the gene for LGMD2B were mapped to the same genetic interval at chromosome 2p13. Two groups independently identified a novel human skeletal muscle gene,
The prevalence is not known. In the initial (1967) description of Miyoshi muscular dystrophy, four affected individuals in two families were from Japan.
Subsequently,
In Libyan Jews, the prevalence of dysferlinopathy is at least 1:1,300, with a carrier rate of approximately 10% for the variant
A founder variant,
A founder variant,
## Clinical Description
Dysferlinopathy includes a spectrum of muscle disease characterized by two major phenotypes (Miyoshi muscular dystrophy [MMD] and limb-girdle muscular dystrophy type 2B [LGMD2B]) and two minor phenotypes (asymptomatic hyperCKemia and distal myopathy with anterior tibial onset [DMAT]) [
The weakness and atrophy may be asymmetric with any of these presentations.
Dysferlinopathy: Comparison of Phenotypes by Select Features
DMAT = distal myopathy with anterior tibial onset; LGMD2B = limb-girdle muscular dystrophy type 2B; MMD = Miyoshi muscular dystrophy
## Genotype-Phenotype Correlations
Studies have reported genotype-phenotype correlates with the following two pathogenic variants [
## Nomenclature
Dysferlinopathy was originally called LGMD2B because at the time that it was mapped to 2p13 it was the second form (2) of autosomal recessive (B) limb-girdle muscular dystrophy (LGMD) to be mapped. The gene for Miyoshi muscular dystrophy and the gene for LGMD2B were mapped to the same genetic interval at chromosome 2p13. Two groups independently identified a novel human skeletal muscle gene,
## Prevalence
The prevalence is not known. In the initial (1967) description of Miyoshi muscular dystrophy, four affected individuals in two families were from Japan.
Subsequently,
In Libyan Jews, the prevalence of dysferlinopathy is at least 1:1,300, with a carrier rate of approximately 10% for the variant
A founder variant,
A founder variant,
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Multigene panels are increasingly used to identify pathogenic variants and confirm a diagnosis of a specific form of LGMD.
Distal Myopathies
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Distal myopathies of unknown genetic cause:
Distal myopathy with
New Finnish distal myopathy (MPD3; OMIM
• Distal myopathy with
• New Finnish distal myopathy (MPD3; OMIM
## Management
No clinical practice guidelines for dysferlinopathy have been published.
To establish the extent of disease and needs in an individual diagnosed with dysferlinopathy, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Dysferlinopathy
Muscle strength & function in arms, hands, legs (esp calves), & feet
Balance
Function
Fine motor skills
Impact on activities of daily living
Need for ongoing PT & OT
Need for AFOs & assistive ambulatory devices
Need for adaptive devices
Need for handicapped parking
Use of community or
Need for social work involvement for caregiver support.
AFOs = ankle-foot orthoses; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MOI = mode of inheritance; OT = occupational therapy; PFTs = pulmonary function tests; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no approved therapy for dysferlinopathy. Treatment is symptomatic only.
Management should be tailored to the individual and the specific subtype. A general approach to appropriate management can prolong survival and improve quality of life.
Treatment of Manifestations in Individuals with Dysferlinopathy
Transfers (e.g., from bed to wheelchair, wheelchair to car)
Medical alert system for those unable to stand after a fall
Techniques & devices to accomplish tasks incl mobility, washing, dressing, eating, cooking, grooming
To assist w/household modifications to meet special needs
OT = occupational therapy; PT = physical therapy
All affected persons should consult their physician before beginning an exercise program.
Routine follow up with the multidisciplinary team (annually or more frequently as determined by managing physician) is recommended. See
Recommended Multidisciplinary Team Surveillance for Individuals with Dysferlinopathy
Muscle strength testing using a quantitative scale (e.g., MMT, hand-held dynamometry, QMA
Physical function (e.g., 6-min walk test, AMAT
Activities of daily living
AFOs = ankle-foot orthoses; AMAT = Adult Myopathy Assessment Tool; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MMT = manual muscle testing; OT = occupational therapy; PFTs = pulmonary function tests; PT = physical therapy; QMA = Quantitative Muscle Assessment
Control weight to avoid obesity; avoid use of steroids [
See
Comparison of the effect of prednisolone with vamorolone on dysferlin-deficient myofiber repair showed that vamorolone stabilized dysferlin-deficient muscle cell membrane and improved repair of dysferlin-deficient mouse myofibers [
Exon skipping is a therapeutic approach that is feasible for various genetic disorders [
Search
• Muscle strength & function in arms, hands, legs (esp calves), & feet
• Balance
• Function
• Fine motor skills
• Impact on activities of daily living
• Need for ongoing PT & OT
• Need for AFOs & assistive ambulatory devices
• Need for adaptive devices
• Need for handicapped parking
• Use of community or
• Need for social work involvement for caregiver support.
• Transfers (e.g., from bed to wheelchair, wheelchair to car)
• Medical alert system for those unable to stand after a fall
• Techniques & devices to accomplish tasks incl mobility, washing, dressing, eating, cooking, grooming
• To assist w/household modifications to meet special needs
• Muscle strength testing using a quantitative scale (e.g., MMT, hand-held dynamometry, QMA
• Physical function (e.g., 6-min walk test, AMAT
• Activities of daily living
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with dysferlinopathy, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Dysferlinopathy
Muscle strength & function in arms, hands, legs (esp calves), & feet
Balance
Function
Fine motor skills
Impact on activities of daily living
Need for ongoing PT & OT
Need for AFOs & assistive ambulatory devices
Need for adaptive devices
Need for handicapped parking
Use of community or
Need for social work involvement for caregiver support.
AFOs = ankle-foot orthoses; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MOI = mode of inheritance; OT = occupational therapy; PFTs = pulmonary function tests; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Muscle strength & function in arms, hands, legs (esp calves), & feet
• Balance
• Function
• Fine motor skills
• Impact on activities of daily living
• Need for ongoing PT & OT
• Need for AFOs & assistive ambulatory devices
• Need for adaptive devices
• Need for handicapped parking
• Use of community or
• Need for social work involvement for caregiver support.
## Treatment of Manifestations
There is no approved therapy for dysferlinopathy. Treatment is symptomatic only.
Management should be tailored to the individual and the specific subtype. A general approach to appropriate management can prolong survival and improve quality of life.
Treatment of Manifestations in Individuals with Dysferlinopathy
Transfers (e.g., from bed to wheelchair, wheelchair to car)
Medical alert system for those unable to stand after a fall
Techniques & devices to accomplish tasks incl mobility, washing, dressing, eating, cooking, grooming
To assist w/household modifications to meet special needs
OT = occupational therapy; PT = physical therapy
All affected persons should consult their physician before beginning an exercise program.
• Transfers (e.g., from bed to wheelchair, wheelchair to car)
• Medical alert system for those unable to stand after a fall
• Techniques & devices to accomplish tasks incl mobility, washing, dressing, eating, cooking, grooming
• To assist w/household modifications to meet special needs
## Surveillance
Routine follow up with the multidisciplinary team (annually or more frequently as determined by managing physician) is recommended. See
Recommended Multidisciplinary Team Surveillance for Individuals with Dysferlinopathy
Muscle strength testing using a quantitative scale (e.g., MMT, hand-held dynamometry, QMA
Physical function (e.g., 6-min walk test, AMAT
Activities of daily living
AFOs = ankle-foot orthoses; AMAT = Adult Myopathy Assessment Tool; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MMT = manual muscle testing; OT = occupational therapy; PFTs = pulmonary function tests; PT = physical therapy; QMA = Quantitative Muscle Assessment
• Muscle strength testing using a quantitative scale (e.g., MMT, hand-held dynamometry, QMA
• Physical function (e.g., 6-min walk test, AMAT
• Activities of daily living
## Agents/Circumstances to Avoid
Control weight to avoid obesity; avoid use of steroids [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Comparison of the effect of prednisolone with vamorolone on dysferlin-deficient myofiber repair showed that vamorolone stabilized dysferlin-deficient muscle cell membrane and improved repair of dysferlin-deficient mouse myofibers [
Exon skipping is a therapeutic approach that is feasible for various genetic disorders [
Search
## Genetic Counseling
Dysferlinopathy is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Intrafamilial clinical variability may be observed between sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal and preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Intrafamilial clinical variability may be observed between sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal and preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Dysferlinopathy is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Intrafamilial clinical variability may be observed between sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Intrafamilial clinical variability may be observed between sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal and preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal and preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
2310 130th Avenue Northeast
Suite B101
Bellevue WA 98005
United Kingdom
•
•
• 2310 130th Avenue Northeast
• Suite B101
• Bellevue WA 98005
•
•
•
•
• United Kingdom
•
## Molecular Genetics
Dysferlinopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Dysferlinopathy (
Dysferlin is expressed in the plasma membrane of skeletal muscles and is involved in calcium-mediated membrane fusion events and plasma membrane repair [
Dysferlin immunohistochemical and immunoblot analyses on muscle tissue that identify dysferlin protein deficiency can assist in interpretation of variants of uncertain significance. However, dysferlin expression can also be reduced in other muscular dystrophies: dystrophinopathy [
Notable
MMD = Miyoshi muscular dystrophy
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Dysferlin immunohistochemical and immunoblot analyses on muscle tissue that identify dysferlin protein deficiency can assist in interpretation of variants of uncertain significance. However, dysferlin expression can also be reduced in other muscular dystrophies: dystrophinopathy [
## Molecular Pathogenesis
Dysferlin is expressed in the plasma membrane of skeletal muscles and is involved in calcium-mediated membrane fusion events and plasma membrane repair [
Dysferlin immunohistochemical and immunoblot analyses on muscle tissue that identify dysferlin protein deficiency can assist in interpretation of variants of uncertain significance. However, dysferlin expression can also be reduced in other muscular dystrophies: dystrophinopathy [
Notable
MMD = Miyoshi muscular dystrophy
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Dysferlin immunohistochemical and immunoblot analyses on muscle tissue that identify dysferlin protein deficiency can assist in interpretation of variants of uncertain significance. However, dysferlin expression can also be reduced in other muscular dystrophies: dystrophinopathy [
## Chapter Notes
27 May 2021 (bp) Comprehensive update posted live
5 March 2015 (me) Comprehensive update posted live
22 April 2010 (me) Comprehensive update posted live
19 April 2006 (me) Comprehensive update posted live
5 February 2004 (me) Review posted live
24 September 2003 (ma) Original submission
• 27 May 2021 (bp) Comprehensive update posted live
• 5 March 2015 (me) Comprehensive update posted live
• 22 April 2010 (me) Comprehensive update posted live
• 19 April 2006 (me) Comprehensive update posted live
• 5 February 2004 (me) Review posted live
• 24 September 2003 (ma) Original submission
## Revision History
27 May 2021 (bp) Comprehensive update posted live
5 March 2015 (me) Comprehensive update posted live
22 April 2010 (me) Comprehensive update posted live
19 April 2006 (me) Comprehensive update posted live
5 February 2004 (me) Review posted live
24 September 2003 (ma) Original submission
• 27 May 2021 (bp) Comprehensive update posted live
• 5 March 2015 (me) Comprehensive update posted live
• 22 April 2010 (me) Comprehensive update posted live
• 19 April 2006 (me) Comprehensive update posted live
• 5 February 2004 (me) Review posted live
• 24 September 2003 (ma) Original submission
## References
## Literature Cited
|
[
"Z Argov, M Sadeh, K Mazor, D Soffer, E Kahana, I Eisenberg, S Mitrani-Rosenbaum, I Richard, J Beckmann, S Keers, R Bashir, K Bushby, H Rosenmann. Muscular dystrophy due to dysferlin deficiency in Libyan Jews. Clinical and genetic features.. Brain 2000;123:1229-37",
"D Bansal, K Miyake, SS Vogel, S Groh, CC Chen, R Williamson, PL McNeil, KP Campbell. Defective membrane repair in dysferlin-deficient muscular dystrophy.. Nature 2003;423:168-72",
"JA Dominov, Ö Uyan, D McKenna-Yasek, BRR Nallamilli, V Kergourlay, M Bartoli, N Levy, J Hudson, T Evangelista, H Lochmuller, M Krahn, L Rufibach, M Hegde, RH Brown. Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation.. Ann Clin Transl Neurol. 2019;6:642-54",
"E Harris, CL Bladen, A Mayhew, M James, K Bettinson, U Moore, FE Smith, L Rufibach, A Cnaan, DX Bharucha-Goebel, AM Blamire, E Bravver, PG Carlier, JW Day, J Díaz-Manera, M Eagle, U Grieben, M Harms, KJ Jones, H Lochmüller, JR Mendell, M Mori-Yoshimura, C Paradas, E Pegoraro, A Pestronk, E Salort-Campana, O Schreiber-Katz, C Semplicini, S Spuler, T Stojkovic, V Straub, S Takeda, C Tesi Rocha, MC Walter, K Bushby. The clinical outcome study for dysferlinopathy: an international multicenter study.. Neurol Genet. 2016;2",
"MO Harris-Love, G Joe, TE Davenport, D Koziol, K Abbett Rose, JA Shrader, OM Vasconcelos, B McElroy, MC Dalakas. Reliability of the Adult Myopathy Assessment Tool in individuals with myositis.. Arthritis Care Res (Hoboken) 2015;67:563-70",
"I Illa, C Serrano-Munuera, E Gallardo, A Lasa, R Rojas-Garcia, J Palmer, P Gallano, M Baiget, C Matsuda, RH Brown. Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype.. Ann Neurol 2001;49:130-4",
"SN Illarioshkin, IA Ivanova-Smolenskaya, CR Greenberg, E Nylen, VS Sukhorukov, VV Poleshchuk, ED Markova, K Wrogemann. Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy.. Neurology 2000;55:1931-3",
"R Izumi, T Takahashi, N Suzuki, T Niihori, H Ono, N Nakamura, S Katada, M Kato, H Warita, M Tateyama, M Aoki. The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype–phenotype relationship and a hotspot on the inner DysF domain.. Hum Mutat. 2020;41:1540-54",
"RH Jebsen, N Taylor, RB Trieschmann, MJ Trotter, LA Howard. An objective and standardized test of hand function.. Arch Phys Med Rehabil. 1969;50:311-9",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"NJ Lennon, A Kho, BJ Bacskai, SL Perlmutter, BT Hyman, RH Brown. Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing.. J Biol Chem 2003;278:50466-73",
"E Leshinsky-Silver, Z Argov, L Rozenboim, S Cohen, Z Tzofi, Y Cohen, Y Wirguin, R Dabby, D Lev, M Sadeh. Dysferlinopathy in the Jews of the Caucasus: a frequent mutation in the dysferlin gene.. Neuromuscul Disord. 2007;17:950-4",
"J Liu, M Aoki, I Illa, C Wu, M Fardeau, C Angelini, C Serrano, JA Urtizberea, F Hentati, MB Hamida, S Bohlega, EJ Culper, AA Amato, K Bossie, J Oeltjen, K Bejaoui, D McKenna-Yasek, BA Hosler, E Schurr, K Arahata, PJ de Jong, RH Brown. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.. Nat Genet 1998;20:31-6",
"I Mahjneh, G Marconi, K Bushby, LV Anderson, H Tolvanen-Mahjneh, H Somer. Dysferlinopathy (LGMD2B): a 23-year follow-up study of 10 patients homozygous for the same frameshifting dysferlin mutations.. Neuromuscul Disord 2001;11:20-6",
"C Matsuda, YK Hayashi, M Ogawa, M Aoki, K Murayama, I Nishino, I Nonaka, K Arahata, RH Brown. The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle.. Hum Mol Genet 2001;10:1761-6",
"M Nakagawa, T Matsuzaki, M Suehara, N Kanzato, H Takashima, I Higuchi, T Matsumura, K Goto, K Arahata, M Osame. Phenotypic variation in a large Japanese family with Miyoshi myopathy with nonsense mutation in exon 19 of dysferlin gene.. J Neurol Sci 2001;184:15-9",
"H Ono, N Suzuki, S Kanno, G Kawahara, R Izumi, T Takahansi, Y Kitajima, S Osana, N Nakamura, T Akiyama, K Ikeda, T Shijo, S Mitsuzawa, R Nagatomi, N Araki, A Yasui, H Warita, YK Hayashi, K Miyake, M Aoki. AMPK complex activation promotes sarcolemmal repair in dysferlinopathy.. Mol Ther. 2020;28:1133-53",
"C Paradas, L González-Quereda, N De Luna, E Gallardo, I García-Consuegra, H Gómez, A Cabello, I Illa, P Gallano. A new phenotype of dysferlinopathy with congenital onset.. Neuromuscul Disord 2009;19:21-5",
"F Piccolo, SA Moore, GC Ford, KP Campbell. Intracellular accumulation and reduced sarcolemmal expression of dysferlin in limb-girdle muscular dystrophies.. Ann Neurol 2000;48:902-12",
"M Rodrigues, T Yokota. An overview of recent advances and clinical applications of exon skipping and splice modulation for muscular dystrophy and various genetic diseases.. Methods Mol Biol. 2018;1828:31-55",
"H Saito, N Suzuki, H Ishiguro, K Hirota, Y Itoyama, T Takahashi, M Aoki. Distal anterior compartment myopathy with early ankle contractures.. Muscle Nerve. 2007;36:525-7",
"SC Sreetama, G Chandra, JH Van der Meulen, MM Ahmad, P Suzuki, S Bhuvanendran, K Nagaraju, EP Hoffman, JK Jaiswal. Membrane stabilization by modified steroid offers a potential therapy for muscular dystrophy due to dysferlin deficit.. Mol Ther. 2018;26:2231-42",
"K Tagawa, M Ogawa, K Kawabe, G Yamanaka, T Matsumura, K Goto, I Nonaka, I Nishino, YK Hayashi. Protein and gene analyses of dysferlinopathy in a large group of Japanese muscular dystrophy patients.. J Neurol Sci 2003;211:23-8",
"T Takahashi, M Aoki, N Suzuki, M Tateyama, C Yaginuma, H Sato, M Hayasaka, H Sugawara, M Ito, E Abe-Kondo, N Shimakura, T Ibi, S Kuru, T Wakayama, G Sobue, N Fujii, T Saito, T Matsumura, I Funakawa, E Mukai, T Kawanami, M Morita, M Yamazaki, T Hasegawa, J Shimizu, S Tsuji, S Kuzuhara, H Tanaka, M Yoshioka, H Konno, H Onodera, Y Itoyama. Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B.. J Neurol Neurosurg Psychiatry. 2013;84:433-40",
"T Takahashi, M Aoki, M Tateyama, E Kondo, T Mizuno, Y Onodera, R Takano, H Kawai, K Kamakura, H Mochizuki, M Shizuka-Ikeda, M Nakagawa, Y Yoshida, J Akanuma, K Hoshino, H Saito, M Nishizawa, S Kato, K Saito, T Miyachi, H Yamashita, M Kawai, T Matsumura, S Kuzuhara, T Ibi, K Sahashi, H Nakai, T Kohnosu, I Nonaka, K Arahata, RH Brown, H Saito, Y Itoyama. Dysferlin mutations in Japanese Miyoshi myopathy: Relationship to phenotype.. Neurology 2003a;60:1799-804",
"H Ueyama, T Kumamoto, H Horinouchi, S Fujimoto, H Aono, T Tsuda. Clinical heterogeneity in dysferlinopathy.. Intern Med 2002;41:532-6",
"H Ueyama, T Kumamoto, S Nagao, T Masuda, H Horinouchi, S Fujimoto, T Tsuda. A new dysferlin gene mutation in two Japanese families with limb-girdle muscular dystrophy 2B and Miyoshi myopathy.. Neuromuscul Disord 2001;11:139-45",
"JJ Vilchez, P Gallano, E Gallardo, A Lasa, R Rojas-Garcia, A Freixas, N De Luna, F Calafell, T Sevilla, F Mayordomo, M Baiget, I Illa. Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population.. Arch Neurol 2005;62:1256-9",
"J Visser, E Mans, M de Visser, RM van den Berg-Vos, H Franssen, JM de Jong, LH van den Berg, JH Wokke, RJ de Haan. Comparison of maximal voluntary isometric contraction and hand-held dynamometry in measuring muscle strength of patients with progressive lower motor neuron syndrome.. Neuromuscul Disord. 2003;13:744-50",
"MC Walter, P Reilich, S Thiele, J Schessl, H Schreiber, K Reiners, W Kress, C Müller-Reible, M Vorgerd, P Urban, B Schrank, M Deschauer, B Schlotter-Weigel, R Kohnen, H Lochmüller. Treatment of dysferlinpathy with deflazacort: a double-blind, placebo-controlled clinical trial.. Orphanet J Rare Dis 2013;8:26",
"T Weiler, R Bashir, LV Anderson, K Davison, JA Moss, S Britton, E Nylen, S Keers, E Vafiadaki, CR Greenberg, CR Bushby, K Wrogemann. Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s).. Hum Mol Genet 1999;8:871-7"
] |
5/2/2004
|
27/5/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mkks
|
mkks
|
[
"Molecular chaperone MKKS",
"MKKS",
"McKusick-Kaufman Syndrome"
] |
McKusick-Kaufman Syndrome
|
Anne M Slavotinek
|
Summary McKusick-Kaufman syndrome (MKS) is characterized by the combination of postaxial polydactyly (PAP), congenital heart disease (CHD), and hydrometrocolpos (HMC) in females and genital malformations in males (most commonly hypospadias, cryptorchidism, and chordee). HMC in infants usually presents as a large cystic abdominal mass arising out of the pelvis, caused by dilatation of the vagina and uterus as a result of the accumulation of cervical secretions from maternal estrogen stimulation. HMC can be caused by failure of the distal third of the vagina to develop (vaginal agenesis), a transverse vaginal membrane, or an imperforate hymen. PAP is the presence of additional digits on the ulnar side of the hand and the fibular side of the foot. A variety of congenital heart defects have been reported including atrioventricular canal, atrial septal defect, ventricular septal defect, or a complex congenital heart malformation. The clinical diagnosis of MKS can be established in a proband based on clinical diagnostic criteria of HMC and PAP in the absence of clinical or molecular genetic findings suggestive of an alternative diagnosis. The molecular diagnosis can be established in proband with suggestive findings and biallelic pathogenic variants in MKS is inherited in an autosomal recessive manner. If both parents of an individual with MKS are known to be heterozygous for an
|
## Diagnosis
No consensus clinical diagnostic criteria for McKusick-Kaufman syndrome (MKS) have been published.
Diagnosis of McKusick-Kaufman syndrome (MKS) should be suspected in individuals with the following features.
Hydrometrocolpos (HMC) *
Postaxial polydactyly (PAP) **
Congenital heart disease (CHD)
Genital malformations (most commonly hypospadias, cryptorchidism, and chordee)
PAP **
CHD
Insufficient manifestations of overlapping syndromes, such as
Family history typically consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity and unaffected parents). Absence of a known family history does not preclude the diagnosis.
* Hydrometrocolpos (HMC) in infants is dilatation of the vagina and uterus caused by the accumulation of cervical secretions as a result of maternal estrogen stimulation. HMC can be caused by:
Failure of the distal third of the vagina to develop (vaginal atresia or agenesis);
A transverse vaginal membrane;
Imperforate hymen; in rare cases, HMC and polydactyly may be associated with an imperforate hymen, but many individuals reported with these findings were described at young ages and it is thus not known if the actual diagnosis was MKS or BBS.
HMC often presents at birth as a large, cystic abdominal mass arising out of the pelvis, which can be sufficiently large to be clinically obvious and is verified using an ultrasound scan. The mass can be large enough to cause intestinal obstruction, urinary outflow obstruction leading to dilatation of the ureter (hydroureter) and kidneys (hydronephrosis), obstruction of the inferior vena cava, and/or elevation of the diaphragm resulting in breathing difficulties.
** Postaxial polydactyly (PAP) is the presence of additional digits on the ulnar side of the hand and the fibular side of the foot.
The additional digit can be fully formed or can be a rudimentary skin tag (often called a "minimus").
If clinical examination is insufficient, radiographs may be used to determine whether the polydactyly is postaxial or mesoaxial (also known as insertional polydactyly); that is, the presence of an extra digit or digits between the thumb and fifth finger. Mesoaxial polydactyly is much less common than postaxial polydactyly.
The clinical diagnosis of McKusick-Kaufman syndrome (MKS) can be
MKS was first described by McKusick in 1978 in the Amish population as a triad of HMC, postaxial polydactyly, and congenital heart disease. For females without a family history and who are not part of the Amish population, HMC with distal vaginal agenesis or a transverse vaginal membrane and postaxial polydactyly have been considered sufficient for a clinical diagnosis MKS [
The molecular diagnosis of MKS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Because the phenotype of MKS is indistinguishable from BBS through early childhood, recommended molecular genetic testing approaches include use of a
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in McKusick-Kaufman Syndrome (MKS)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Hydrometrocolpos (HMC) *
• Postaxial polydactyly (PAP) **
• Congenital heart disease (CHD)
• Genital malformations (most commonly hypospadias, cryptorchidism, and chordee)
• PAP **
• CHD
• Insufficient manifestations of overlapping syndromes, such as
• Family history typically consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity and unaffected parents). Absence of a known family history does not preclude the diagnosis.
• Failure of the distal third of the vagina to develop (vaginal atresia or agenesis);
• A transverse vaginal membrane;
• Imperforate hymen; in rare cases, HMC and polydactyly may be associated with an imperforate hymen, but many individuals reported with these findings were described at young ages and it is thus not known if the actual diagnosis was MKS or BBS.
• The additional digit can be fully formed or can be a rudimentary skin tag (often called a "minimus").
• If clinical examination is insufficient, radiographs may be used to determine whether the polydactyly is postaxial or mesoaxial (also known as insertional polydactyly); that is, the presence of an extra digit or digits between the thumb and fifth finger. Mesoaxial polydactyly is much less common than postaxial polydactyly.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Diagnosis of McKusick-Kaufman syndrome (MKS) should be suspected in individuals with the following features.
Hydrometrocolpos (HMC) *
Postaxial polydactyly (PAP) **
Congenital heart disease (CHD)
Genital malformations (most commonly hypospadias, cryptorchidism, and chordee)
PAP **
CHD
Insufficient manifestations of overlapping syndromes, such as
Family history typically consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity and unaffected parents). Absence of a known family history does not preclude the diagnosis.
* Hydrometrocolpos (HMC) in infants is dilatation of the vagina and uterus caused by the accumulation of cervical secretions as a result of maternal estrogen stimulation. HMC can be caused by:
Failure of the distal third of the vagina to develop (vaginal atresia or agenesis);
A transverse vaginal membrane;
Imperforate hymen; in rare cases, HMC and polydactyly may be associated with an imperforate hymen, but many individuals reported with these findings were described at young ages and it is thus not known if the actual diagnosis was MKS or BBS.
HMC often presents at birth as a large, cystic abdominal mass arising out of the pelvis, which can be sufficiently large to be clinically obvious and is verified using an ultrasound scan. The mass can be large enough to cause intestinal obstruction, urinary outflow obstruction leading to dilatation of the ureter (hydroureter) and kidneys (hydronephrosis), obstruction of the inferior vena cava, and/or elevation of the diaphragm resulting in breathing difficulties.
** Postaxial polydactyly (PAP) is the presence of additional digits on the ulnar side of the hand and the fibular side of the foot.
The additional digit can be fully formed or can be a rudimentary skin tag (often called a "minimus").
If clinical examination is insufficient, radiographs may be used to determine whether the polydactyly is postaxial or mesoaxial (also known as insertional polydactyly); that is, the presence of an extra digit or digits between the thumb and fifth finger. Mesoaxial polydactyly is much less common than postaxial polydactyly.
• Hydrometrocolpos (HMC) *
• Postaxial polydactyly (PAP) **
• Congenital heart disease (CHD)
• Genital malformations (most commonly hypospadias, cryptorchidism, and chordee)
• PAP **
• CHD
• Insufficient manifestations of overlapping syndromes, such as
• Family history typically consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity and unaffected parents). Absence of a known family history does not preclude the diagnosis.
• Failure of the distal third of the vagina to develop (vaginal atresia or agenesis);
• A transverse vaginal membrane;
• Imperforate hymen; in rare cases, HMC and polydactyly may be associated with an imperforate hymen, but many individuals reported with these findings were described at young ages and it is thus not known if the actual diagnosis was MKS or BBS.
• The additional digit can be fully formed or can be a rudimentary skin tag (often called a "minimus").
• If clinical examination is insufficient, radiographs may be used to determine whether the polydactyly is postaxial or mesoaxial (also known as insertional polydactyly); that is, the presence of an extra digit or digits between the thumb and fifth finger. Mesoaxial polydactyly is much less common than postaxial polydactyly.
## Establishing the Diagnosis
The clinical diagnosis of McKusick-Kaufman syndrome (MKS) can be
MKS was first described by McKusick in 1978 in the Amish population as a triad of HMC, postaxial polydactyly, and congenital heart disease. For females without a family history and who are not part of the Amish population, HMC with distal vaginal agenesis or a transverse vaginal membrane and postaxial polydactyly have been considered sufficient for a clinical diagnosis MKS [
The molecular diagnosis of MKS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Because the phenotype of MKS is indistinguishable from BBS through early childhood, recommended molecular genetic testing approaches include use of a
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in McKusick-Kaufman Syndrome (MKS)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Diagnosis
MKS was first described by McKusick in 1978 in the Amish population as a triad of HMC, postaxial polydactyly, and congenital heart disease. For females without a family history and who are not part of the Amish population, HMC with distal vaginal agenesis or a transverse vaginal membrane and postaxial polydactyly have been considered sufficient for a clinical diagnosis MKS [
## Molecular Diagnosis
The molecular diagnosis of MKS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Because the phenotype of MKS is indistinguishable from BBS through early childhood, recommended molecular genetic testing approaches include use of a
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in McKusick-Kaufman Syndrome (MKS)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
McKusick-Kaufman syndrome (MKS), defined as hydrometrocolpos (HMC) and postaxial polydactyly (PAP) without the development of the age-dependent features of BBS, was first diagnosed in a large Amish family [
The incidence of genital findings in males has also been difficult to establish outside the Amish population due to the rarity of the condition, but in 11 males who had affected sisters or other female relatives diagnosed with MKS, polydactyly was present in all cases and only one had genital abnormalities comprising cryptorchidism and hypospadias [
Phenotypic Features of Individuals with McKusick-Kaufman Syndrome (MKS)
From
GI = gastrointestinal; PAP = postaxial polydactyly
Four-limb polydactyly involves both hands and both feet; polydactyly of the hands and feet means that both upper and lower limbs are affected, but not every limb.
Renal dysplasia is a histologic diagnosis that describes abnormal differentiation of the renal parenchyma.
Corticomedullary dysplasia is abnormal differentiation of both the cortex and the medulla of the kidney. If focal, renal function may be preserved; if bilateral and extensive, renal failure can result.
Congenital heart defects comprising: atrioventricular canal defect; atrial septal defect; ventricular septal defect; complex congenital heart disease with an atrioventricular canal defect, small aorta, and hypoplastic left ventricle; tetralogy of Fallot; and a patent ductus arteriosus have been reported in individuals with an MKS phenotype [
Although both renal anomalies and GI malformations have been identified in those with a clinical diagnosis of MKS, not all of these individuals have had molecular genetic testing nor were they followed to an age in which an eye exam could exclude the diagnosis of BBS. Since these physical findings are more common in those with a molecularly confirmed diagnosis of BBS, they should prompt screening for other clinical manifestations of BBS or molecular genetic testing for BBS.
No genotype-phenotype correlations for
Non-penetrance has been estimated to occur in at least 9% of affected Amish males and 3% of affected Amish females [
Determination of penetrance in the non-Amish population has not yet been possible due to the rarity of the syndrome.
MKS was first described as HMC and PAP in the Amish population.
More than 100 individuals with the MKS phenotype from different ethnic groups have been reported. The majority were reported at birth or in the neonatal period because of HMC; thus, BBS was frequently not excluded. The true prevalence of MKS is unknown, and the incidence of MKS has not been estimated in the non-Amish population.
## Clinical Description
McKusick-Kaufman syndrome (MKS), defined as hydrometrocolpos (HMC) and postaxial polydactyly (PAP) without the development of the age-dependent features of BBS, was first diagnosed in a large Amish family [
The incidence of genital findings in males has also been difficult to establish outside the Amish population due to the rarity of the condition, but in 11 males who had affected sisters or other female relatives diagnosed with MKS, polydactyly was present in all cases and only one had genital abnormalities comprising cryptorchidism and hypospadias [
Phenotypic Features of Individuals with McKusick-Kaufman Syndrome (MKS)
From
GI = gastrointestinal; PAP = postaxial polydactyly
Four-limb polydactyly involves both hands and both feet; polydactyly of the hands and feet means that both upper and lower limbs are affected, but not every limb.
Renal dysplasia is a histologic diagnosis that describes abnormal differentiation of the renal parenchyma.
Corticomedullary dysplasia is abnormal differentiation of both the cortex and the medulla of the kidney. If focal, renal function may be preserved; if bilateral and extensive, renal failure can result.
Congenital heart defects comprising: atrioventricular canal defect; atrial septal defect; ventricular septal defect; complex congenital heart disease with an atrioventricular canal defect, small aorta, and hypoplastic left ventricle; tetralogy of Fallot; and a patent ductus arteriosus have been reported in individuals with an MKS phenotype [
Although both renal anomalies and GI malformations have been identified in those with a clinical diagnosis of MKS, not all of these individuals have had molecular genetic testing nor were they followed to an age in which an eye exam could exclude the diagnosis of BBS. Since these physical findings are more common in those with a molecularly confirmed diagnosis of BBS, they should prompt screening for other clinical manifestations of BBS or molecular genetic testing for BBS.
## Cardiovascular Malformations
Congenital heart defects comprising: atrioventricular canal defect; atrial septal defect; ventricular septal defect; complex congenital heart disease with an atrioventricular canal defect, small aorta, and hypoplastic left ventricle; tetralogy of Fallot; and a patent ductus arteriosus have been reported in individuals with an MKS phenotype [
## Renal Anomalies and GI Malformations
Although both renal anomalies and GI malformations have been identified in those with a clinical diagnosis of MKS, not all of these individuals have had molecular genetic testing nor were they followed to an age in which an eye exam could exclude the diagnosis of BBS. Since these physical findings are more common in those with a molecularly confirmed diagnosis of BBS, they should prompt screening for other clinical manifestations of BBS or molecular genetic testing for BBS.
## Other Findings Associated with MKS
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for
## Penetrance
Non-penetrance has been estimated to occur in at least 9% of affected Amish males and 3% of affected Amish females [
Determination of penetrance in the non-Amish population has not yet been possible due to the rarity of the syndrome.
## Nomenclature
MKS was first described as HMC and PAP in the Amish population.
## Prevalence
More than 100 individuals with the MKS phenotype from different ethnic groups have been reported. The majority were reported at birth or in the neonatal period because of HMC; thus, BBS was frequently not excluded. The true prevalence of MKS is unknown, and the incidence of MKS has not been estimated in the non-Amish population.
## Genetically Related (Allelic) Disorders
It therefore becomes pertinent to consider whether MKS should continue to remain a separate entity or henceforth be considered as belonging to the wider phenotypic spectrum that includes BBS (see
## Differential Diagnosis
At least 26 genes are known to be associated with BBS. Pathogenic variants in
The genital malformations associated with MKS, including HMC, vaginal atresia, and cryptorchidism, have also been associated with BBS-related genes including
Note: Although several reports have described BBS phenotypes with three pathogenic variants and at least one variant involving the
Phenotypic Overlap Between McKusick-Kaufman Syndrome and Bardet-Biedl Syndrome
= major feature; ± = minor feature
BBS = Bardet-Biedl syndrome; MKS = McKusick-Kaufman syndrome
A woman age 19 years with lack of müllerian fusion, vaginal agenesis, a unicornuate uterus, postaxial polydactyly, brachydactyly, and tetralogy of Fallot had normal development, normal weight, and no evidence of retinal dystrophy. No
Mayer-Rokitansky-Küster-Hauser syndrome
Herlyn-Werner-Wunderlich syndrome
Intraabdominal teratoma
VACTERL association. VACTERL is an acronym for an association of physical findings that comprises
Trichorhinophalangeal syndrome. HMC is a rare finding in
• A woman age 19 years with lack of müllerian fusion, vaginal agenesis, a unicornuate uterus, postaxial polydactyly, brachydactyly, and tetralogy of Fallot had normal development, normal weight, and no evidence of retinal dystrophy. No
• Mayer-Rokitansky-Küster-Hauser syndrome
• Herlyn-Werner-Wunderlich syndrome
• Intraabdominal teratoma
• VACTERL association. VACTERL is an acronym for an association of physical findings that comprises
• Trichorhinophalangeal syndrome. HMC is a rare finding in
## Other Disorders with Overlapping Clinical Features
A woman age 19 years with lack of müllerian fusion, vaginal agenesis, a unicornuate uterus, postaxial polydactyly, brachydactyly, and tetralogy of Fallot had normal development, normal weight, and no evidence of retinal dystrophy. No
Mayer-Rokitansky-Küster-Hauser syndrome
Herlyn-Werner-Wunderlich syndrome
Intraabdominal teratoma
VACTERL association. VACTERL is an acronym for an association of physical findings that comprises
Trichorhinophalangeal syndrome. HMC is a rare finding in
• A woman age 19 years with lack of müllerian fusion, vaginal agenesis, a unicornuate uterus, postaxial polydactyly, brachydactyly, and tetralogy of Fallot had normal development, normal weight, and no evidence of retinal dystrophy. No
• Mayer-Rokitansky-Küster-Hauser syndrome
• Herlyn-Werner-Wunderlich syndrome
• Intraabdominal teratoma
• VACTERL association. VACTERL is an acronym for an association of physical findings that comprises
• Trichorhinophalangeal syndrome. HMC is a rare finding in
## Management
No clinical practice guidelines for MKS have been published.
To establish the extent of disease and needs in an individual diagnosed with McKusick-Kaufman syndrome (MKS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with McKusick-Kaufman Syndrome (MKS)
DD = developmental delay; ERG = electroretinogram; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
A subset of those with a diagnosis of MKS as infants may with age develop findings that lead to a revised diagnosis of BBS.
Treatment of Manifestations in Individuals with McKusick-Kaufman Syndrome (MKS)
Recommended Surveillance for Individuals with McKusick-Kaufman Syndrome (MKS)
ERG = electroretinogram; RP = retinitis pigmentosa
A subset of those with a diagnosis of MKS as infants may with age develop findings that lead to revision of the diagnosis to BBS.
In the newborn with severe HMC, care with anesthesia in the neonatal period is appropriate, as HMC can cause diaphragmatic compression [
It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.
If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
If the pathogenic variants in the family are not known:
See
Search
• If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
• If the pathogenic variants in the family are not known:
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with McKusick-Kaufman syndrome (MKS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with McKusick-Kaufman Syndrome (MKS)
DD = developmental delay; ERG = electroretinogram; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
A subset of those with a diagnosis of MKS as infants may with age develop findings that lead to a revised diagnosis of BBS.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with McKusick-Kaufman Syndrome (MKS)
## Surveillance
Recommended Surveillance for Individuals with McKusick-Kaufman Syndrome (MKS)
ERG = electroretinogram; RP = retinitis pigmentosa
A subset of those with a diagnosis of MKS as infants may with age develop findings that lead to revision of the diagnosis to BBS.
## Agents/Circumstances to Avoid
In the newborn with severe HMC, care with anesthesia in the neonatal period is appropriate, as HMC can cause diaphragmatic compression [
## Evaluation of Relatives at Risk
It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.
If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
If the pathogenic variants in the family are not known:
See
• If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
• If the pathogenic variants in the family are not known:
## Therapies Under Investigation
Search
## Genetic Counseling
McKusick-Kaufman syndrome (MKS) is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents of an individual with MKS are known to be heterozygous for an
Intrafamilial clinical variability has been observed in sibs with biallelic pathogenic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
The offspring of an individual with MKS are obligate heterozygotes (carriers) for a pathogenic variant in
The heterozygote frequency of MKS in the Amish population is estimated to be 1%-3% (see
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents of an individual with MKS are known to be heterozygous for an
• Intrafamilial clinical variability has been observed in sibs with biallelic pathogenic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The offspring of an individual with MKS are obligate heterozygotes (carriers) for a pathogenic variant in
• The heterozygote frequency of MKS in the Amish population is estimated to be 1%-3% (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
McKusick-Kaufman syndrome (MKS) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents of an individual with MKS are known to be heterozygous for an
Intrafamilial clinical variability has been observed in sibs with biallelic pathogenic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
The offspring of an individual with MKS are obligate heterozygotes (carriers) for a pathogenic variant in
The heterozygote frequency of MKS in the Amish population is estimated to be 1%-3% (see
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents of an individual with MKS are known to be heterozygous for an
• Intrafamilial clinical variability has been observed in sibs with biallelic pathogenic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The offspring of an individual with MKS are obligate heterozygotes (carriers) for a pathogenic variant in
• The heterozygote frequency of MKS in the Amish population is estimated to be 1%-3% (see
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
McKusick-Kaufman Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for McKusick-Kaufman Syndrome (
McKusick-Kaufman syndrome (MKS), like Bardet-Biedl syndrome (BBS), is part of a group of disorders known as ciliopathies. At least 26 different genes are associated with BBS and it has long been recognized that pathogenic variants in
In the Old Order Amish kindred in which MKS was first described, the phenotype was recorded as due to homozygosity for two pathogenic variants, p.His84Tyr and p.Ala242Ser, on the same allele (i.e., p.[His84Tyr, Ala242Ser]; [His84Tyr, Ala242Ser]). The p.[His84Tyr, Ala242Ser] allele, with both variants, is present in approximately 2% of the Amish population, but is very rare outside of this ancestry. To date, very few individuals outside the Amish population diagnosed clinically with MKS have been found to have biallelic pathogenic variants in
The proteins encoded by the genes that cause BBS form two main complexes: the BBSome (a multi-protein complex) and the BBS chaperonin complex [
Wild type MKKS protein binds SMARCC1 and is actively transported between the cytoplasm and nucleus, whereas the MKKS protein resulting from the MKS-associated allele,
Notable
Variants listed in the table have been provided by the author.
## Molecular Pathogenesis
McKusick-Kaufman syndrome (MKS), like Bardet-Biedl syndrome (BBS), is part of a group of disorders known as ciliopathies. At least 26 different genes are associated with BBS and it has long been recognized that pathogenic variants in
In the Old Order Amish kindred in which MKS was first described, the phenotype was recorded as due to homozygosity for two pathogenic variants, p.His84Tyr and p.Ala242Ser, on the same allele (i.e., p.[His84Tyr, Ala242Ser]; [His84Tyr, Ala242Ser]). The p.[His84Tyr, Ala242Ser] allele, with both variants, is present in approximately 2% of the Amish population, but is very rare outside of this ancestry. To date, very few individuals outside the Amish population diagnosed clinically with MKS have been found to have biallelic pathogenic variants in
The proteins encoded by the genes that cause BBS form two main complexes: the BBSome (a multi-protein complex) and the BBS chaperonin complex [
Wild type MKKS protein binds SMARCC1 and is actively transported between the cytoplasm and nucleus, whereas the MKKS protein resulting from the MKS-associated allele,
Notable
Variants listed in the table have been provided by the author.
## Chapter Notes
Dr Slavotinek received her medical degree from the University of Adelaide and her PhD from Flinders University in South Australia. She trained in Clinical Genetics in the United Kingdom and subsequently did a Genetics Fellowship at the National Institutes of Health to become Board certified in Clinical Genetics in the USA. She joined the Department of Pediatrics at UCSF in 2002 and is now a Professor of Clinical Pediatrics. Dr Slavotinek is an author on more than 195 peer-reviewed publications in addition to book chapters and reviews. Dr Slavotinek divides her time between practicing in clinical genetics, clinical genomics research, and basic laboratory research.
Web page:
The author is grateful to Dr Leslie Biesecker for his role in the discovery of
3 December 2020 (ha) Comprehensive update posted live
4 June 2015 (me) Comprehensive update posted live
29 June 2010 (me) Comprehensive update posted live
8 October 2009 (cd) Revision: sequence analysis available clinically
20 October 2006 (me) Comprehensive update posted live
2 August 2004 (me) Comprehensive update posted live
10 September 2002 (me) Review posted live
5 March 2002 (as) Original submission
• 3 December 2020 (ha) Comprehensive update posted live
• 4 June 2015 (me) Comprehensive update posted live
• 29 June 2010 (me) Comprehensive update posted live
• 8 October 2009 (cd) Revision: sequence analysis available clinically
• 20 October 2006 (me) Comprehensive update posted live
• 2 August 2004 (me) Comprehensive update posted live
• 10 September 2002 (me) Review posted live
• 5 March 2002 (as) Original submission
## Author Notes
Dr Slavotinek received her medical degree from the University of Adelaide and her PhD from Flinders University in South Australia. She trained in Clinical Genetics in the United Kingdom and subsequently did a Genetics Fellowship at the National Institutes of Health to become Board certified in Clinical Genetics in the USA. She joined the Department of Pediatrics at UCSF in 2002 and is now a Professor of Clinical Pediatrics. Dr Slavotinek is an author on more than 195 peer-reviewed publications in addition to book chapters and reviews. Dr Slavotinek divides her time between practicing in clinical genetics, clinical genomics research, and basic laboratory research.
Web page:
## Acknowledgments
The author is grateful to Dr Leslie Biesecker for his role in the discovery of
## Revision History
3 December 2020 (ha) Comprehensive update posted live
4 June 2015 (me) Comprehensive update posted live
29 June 2010 (me) Comprehensive update posted live
8 October 2009 (cd) Revision: sequence analysis available clinically
20 October 2006 (me) Comprehensive update posted live
2 August 2004 (me) Comprehensive update posted live
10 September 2002 (me) Review posted live
5 March 2002 (as) Original submission
• 3 December 2020 (ha) Comprehensive update posted live
• 4 June 2015 (me) Comprehensive update posted live
• 29 June 2010 (me) Comprehensive update posted live
• 8 October 2009 (cd) Revision: sequence analysis available clinically
• 20 October 2006 (me) Comprehensive update posted live
• 2 August 2004 (me) Comprehensive update posted live
• 10 September 2002 (me) Review posted live
• 5 March 2002 (as) Original submission
## References
## Literature Cited
|
[] |
10/9/2002
|
3/12/2020
|
8/10/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
ml2
|
ml2
|
[
"Mucolipidosis II (ML II)",
"Mucolipidosis III Alpha/Beta",
"N-acetylglucosamine-1-phosphotransferase subunits alpha/beta",
"GNPTAB",
"GNPTAB-Related Disorders"
] |
Jules G Leroy, Sara S Cathey, Michael J Friez
|
Summary The diagnosis of a
|
Mucolipidosis II (ML II)
Mucolipidosis IIIα/β (ML IIIα/β)
Phenotypes intermediate between ML II and IIIα/β
For synonyms and outdated names, see
For other genetic causes of these phenotypes see
• Mucolipidosis II (ML II)
• Mucolipidosis IIIα/β (ML IIIα/β)
• Phenotypes intermediate between ML II and IIIα/β
## Diagnosis
Small to low-normal anthropometric measurements for gestational age
Restricted range of passive motion in the shoulders
Flat face, shallow orbits, and depressed nasal bridge
Thick skin with wax-like texture (in neonates, most evident in and around the earlobes)
Variable musculoskeletal findings that may include one or more of the following:
Thoracic deformity including kyphosis
Clubfeet
Deformed long bones (See
Dislocation of the hip(s)
Dysmorphic facies and musculoskeletal features that may have been mistakenly overlooked at birth become undeniable over the first year of life: overall coarsening of features, poor growth, and restriction of joint movements at the hips, knees, shoulders, and hands.
Developmental milestones are not met.
Onset late infancy to late childhood
Musculoskeletal findings
Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
Joint stiffness in the shoulders, hips, and fingers
Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
Variable kyphoscoliosis, mild to severe
Osteoporosis associated with bone pain
Gradual mild coarsening of facial features
Slight corneal cloudiness (in some but not all) only by slit-lamp examination
Upper-respiratory infection and/or otitis media (variably present)
No organomegaly
Developmental milestones are met appropriately with the exception of late walking in a minority of children with ML III. Language skills are normal. Cognitive development is usually normal, and most children attend regular classes, irrespective of the physical handicap that gradually worsens.
The severe dysostosis multiplex in ML II includes the following [
Skeletal age is significantly delayed. Generalized osteopenia and coarse bony trabeculation are consistent findings.
Skull size and shape remain near normal; the sella turcica becomes oblong in children surviving into middle childhood.
All vertebral bodies have a much shortened anteroposterior diameter, are taller posteriorly than anteriorly, and have concave anterior borders and mildly convex superior and inferior borders.
The length of large and small long bones is much reduced. All large appendicular long bones have undertubulated diaphyses, dysplastic and small epiphyses, and overconstriction of the submetaphyseal regions.
Diaphyseal widening in all small long bones of the hands becomes pronounced by early childhood and is accompanied by progressive claw-type deformation.
Ribs have widened costochondral junctions but narrowed juxtavertebral parts.
Pelvic dysplasia is manifest as narrow basilar portions of the ilia and relatively long pubic and ischial bones; slanting, shallow acetabular roofs and bilateral coxa valga, with varying degrees of (often asymmetric) hip dislocation
In the most severely affected infants, transient signs reminiscent of rickets and osteopenia, and punctate calcifications in soft tissue (most frequently about the tarsal bones) are observed. In most infants, periosteal cloaking is observed around the diaphyses of the large long bones; this transient phenomenon is rarely detectable after age one year.
Generalized osteopenia is slowly progressive.
The sella turcica remains normal as the calvarium thickens gradually. Cranial size remains proportional to stature.
The mildly platyspondylic vertebra remain rectangular with irregular endplates, dorsal scalloping, and narrow intervertebral spaces. Kyphoscoliosis may become severe and requires orthopedic attention.
The shortened long bones show normal or slightly undertubulated diaphyses, small epiphyses, and widened irregular metaphyses. Progressive dysplasia of the proximal femoral epiphyses may be asymmetric and quite severe.
The shape and size of phalanges corresponds to metacarpal changes, which may be mildly shortened or completely normal. The carpal bones are often smaller than normal with irregular borders. Even in the event of normal or near-normal small hand bones, colinear axis deviation of the fingers is frequent due to slowly progressive hardening of periarticular and tendon connective tissue; true claw-type hand deformation is rare in ML IIIα/β, but carpal tunnel syndrome is a regular feature.
Historically, measurement of the accumulating oligosaccharides utilized older technologies such as thin layer chromatography (TLC). Although still widely used, TLC has several limitations including intrinsic poor resolution, interference from drugs and diet, subjective interpretation, and lack of quantification. Ultra-performance liquid chromatography-tandem mass spectrometry for FOS analysis is far more sensitive and specific.
Note: In
Click
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular Genetic Testing Used in Mucolipidosis II / Mucolipidosis III α/β
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A 897-bp deletion spanning exon 19 [
• Small to low-normal anthropometric measurements for gestational age
• Restricted range of passive motion in the shoulders
• Flat face, shallow orbits, and depressed nasal bridge
• Thick skin with wax-like texture (in neonates, most evident in and around the earlobes)
• Variable musculoskeletal findings that may include one or more of the following:
• Thoracic deformity including kyphosis
• Clubfeet
• Deformed long bones (See
• Dislocation of the hip(s)
• Thoracic deformity including kyphosis
• Clubfeet
• Deformed long bones (See
• Dislocation of the hip(s)
• Thoracic deformity including kyphosis
• Clubfeet
• Deformed long bones (See
• Dislocation of the hip(s)
• Dysmorphic facies and musculoskeletal features that may have been mistakenly overlooked at birth become undeniable over the first year of life: overall coarsening of features, poor growth, and restriction of joint movements at the hips, knees, shoulders, and hands.
• Developmental milestones are not met.
• Onset late infancy to late childhood
• Musculoskeletal findings
• Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
• Joint stiffness in the shoulders, hips, and fingers
• Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
• Variable kyphoscoliosis, mild to severe
• Osteoporosis associated with bone pain
• Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
• Joint stiffness in the shoulders, hips, and fingers
• Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
• Variable kyphoscoliosis, mild to severe
• Osteoporosis associated with bone pain
• Gradual mild coarsening of facial features
• Slight corneal cloudiness (in some but not all) only by slit-lamp examination
• Upper-respiratory infection and/or otitis media (variably present)
• No organomegaly
• Developmental milestones are met appropriately with the exception of late walking in a minority of children with ML III. Language skills are normal. Cognitive development is usually normal, and most children attend regular classes, irrespective of the physical handicap that gradually worsens.
• Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
• Joint stiffness in the shoulders, hips, and fingers
• Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
• Variable kyphoscoliosis, mild to severe
• Osteoporosis associated with bone pain
• Skeletal age is significantly delayed. Generalized osteopenia and coarse bony trabeculation are consistent findings.
• Skull size and shape remain near normal; the sella turcica becomes oblong in children surviving into middle childhood.
• All vertebral bodies have a much shortened anteroposterior diameter, are taller posteriorly than anteriorly, and have concave anterior borders and mildly convex superior and inferior borders.
• The length of large and small long bones is much reduced. All large appendicular long bones have undertubulated diaphyses, dysplastic and small epiphyses, and overconstriction of the submetaphyseal regions.
• Diaphyseal widening in all small long bones of the hands becomes pronounced by early childhood and is accompanied by progressive claw-type deformation.
• Ribs have widened costochondral junctions but narrowed juxtavertebral parts.
• Pelvic dysplasia is manifest as narrow basilar portions of the ilia and relatively long pubic and ischial bones; slanting, shallow acetabular roofs and bilateral coxa valga, with varying degrees of (often asymmetric) hip dislocation
• In the most severely affected infants, transient signs reminiscent of rickets and osteopenia, and punctate calcifications in soft tissue (most frequently about the tarsal bones) are observed. In most infants, periosteal cloaking is observed around the diaphyses of the large long bones; this transient phenomenon is rarely detectable after age one year.
• Generalized osteopenia is slowly progressive.
• The sella turcica remains normal as the calvarium thickens gradually. Cranial size remains proportional to stature.
• The mildly platyspondylic vertebra remain rectangular with irregular endplates, dorsal scalloping, and narrow intervertebral spaces. Kyphoscoliosis may become severe and requires orthopedic attention.
• The shortened long bones show normal or slightly undertubulated diaphyses, small epiphyses, and widened irregular metaphyses. Progressive dysplasia of the proximal femoral epiphyses may be asymmetric and quite severe.
• The shape and size of phalanges corresponds to metacarpal changes, which may be mildly shortened or completely normal. The carpal bones are often smaller than normal with irregular borders. Even in the event of normal or near-normal small hand bones, colinear axis deviation of the fingers is frequent due to slowly progressive hardening of periarticular and tendon connective tissue; true claw-type hand deformation is rare in ML IIIα/β, but carpal tunnel syndrome is a regular feature.
## Suggestive Findings
Small to low-normal anthropometric measurements for gestational age
Restricted range of passive motion in the shoulders
Flat face, shallow orbits, and depressed nasal bridge
Thick skin with wax-like texture (in neonates, most evident in and around the earlobes)
Variable musculoskeletal findings that may include one or more of the following:
Thoracic deformity including kyphosis
Clubfeet
Deformed long bones (See
Dislocation of the hip(s)
Dysmorphic facies and musculoskeletal features that may have been mistakenly overlooked at birth become undeniable over the first year of life: overall coarsening of features, poor growth, and restriction of joint movements at the hips, knees, shoulders, and hands.
Developmental milestones are not met.
Onset late infancy to late childhood
Musculoskeletal findings
Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
Joint stiffness in the shoulders, hips, and fingers
Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
Variable kyphoscoliosis, mild to severe
Osteoporosis associated with bone pain
Gradual mild coarsening of facial features
Slight corneal cloudiness (in some but not all) only by slit-lamp examination
Upper-respiratory infection and/or otitis media (variably present)
No organomegaly
Developmental milestones are met appropriately with the exception of late walking in a minority of children with ML III. Language skills are normal. Cognitive development is usually normal, and most children attend regular classes, irrespective of the physical handicap that gradually worsens.
The severe dysostosis multiplex in ML II includes the following [
Skeletal age is significantly delayed. Generalized osteopenia and coarse bony trabeculation are consistent findings.
Skull size and shape remain near normal; the sella turcica becomes oblong in children surviving into middle childhood.
All vertebral bodies have a much shortened anteroposterior diameter, are taller posteriorly than anteriorly, and have concave anterior borders and mildly convex superior and inferior borders.
The length of large and small long bones is much reduced. All large appendicular long bones have undertubulated diaphyses, dysplastic and small epiphyses, and overconstriction of the submetaphyseal regions.
Diaphyseal widening in all small long bones of the hands becomes pronounced by early childhood and is accompanied by progressive claw-type deformation.
Ribs have widened costochondral junctions but narrowed juxtavertebral parts.
Pelvic dysplasia is manifest as narrow basilar portions of the ilia and relatively long pubic and ischial bones; slanting, shallow acetabular roofs and bilateral coxa valga, with varying degrees of (often asymmetric) hip dislocation
In the most severely affected infants, transient signs reminiscent of rickets and osteopenia, and punctate calcifications in soft tissue (most frequently about the tarsal bones) are observed. In most infants, periosteal cloaking is observed around the diaphyses of the large long bones; this transient phenomenon is rarely detectable after age one year.
Generalized osteopenia is slowly progressive.
The sella turcica remains normal as the calvarium thickens gradually. Cranial size remains proportional to stature.
The mildly platyspondylic vertebra remain rectangular with irregular endplates, dorsal scalloping, and narrow intervertebral spaces. Kyphoscoliosis may become severe and requires orthopedic attention.
The shortened long bones show normal or slightly undertubulated diaphyses, small epiphyses, and widened irregular metaphyses. Progressive dysplasia of the proximal femoral epiphyses may be asymmetric and quite severe.
The shape and size of phalanges corresponds to metacarpal changes, which may be mildly shortened or completely normal. The carpal bones are often smaller than normal with irregular borders. Even in the event of normal or near-normal small hand bones, colinear axis deviation of the fingers is frequent due to slowly progressive hardening of periarticular and tendon connective tissue; true claw-type hand deformation is rare in ML IIIα/β, but carpal tunnel syndrome is a regular feature.
Historically, measurement of the accumulating oligosaccharides utilized older technologies such as thin layer chromatography (TLC). Although still widely used, TLC has several limitations including intrinsic poor resolution, interference from drugs and diet, subjective interpretation, and lack of quantification. Ultra-performance liquid chromatography-tandem mass spectrometry for FOS analysis is far more sensitive and specific.
Note: In
Click
• Small to low-normal anthropometric measurements for gestational age
• Restricted range of passive motion in the shoulders
• Flat face, shallow orbits, and depressed nasal bridge
• Thick skin with wax-like texture (in neonates, most evident in and around the earlobes)
• Variable musculoskeletal findings that may include one or more of the following:
• Thoracic deformity including kyphosis
• Clubfeet
• Deformed long bones (See
• Dislocation of the hip(s)
• Thoracic deformity including kyphosis
• Clubfeet
• Deformed long bones (See
• Dislocation of the hip(s)
• Thoracic deformity including kyphosis
• Clubfeet
• Deformed long bones (See
• Dislocation of the hip(s)
• Dysmorphic facies and musculoskeletal features that may have been mistakenly overlooked at birth become undeniable over the first year of life: overall coarsening of features, poor growth, and restriction of joint movements at the hips, knees, shoulders, and hands.
• Developmental milestones are not met.
• Onset late infancy to late childhood
• Musculoskeletal findings
• Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
• Joint stiffness in the shoulders, hips, and fingers
• Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
• Variable kyphoscoliosis, mild to severe
• Osteoporosis associated with bone pain
• Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
• Joint stiffness in the shoulders, hips, and fingers
• Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
• Variable kyphoscoliosis, mild to severe
• Osteoporosis associated with bone pain
• Gradual mild coarsening of facial features
• Slight corneal cloudiness (in some but not all) only by slit-lamp examination
• Upper-respiratory infection and/or otitis media (variably present)
• No organomegaly
• Developmental milestones are met appropriately with the exception of late walking in a minority of children with ML III. Language skills are normal. Cognitive development is usually normal, and most children attend regular classes, irrespective of the physical handicap that gradually worsens.
• Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
• Joint stiffness in the shoulders, hips, and fingers
• Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
• Variable kyphoscoliosis, mild to severe
• Osteoporosis associated with bone pain
• Skeletal age is significantly delayed. Generalized osteopenia and coarse bony trabeculation are consistent findings.
• Skull size and shape remain near normal; the sella turcica becomes oblong in children surviving into middle childhood.
• All vertebral bodies have a much shortened anteroposterior diameter, are taller posteriorly than anteriorly, and have concave anterior borders and mildly convex superior and inferior borders.
• The length of large and small long bones is much reduced. All large appendicular long bones have undertubulated diaphyses, dysplastic and small epiphyses, and overconstriction of the submetaphyseal regions.
• Diaphyseal widening in all small long bones of the hands becomes pronounced by early childhood and is accompanied by progressive claw-type deformation.
• Ribs have widened costochondral junctions but narrowed juxtavertebral parts.
• Pelvic dysplasia is manifest as narrow basilar portions of the ilia and relatively long pubic and ischial bones; slanting, shallow acetabular roofs and bilateral coxa valga, with varying degrees of (often asymmetric) hip dislocation
• In the most severely affected infants, transient signs reminiscent of rickets and osteopenia, and punctate calcifications in soft tissue (most frequently about the tarsal bones) are observed. In most infants, periosteal cloaking is observed around the diaphyses of the large long bones; this transient phenomenon is rarely detectable after age one year.
• Generalized osteopenia is slowly progressive.
• The sella turcica remains normal as the calvarium thickens gradually. Cranial size remains proportional to stature.
• The mildly platyspondylic vertebra remain rectangular with irregular endplates, dorsal scalloping, and narrow intervertebral spaces. Kyphoscoliosis may become severe and requires orthopedic attention.
• The shortened long bones show normal or slightly undertubulated diaphyses, small epiphyses, and widened irregular metaphyses. Progressive dysplasia of the proximal femoral epiphyses may be asymmetric and quite severe.
• The shape and size of phalanges corresponds to metacarpal changes, which may be mildly shortened or completely normal. The carpal bones are often smaller than normal with irregular borders. Even in the event of normal or near-normal small hand bones, colinear axis deviation of the fingers is frequent due to slowly progressive hardening of periarticular and tendon connective tissue; true claw-type hand deformation is rare in ML IIIα/β, but carpal tunnel syndrome is a regular feature.
## Clinical Findings
Small to low-normal anthropometric measurements for gestational age
Restricted range of passive motion in the shoulders
Flat face, shallow orbits, and depressed nasal bridge
Thick skin with wax-like texture (in neonates, most evident in and around the earlobes)
Variable musculoskeletal findings that may include one or more of the following:
Thoracic deformity including kyphosis
Clubfeet
Deformed long bones (See
Dislocation of the hip(s)
Dysmorphic facies and musculoskeletal features that may have been mistakenly overlooked at birth become undeniable over the first year of life: overall coarsening of features, poor growth, and restriction of joint movements at the hips, knees, shoulders, and hands.
Developmental milestones are not met.
Onset late infancy to late childhood
Musculoskeletal findings
Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
Joint stiffness in the shoulders, hips, and fingers
Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
Variable kyphoscoliosis, mild to severe
Osteoporosis associated with bone pain
Gradual mild coarsening of facial features
Slight corneal cloudiness (in some but not all) only by slit-lamp examination
Upper-respiratory infection and/or otitis media (variably present)
No organomegaly
Developmental milestones are met appropriately with the exception of late walking in a minority of children with ML III. Language skills are normal. Cognitive development is usually normal, and most children attend regular classes, irrespective of the physical handicap that gradually worsens.
• Small to low-normal anthropometric measurements for gestational age
• Restricted range of passive motion in the shoulders
• Flat face, shallow orbits, and depressed nasal bridge
• Thick skin with wax-like texture (in neonates, most evident in and around the earlobes)
• Variable musculoskeletal findings that may include one or more of the following:
• Thoracic deformity including kyphosis
• Clubfeet
• Deformed long bones (See
• Dislocation of the hip(s)
• Thoracic deformity including kyphosis
• Clubfeet
• Deformed long bones (See
• Dislocation of the hip(s)
• Thoracic deformity including kyphosis
• Clubfeet
• Deformed long bones (See
• Dislocation of the hip(s)
• Dysmorphic facies and musculoskeletal features that may have been mistakenly overlooked at birth become undeniable over the first year of life: overall coarsening of features, poor growth, and restriction of joint movements at the hips, knees, shoulders, and hands.
• Developmental milestones are not met.
• Onset late infancy to late childhood
• Musculoskeletal findings
• Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
• Joint stiffness in the shoulders, hips, and fingers
• Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
• Variable kyphoscoliosis, mild to severe
• Osteoporosis associated with bone pain
• Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
• Joint stiffness in the shoulders, hips, and fingers
• Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
• Variable kyphoscoliosis, mild to severe
• Osteoporosis associated with bone pain
• Gradual mild coarsening of facial features
• Slight corneal cloudiness (in some but not all) only by slit-lamp examination
• Upper-respiratory infection and/or otitis media (variably present)
• No organomegaly
• Developmental milestones are met appropriately with the exception of late walking in a minority of children with ML III. Language skills are normal. Cognitive development is usually normal, and most children attend regular classes, irrespective of the physical handicap that gradually worsens.
• Growth parameters are typically normal at birth. Growth rate slows in preschool and early school years
• Joint stiffness in the shoulders, hips, and fingers
• Joint pain that is exacerbated by strenuous exercise or vigorous physical therapy
• Variable kyphoscoliosis, mild to severe
• Osteoporosis associated with bone pain
## Radiographic Findings
The severe dysostosis multiplex in ML II includes the following [
Skeletal age is significantly delayed. Generalized osteopenia and coarse bony trabeculation are consistent findings.
Skull size and shape remain near normal; the sella turcica becomes oblong in children surviving into middle childhood.
All vertebral bodies have a much shortened anteroposterior diameter, are taller posteriorly than anteriorly, and have concave anterior borders and mildly convex superior and inferior borders.
The length of large and small long bones is much reduced. All large appendicular long bones have undertubulated diaphyses, dysplastic and small epiphyses, and overconstriction of the submetaphyseal regions.
Diaphyseal widening in all small long bones of the hands becomes pronounced by early childhood and is accompanied by progressive claw-type deformation.
Ribs have widened costochondral junctions but narrowed juxtavertebral parts.
Pelvic dysplasia is manifest as narrow basilar portions of the ilia and relatively long pubic and ischial bones; slanting, shallow acetabular roofs and bilateral coxa valga, with varying degrees of (often asymmetric) hip dislocation
In the most severely affected infants, transient signs reminiscent of rickets and osteopenia, and punctate calcifications in soft tissue (most frequently about the tarsal bones) are observed. In most infants, periosteal cloaking is observed around the diaphyses of the large long bones; this transient phenomenon is rarely detectable after age one year.
Generalized osteopenia is slowly progressive.
The sella turcica remains normal as the calvarium thickens gradually. Cranial size remains proportional to stature.
The mildly platyspondylic vertebra remain rectangular with irregular endplates, dorsal scalloping, and narrow intervertebral spaces. Kyphoscoliosis may become severe and requires orthopedic attention.
The shortened long bones show normal or slightly undertubulated diaphyses, small epiphyses, and widened irregular metaphyses. Progressive dysplasia of the proximal femoral epiphyses may be asymmetric and quite severe.
The shape and size of phalanges corresponds to metacarpal changes, which may be mildly shortened or completely normal. The carpal bones are often smaller than normal with irregular borders. Even in the event of normal or near-normal small hand bones, colinear axis deviation of the fingers is frequent due to slowly progressive hardening of periarticular and tendon connective tissue; true claw-type hand deformation is rare in ML IIIα/β, but carpal tunnel syndrome is a regular feature.
• Skeletal age is significantly delayed. Generalized osteopenia and coarse bony trabeculation are consistent findings.
• Skull size and shape remain near normal; the sella turcica becomes oblong in children surviving into middle childhood.
• All vertebral bodies have a much shortened anteroposterior diameter, are taller posteriorly than anteriorly, and have concave anterior borders and mildly convex superior and inferior borders.
• The length of large and small long bones is much reduced. All large appendicular long bones have undertubulated diaphyses, dysplastic and small epiphyses, and overconstriction of the submetaphyseal regions.
• Diaphyseal widening in all small long bones of the hands becomes pronounced by early childhood and is accompanied by progressive claw-type deformation.
• Ribs have widened costochondral junctions but narrowed juxtavertebral parts.
• Pelvic dysplasia is manifest as narrow basilar portions of the ilia and relatively long pubic and ischial bones; slanting, shallow acetabular roofs and bilateral coxa valga, with varying degrees of (often asymmetric) hip dislocation
• In the most severely affected infants, transient signs reminiscent of rickets and osteopenia, and punctate calcifications in soft tissue (most frequently about the tarsal bones) are observed. In most infants, periosteal cloaking is observed around the diaphyses of the large long bones; this transient phenomenon is rarely detectable after age one year.
• Generalized osteopenia is slowly progressive.
• The sella turcica remains normal as the calvarium thickens gradually. Cranial size remains proportional to stature.
• The mildly platyspondylic vertebra remain rectangular with irregular endplates, dorsal scalloping, and narrow intervertebral spaces. Kyphoscoliosis may become severe and requires orthopedic attention.
• The shortened long bones show normal or slightly undertubulated diaphyses, small epiphyses, and widened irregular metaphyses. Progressive dysplasia of the proximal femoral epiphyses may be asymmetric and quite severe.
• The shape and size of phalanges corresponds to metacarpal changes, which may be mildly shortened or completely normal. The carpal bones are often smaller than normal with irregular borders. Even in the event of normal or near-normal small hand bones, colinear axis deviation of the fingers is frequent due to slowly progressive hardening of periarticular and tendon connective tissue; true claw-type hand deformation is rare in ML IIIα/β, but carpal tunnel syndrome is a regular feature.
## Supportive Biochemical Findings
Historically, measurement of the accumulating oligosaccharides utilized older technologies such as thin layer chromatography (TLC). Although still widely used, TLC has several limitations including intrinsic poor resolution, interference from drugs and diet, subjective interpretation, and lack of quantification. Ultra-performance liquid chromatography-tandem mass spectrometry for FOS analysis is far more sensitive and specific.
Note: In
Click
## Establishing the Diagnosis
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular Genetic Testing Used in Mucolipidosis II / Mucolipidosis III α/β
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A 897-bp deletion spanning exon 19 [
## Clinical Characteristics
Mucolipidosis II and mucolipidosis III α/β are distinct clinical disorders with different age of onset and clinical course. Although the experienced clinician observes variation within each phenotype, the phenotypic spectrum between ML II and ML IIIα/β is discontinuous. Knowledge of these two "classic" phenotypes allows recognition of an interesting minority of intermediate clinical types in which physical growth in infancy resembles that in the ML II whereas neuromotor and speech development follow the course of ML IIIα/β.
Mucolipidosis II (ML II) is slowly progressive with clinical onset at birth and death most often in early childhood [
The skin is thickened especially around the earlobes. Additional cutaneous findings include prominent periorbital tortuous veins and telangiectatic capillaries in the subcutis over the cheeks. Hair texture and color may be atypical for families of northern European origin as the hair texture is fine and, in some instances, white to golden in color, even in neonates.
Metopic prominence is observed in some children. Craniosynostosis is regularly suspected but not formally confirmed and, in some instances, has resulted in inappropriate cranial surgery.
Breathing remains noisy throughout life. The airways are narrow and subject to slowly progressive mucosal thickening and overall stiffening of the connective tissues. These factors also adversely affect the lung parenchyma. The gradual stiffening of the thoracic cage compounds the restrictive respiratory insufficiency.
Severe pulmonary hypertension (PH) has been more formally documented in a longer-surviving individual with ML II [
Respiratory support is only infrequently required in newborns. Obstructive sleep apnea necessitates nighttime respiratory support in some children; a minority of longer-surviving children require persistent assisted ventilation. In these cases, invariably, respiratory support was initiated during treatment of an acute infection.
The range of motion of all major and small joints is significantly limited. Mobility of the shoulders is significantly reduced despite consistent axial and appendicular hypotonia. The wrists gradually lose range of motion, the hands and fingers broaden gradually in the few years after infancy and become progressively stiffer and fixed in volar claw-like flexion and usually deviate from the appendicular axis.
Early motor milestones are significantly delayed: sitting upright with support is usually acquired around age one year; unassisted sitting may not be achieved until age two years. In the majority of affected children, unaided walking is never achieved. Onset of expressive language is late and limited to single words. Receptive communication, which is much better than expressive language, is not age appropriate. Cognitive functioning, although obviously below normal for age, enables the child to understand, interact with, and enjoy the immediate environment.
ML IIIα/β is slowly progressive with clinical onset at approximately age three years and death in early-to-middle adulthood [
Adults exhibit restrictive lung disease caused by stiffening of the thoracic cage, slowly progressive sclerosis of bronchi, and hardening and thickening of the interstitial tissue (extracellular matrix) in lung parenchyma.
Left and/or right ventricular hypertrophy are often documented on echocardiography in older individuals. Pulmonary hypertension may occur in some older individuals, but to date remains insufficiently documented.
Rapid progression of cardiac disease is rarely observed in ML IIIα/β.
Pneumonia may compound mild cardiac insufficiency. Death in early adulthood is often from cardiopulmonary causes, even without complicating factors such as pneumonia.
Limited range of motion in the hips and knees explains the slow gait and inability of children to run effectively. Flexion contractures in the hips and knees cause the squatting standing posture, most apparent in lateral view (
Secondary but severe arthritic changes in the hips that can lead to destruction of the proximal femoral epiphyses make walking increasingly difficult and painful. Significant hardening of the surrounding soft tissues contributes to hip dysfunction. Many affected individuals become wheelchair bound before or during early adulthood.
Range of motion is less adversely affected in the wrists and ankles than in the other large joints. Dupuytren-type palmar contractures may appear from late childhood onward and exacerbate the moderate to severe claw-like flexion deformity of the fingers associated with recurrent swelling and progressive stiffness (
In ML IIIα/β the hands and fingers are usually of near-normal length in contrast to the severely affected hands in ML II.
Before the appropriate diagnosis is made, many individuals with ML IIIα/β are evaluated for a rheumatologic disorder.
Osteoporosis affects the entire skeleton. Bone pain becomes the most distressing symptom in ML IIIα/β, even in individuals with limited ambulation. Osteolytic bone lesions also are associated with significant bone pain in those who are nonambulatory.
The neck is short.
Thickening of the skin is inconsistent and mild.
While the majority of individuals with a
All affected individuals had normal anthropometric data when born at term following normal pregnancies. In some facial features were considered coarse and flat. Contractures of some large joints and mild dorsolumbar kyphoscoliosis were noticed in infancy. Growth slowed near the end of the second year. The diagnosis of ML II was made before the third birthday. However, in later childhood the diagnosis was changed to ML IIIα/β or still later to ML II / ML IIIα/β [
Physical growth ceased by the time that maximal height was below 90 cm coincident with radiographic evidence of dysostosis multiplex. Even when the skeletal dysplasia was consistent with ML II, neuromotor development slowly progressed. All children were able to walk unaided at about age three years. Speech development was close to normal in some, and consistently better than that observed in ML II. Cognitive development was slow and deficient resulting in mild intellectual disability. Near-normal social interaction was reminiscent of that observed in ML IIIα/β.
Average life expectancy in this particular intermediate phenotype was similar to that in ML IIIα/β. Respiratory problems were mild and infrequent; however, slowly progressive hardening and thickening of the cardiac valves causing valvular insufficiency and subsequent myocardial hypertrophy and failure was the most common cause of death. The postmortem findings in one individual (originally reported to have had the ML IIIα/β phenotype) were published [
Genotype-phenotype correlations support the clinical distinction between the phenotypes ML II, ML IIIα/β, and at least the type of intermediate ML described in
Of note, intellectual disability in one individual with ML IIIα/β homozygous for c.342delCA, whose parents were consanguineous, was significantly below the near-normal range of intellect typically observed in ML IIIα/β; it is unclear to what degree homozygosity for other variants could have affected this aspect of the phenotype.
Other intermediate phenotypes are to date less well defined. Some homozygous variant genotypes appear to be well represented and clinically heterogeneous.
The term "mucolipidosis" has been used in four different inborn errors of metabolism; only ML II, ML IIIα/β, and intermediate ML are
During the 1970s excessive urinary excretion of oligosaccharides was documented in most of the mucolipidoses; therefore, the terms "oligosaccharidoses" or "glycoproteinoses" may be substituted for the term "mucolipidoses."
Terms Used to Describe GNPTAB-Related Disorders
MPS = mucopolysaccharidosis
ML II, introduced in 1970 by Spranger in an attempt to provide the first clinical classification of the group of metabolic disorders, clinically considered intermediate between the lipidoses and the mucopolysaccharidoses (storage disorders of glycosaminoglycans). Although mucolipidosis is a clinically useful designation, biochemists consider it a misnomer because "mucolipids" do not exist in nature.
The finding by Jules Leroy and Robert DeMars by phase-contrast microscopy of large amounts of dark and dense granules filling almost the entire cytoplasm of cultured fibroblasts from skin biopsies of two unrelated children resulted in the use of the term "inclusion cells," abbreviated as "I-cells." Hence, the term "I-cell disease" was introduced.
See
If these findings reflect a global prevalence ranging between 2.5x10
ML II has been reported in nearly all parts of the world.
An unusually high prevalence of ML II in 1:6,184 live births with an estimated carrier rate of 1:39 was found in the northeastern region of the province of Quebec, Canada [
The combined prevalence of ML II and ML IIIα/β is 0.22 per 100,000 in the Czech Republic [
• The neck is short.
• Thickening of the skin is inconsistent and mild.
## Clinical Description
Mucolipidosis II and mucolipidosis III α/β are distinct clinical disorders with different age of onset and clinical course. Although the experienced clinician observes variation within each phenotype, the phenotypic spectrum between ML II and ML IIIα/β is discontinuous. Knowledge of these two "classic" phenotypes allows recognition of an interesting minority of intermediate clinical types in which physical growth in infancy resembles that in the ML II whereas neuromotor and speech development follow the course of ML IIIα/β.
Mucolipidosis II (ML II) is slowly progressive with clinical onset at birth and death most often in early childhood [
The skin is thickened especially around the earlobes. Additional cutaneous findings include prominent periorbital tortuous veins and telangiectatic capillaries in the subcutis over the cheeks. Hair texture and color may be atypical for families of northern European origin as the hair texture is fine and, in some instances, white to golden in color, even in neonates.
Metopic prominence is observed in some children. Craniosynostosis is regularly suspected but not formally confirmed and, in some instances, has resulted in inappropriate cranial surgery.
Breathing remains noisy throughout life. The airways are narrow and subject to slowly progressive mucosal thickening and overall stiffening of the connective tissues. These factors also adversely affect the lung parenchyma. The gradual stiffening of the thoracic cage compounds the restrictive respiratory insufficiency.
Severe pulmonary hypertension (PH) has been more formally documented in a longer-surviving individual with ML II [
Respiratory support is only infrequently required in newborns. Obstructive sleep apnea necessitates nighttime respiratory support in some children; a minority of longer-surviving children require persistent assisted ventilation. In these cases, invariably, respiratory support was initiated during treatment of an acute infection.
The range of motion of all major and small joints is significantly limited. Mobility of the shoulders is significantly reduced despite consistent axial and appendicular hypotonia. The wrists gradually lose range of motion, the hands and fingers broaden gradually in the few years after infancy and become progressively stiffer and fixed in volar claw-like flexion and usually deviate from the appendicular axis.
Early motor milestones are significantly delayed: sitting upright with support is usually acquired around age one year; unassisted sitting may not be achieved until age two years. In the majority of affected children, unaided walking is never achieved. Onset of expressive language is late and limited to single words. Receptive communication, which is much better than expressive language, is not age appropriate. Cognitive functioning, although obviously below normal for age, enables the child to understand, interact with, and enjoy the immediate environment.
ML IIIα/β is slowly progressive with clinical onset at approximately age three years and death in early-to-middle adulthood [
Adults exhibit restrictive lung disease caused by stiffening of the thoracic cage, slowly progressive sclerosis of bronchi, and hardening and thickening of the interstitial tissue (extracellular matrix) in lung parenchyma.
Left and/or right ventricular hypertrophy are often documented on echocardiography in older individuals. Pulmonary hypertension may occur in some older individuals, but to date remains insufficiently documented.
Rapid progression of cardiac disease is rarely observed in ML IIIα/β.
Pneumonia may compound mild cardiac insufficiency. Death in early adulthood is often from cardiopulmonary causes, even without complicating factors such as pneumonia.
Limited range of motion in the hips and knees explains the slow gait and inability of children to run effectively. Flexion contractures in the hips and knees cause the squatting standing posture, most apparent in lateral view (
Secondary but severe arthritic changes in the hips that can lead to destruction of the proximal femoral epiphyses make walking increasingly difficult and painful. Significant hardening of the surrounding soft tissues contributes to hip dysfunction. Many affected individuals become wheelchair bound before or during early adulthood.
Range of motion is less adversely affected in the wrists and ankles than in the other large joints. Dupuytren-type palmar contractures may appear from late childhood onward and exacerbate the moderate to severe claw-like flexion deformity of the fingers associated with recurrent swelling and progressive stiffness (
In ML IIIα/β the hands and fingers are usually of near-normal length in contrast to the severely affected hands in ML II.
Before the appropriate diagnosis is made, many individuals with ML IIIα/β are evaluated for a rheumatologic disorder.
Osteoporosis affects the entire skeleton. Bone pain becomes the most distressing symptom in ML IIIα/β, even in individuals with limited ambulation. Osteolytic bone lesions also are associated with significant bone pain in those who are nonambulatory.
The neck is short.
Thickening of the skin is inconsistent and mild.
While the majority of individuals with a
All affected individuals had normal anthropometric data when born at term following normal pregnancies. In some facial features were considered coarse and flat. Contractures of some large joints and mild dorsolumbar kyphoscoliosis were noticed in infancy. Growth slowed near the end of the second year. The diagnosis of ML II was made before the third birthday. However, in later childhood the diagnosis was changed to ML IIIα/β or still later to ML II / ML IIIα/β [
Physical growth ceased by the time that maximal height was below 90 cm coincident with radiographic evidence of dysostosis multiplex. Even when the skeletal dysplasia was consistent with ML II, neuromotor development slowly progressed. All children were able to walk unaided at about age three years. Speech development was close to normal in some, and consistently better than that observed in ML II. Cognitive development was slow and deficient resulting in mild intellectual disability. Near-normal social interaction was reminiscent of that observed in ML IIIα/β.
Average life expectancy in this particular intermediate phenotype was similar to that in ML IIIα/β. Respiratory problems were mild and infrequent; however, slowly progressive hardening and thickening of the cardiac valves causing valvular insufficiency and subsequent myocardial hypertrophy and failure was the most common cause of death. The postmortem findings in one individual (originally reported to have had the ML IIIα/β phenotype) were published [
• The neck is short.
• Thickening of the skin is inconsistent and mild.
## Mucolipidosis II
Mucolipidosis II (ML II) is slowly progressive with clinical onset at birth and death most often in early childhood [
The skin is thickened especially around the earlobes. Additional cutaneous findings include prominent periorbital tortuous veins and telangiectatic capillaries in the subcutis over the cheeks. Hair texture and color may be atypical for families of northern European origin as the hair texture is fine and, in some instances, white to golden in color, even in neonates.
Metopic prominence is observed in some children. Craniosynostosis is regularly suspected but not formally confirmed and, in some instances, has resulted in inappropriate cranial surgery.
Breathing remains noisy throughout life. The airways are narrow and subject to slowly progressive mucosal thickening and overall stiffening of the connective tissues. These factors also adversely affect the lung parenchyma. The gradual stiffening of the thoracic cage compounds the restrictive respiratory insufficiency.
Severe pulmonary hypertension (PH) has been more formally documented in a longer-surviving individual with ML II [
Respiratory support is only infrequently required in newborns. Obstructive sleep apnea necessitates nighttime respiratory support in some children; a minority of longer-surviving children require persistent assisted ventilation. In these cases, invariably, respiratory support was initiated during treatment of an acute infection.
The range of motion of all major and small joints is significantly limited. Mobility of the shoulders is significantly reduced despite consistent axial and appendicular hypotonia. The wrists gradually lose range of motion, the hands and fingers broaden gradually in the few years after infancy and become progressively stiffer and fixed in volar claw-like flexion and usually deviate from the appendicular axis.
Early motor milestones are significantly delayed: sitting upright with support is usually acquired around age one year; unassisted sitting may not be achieved until age two years. In the majority of affected children, unaided walking is never achieved. Onset of expressive language is late and limited to single words. Receptive communication, which is much better than expressive language, is not age appropriate. Cognitive functioning, although obviously below normal for age, enables the child to understand, interact with, and enjoy the immediate environment.
## Mucolipidosis IIIα/β
ML IIIα/β is slowly progressive with clinical onset at approximately age three years and death in early-to-middle adulthood [
Adults exhibit restrictive lung disease caused by stiffening of the thoracic cage, slowly progressive sclerosis of bronchi, and hardening and thickening of the interstitial tissue (extracellular matrix) in lung parenchyma.
Left and/or right ventricular hypertrophy are often documented on echocardiography in older individuals. Pulmonary hypertension may occur in some older individuals, but to date remains insufficiently documented.
Rapid progression of cardiac disease is rarely observed in ML IIIα/β.
Pneumonia may compound mild cardiac insufficiency. Death in early adulthood is often from cardiopulmonary causes, even without complicating factors such as pneumonia.
Limited range of motion in the hips and knees explains the slow gait and inability of children to run effectively. Flexion contractures in the hips and knees cause the squatting standing posture, most apparent in lateral view (
Secondary but severe arthritic changes in the hips that can lead to destruction of the proximal femoral epiphyses make walking increasingly difficult and painful. Significant hardening of the surrounding soft tissues contributes to hip dysfunction. Many affected individuals become wheelchair bound before or during early adulthood.
Range of motion is less adversely affected in the wrists and ankles than in the other large joints. Dupuytren-type palmar contractures may appear from late childhood onward and exacerbate the moderate to severe claw-like flexion deformity of the fingers associated with recurrent swelling and progressive stiffness (
In ML IIIα/β the hands and fingers are usually of near-normal length in contrast to the severely affected hands in ML II.
Before the appropriate diagnosis is made, many individuals with ML IIIα/β are evaluated for a rheumatologic disorder.
Osteoporosis affects the entire skeleton. Bone pain becomes the most distressing symptom in ML IIIα/β, even in individuals with limited ambulation. Osteolytic bone lesions also are associated with significant bone pain in those who are nonambulatory.
The neck is short.
Thickening of the skin is inconsistent and mild.
• The neck is short.
• Thickening of the skin is inconsistent and mild.
## Phenotypes Intermediate Between ML II and ML IIIα/β
While the majority of individuals with a
All affected individuals had normal anthropometric data when born at term following normal pregnancies. In some facial features were considered coarse and flat. Contractures of some large joints and mild dorsolumbar kyphoscoliosis were noticed in infancy. Growth slowed near the end of the second year. The diagnosis of ML II was made before the third birthday. However, in later childhood the diagnosis was changed to ML IIIα/β or still later to ML II / ML IIIα/β [
Physical growth ceased by the time that maximal height was below 90 cm coincident with radiographic evidence of dysostosis multiplex. Even when the skeletal dysplasia was consistent with ML II, neuromotor development slowly progressed. All children were able to walk unaided at about age three years. Speech development was close to normal in some, and consistently better than that observed in ML II. Cognitive development was slow and deficient resulting in mild intellectual disability. Near-normal social interaction was reminiscent of that observed in ML IIIα/β.
Average life expectancy in this particular intermediate phenotype was similar to that in ML IIIα/β. Respiratory problems were mild and infrequent; however, slowly progressive hardening and thickening of the cardiac valves causing valvular insufficiency and subsequent myocardial hypertrophy and failure was the most common cause of death. The postmortem findings in one individual (originally reported to have had the ML IIIα/β phenotype) were published [
## Genotype-Phenotype Correlations
Genotype-phenotype correlations support the clinical distinction between the phenotypes ML II, ML IIIα/β, and at least the type of intermediate ML described in
Of note, intellectual disability in one individual with ML IIIα/β homozygous for c.342delCA, whose parents were consanguineous, was significantly below the near-normal range of intellect typically observed in ML IIIα/β; it is unclear to what degree homozygosity for other variants could have affected this aspect of the phenotype.
Other intermediate phenotypes are to date less well defined. Some homozygous variant genotypes appear to be well represented and clinically heterogeneous.
## Nomenclature
The term "mucolipidosis" has been used in four different inborn errors of metabolism; only ML II, ML IIIα/β, and intermediate ML are
During the 1970s excessive urinary excretion of oligosaccharides was documented in most of the mucolipidoses; therefore, the terms "oligosaccharidoses" or "glycoproteinoses" may be substituted for the term "mucolipidoses."
Terms Used to Describe GNPTAB-Related Disorders
MPS = mucopolysaccharidosis
ML II, introduced in 1970 by Spranger in an attempt to provide the first clinical classification of the group of metabolic disorders, clinically considered intermediate between the lipidoses and the mucopolysaccharidoses (storage disorders of glycosaminoglycans). Although mucolipidosis is a clinically useful designation, biochemists consider it a misnomer because "mucolipids" do not exist in nature.
The finding by Jules Leroy and Robert DeMars by phase-contrast microscopy of large amounts of dark and dense granules filling almost the entire cytoplasm of cultured fibroblasts from skin biopsies of two unrelated children resulted in the use of the term "inclusion cells," abbreviated as "I-cells." Hence, the term "I-cell disease" was introduced.
See
## Prevalence
If these findings reflect a global prevalence ranging between 2.5x10
ML II has been reported in nearly all parts of the world.
An unusually high prevalence of ML II in 1:6,184 live births with an estimated carrier rate of 1:39 was found in the northeastern region of the province of Quebec, Canada [
The combined prevalence of ML II and ML IIIα/β is 0.22 per 100,000 in the Czech Republic [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this chapter have been associated with biallelic
## Differential Diagnosis
In addition to the disorders to consider in the differential diagnosis of
Autosomal Recessive Lysosomal Storage Disorders to Consider in the Differential Diagnosis of ML II
Coarse features
Slowed statural growth
Clawed hands
Growth restriction
Skeletal dysplasia
Storage phenomena more pronounced
Presents as nonimmune hydrops fetalis more often than ML II
Dysmorphic
Coarse features
May present as nonimmune hydrops fetalis
In infants: more chronic disorder w/moderate organomegaly, dysostosis multiplex that is milder than in ML II,
Growth & cognitive development much less impaired
Coarse features
Significant DD
Less facial dysmorphism & much less dysostosis multiplex
Severe DD
DD = developmental delay
Barring the few instances with a rapidly evolving glomerular nephropathy & early fatal outcome
Mucopolysaccharidosis 1 (see
Mucopolysaccharidosis 1 and other disorders with a known genetic etiology are described in
Inherited Disorders to Consider in the Differential Diagnosis of ML IIIα/β
Clinical findings in ML IIIα/β overlap those observed in nearly all late-onset mild MPSs
Share several clinical & radiographic aspects of dysostosis multiplex
Evidence of more severe storage on physical exam
Enlarged head size in all MPSs (not seen in ML IIIα/β)
Slowly coarsening features
Mild dysostosis
Early hearing loss
More significant DD
Coarse facies
Vertebral abnormalities
Infantile form can present w/nonimmune hydrops fetalis.
Hepatosplenomegaly
Myoclonus & ataxia in juvenile form
Coarse facies
Short trunk
Short stature
Myoclonus
Seizures
DD
Coarse facies
Much more prominent neurodegenerative aspects
Absent/minimal dysostosis multiplex
DD
Restricted range of motion in joints
Dysostosis multiplex on skeletal radiographs
Much more prominent neurodegenerative aspects
Joint stiffness & bone pain
Limited joint mobility
Later onset of symptoms
Absence of radiologic signs of dysostosis multiplex
AD = autosomal dominant; AMPS = acid mucopolysaccharides; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked
Formerly referred to as Hurler-Scheie syndrome or Scheie syndrome
Also referred to as Hunter syndrome
In the past, mucopolysaccharidosis type IVB was referred to as Morquio syndrome type B.
Also referred to as Maroteaux-Lamy syndrome
Also referred to as Sly syndrome
A late-manifesting type II collagenopathy
• Coarse features
• Slowed statural growth
• Clawed hands
• Growth restriction
• Skeletal dysplasia
• Storage phenomena more pronounced
• Presents as nonimmune hydrops fetalis more often than ML II
• Dysmorphic
• Coarse features
• May present as nonimmune hydrops fetalis
• In infants: more chronic disorder w/moderate organomegaly, dysostosis multiplex that is milder than in ML II,
• Growth & cognitive development much less impaired
• Coarse features
• Significant DD
• Less facial dysmorphism & much less dysostosis multiplex
• Severe DD
• Clinical findings in ML IIIα/β overlap those observed in nearly all late-onset mild MPSs
• Share several clinical & radiographic aspects of dysostosis multiplex
• Evidence of more severe storage on physical exam
• Enlarged head size in all MPSs (not seen in ML IIIα/β)
• Slowly coarsening features
• Mild dysostosis
• Early hearing loss
• More significant DD
• Coarse facies
• Vertebral abnormalities
• Infantile form can present w/nonimmune hydrops fetalis.
• Hepatosplenomegaly
• Myoclonus & ataxia in juvenile form
• Coarse facies
• Short trunk
• Short stature
• Myoclonus
• Seizures
• DD
• Coarse facies
• Much more prominent neurodegenerative aspects
• Absent/minimal dysostosis multiplex
• DD
• Restricted range of motion in joints
• Dysostosis multiplex on skeletal radiographs
• Much more prominent neurodegenerative aspects
• Joint stiffness & bone pain
• Limited joint mobility
• Later onset of symptoms
• Absence of radiologic signs of dysostosis multiplex
## Mucolipidosis II (ML II)
Autosomal Recessive Lysosomal Storage Disorders to Consider in the Differential Diagnosis of ML II
Coarse features
Slowed statural growth
Clawed hands
Growth restriction
Skeletal dysplasia
Storage phenomena more pronounced
Presents as nonimmune hydrops fetalis more often than ML II
Dysmorphic
Coarse features
May present as nonimmune hydrops fetalis
In infants: more chronic disorder w/moderate organomegaly, dysostosis multiplex that is milder than in ML II,
Growth & cognitive development much less impaired
Coarse features
Significant DD
Less facial dysmorphism & much less dysostosis multiplex
Severe DD
DD = developmental delay
Barring the few instances with a rapidly evolving glomerular nephropathy & early fatal outcome
• Coarse features
• Slowed statural growth
• Clawed hands
• Growth restriction
• Skeletal dysplasia
• Storage phenomena more pronounced
• Presents as nonimmune hydrops fetalis more often than ML II
• Dysmorphic
• Coarse features
• May present as nonimmune hydrops fetalis
• In infants: more chronic disorder w/moderate organomegaly, dysostosis multiplex that is milder than in ML II,
• Growth & cognitive development much less impaired
• Coarse features
• Significant DD
• Less facial dysmorphism & much less dysostosis multiplex
• Severe DD
## Mucolipidosis IIIα/β (ML IIIα/β)
Mucopolysaccharidosis 1 (see
Mucopolysaccharidosis 1 and other disorders with a known genetic etiology are described in
Inherited Disorders to Consider in the Differential Diagnosis of ML IIIα/β
Clinical findings in ML IIIα/β overlap those observed in nearly all late-onset mild MPSs
Share several clinical & radiographic aspects of dysostosis multiplex
Evidence of more severe storage on physical exam
Enlarged head size in all MPSs (not seen in ML IIIα/β)
Slowly coarsening features
Mild dysostosis
Early hearing loss
More significant DD
Coarse facies
Vertebral abnormalities
Infantile form can present w/nonimmune hydrops fetalis.
Hepatosplenomegaly
Myoclonus & ataxia in juvenile form
Coarse facies
Short trunk
Short stature
Myoclonus
Seizures
DD
Coarse facies
Much more prominent neurodegenerative aspects
Absent/minimal dysostosis multiplex
DD
Restricted range of motion in joints
Dysostosis multiplex on skeletal radiographs
Much more prominent neurodegenerative aspects
Joint stiffness & bone pain
Limited joint mobility
Later onset of symptoms
Absence of radiologic signs of dysostosis multiplex
AD = autosomal dominant; AMPS = acid mucopolysaccharides; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked
Formerly referred to as Hurler-Scheie syndrome or Scheie syndrome
Also referred to as Hunter syndrome
In the past, mucopolysaccharidosis type IVB was referred to as Morquio syndrome type B.
Also referred to as Maroteaux-Lamy syndrome
Also referred to as Sly syndrome
A late-manifesting type II collagenopathy
• Clinical findings in ML IIIα/β overlap those observed in nearly all late-onset mild MPSs
• Share several clinical & radiographic aspects of dysostosis multiplex
• Evidence of more severe storage on physical exam
• Enlarged head size in all MPSs (not seen in ML IIIα/β)
• Slowly coarsening features
• Mild dysostosis
• Early hearing loss
• More significant DD
• Coarse facies
• Vertebral abnormalities
• Infantile form can present w/nonimmune hydrops fetalis.
• Hepatosplenomegaly
• Myoclonus & ataxia in juvenile form
• Coarse facies
• Short trunk
• Short stature
• Myoclonus
• Seizures
• DD
• Coarse facies
• Much more prominent neurodegenerative aspects
• Absent/minimal dysostosis multiplex
• DD
• Restricted range of motion in joints
• Dysostosis multiplex on skeletal radiographs
• Much more prominent neurodegenerative aspects
• Joint stiffness & bone pain
• Limited joint mobility
• Later onset of symptoms
• Absence of radiologic signs of dysostosis multiplex
## Management
To establish the extent of disease and needs of an individual diagnosed with a
Radiographic skeletal survey, if not performed or incomplete in the diagnostic evaluation. Such survey in early infancy is important for comparison with similar radiographs in the third year of life.
Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
Pulmonary radiographs to monitor interstitial lung disease in any serious lower respiratory infection. Chest CT may better show fibrotic changes in the lungs. It is doubtful that the child with ML II can cooperate sufficiently to achieve reliable pulmonary function tests, by which restrictive respiratory deficiency could be documented more objectively.
Feeding problems concern parents as the affected child consumes fewer calories than expected. Poor suck, which may contribute to feeding difficulties early on, generally resolves quickly. Caloric need is less than that of an unaffected sib.
Baseline ophthalmologic examination in a neonate with ML II is useful, but significant visual impairment is not a usual issue. An ophthalmologic evaluation between six and 12 months is recommended: Slit lamp examination will reveal corneal haziness, apparently without clinical implication; fundoscopic examination will show no specific retinal abnormalities.
Hearing screen for conductive hearing loss secondary to recurrent otitis media. Hearing may be normal during the first year, but should be checked at least once after age six months. In the second year, some conductive hearing loss may be present, even without – but certainly following – upper airway infections.
Developmental assessment to help establish appropriate expectations for the child’s developmental progress
Consultation with a clinical geneticist and/or genetic counselor
Radiographic skeletal survey if either not performed or incomplete in the diagnostic evaluation
Baseline evaluations with an orthopedic surgeon and a metabolic bone specialist to better determine if/when surgical interventions or bisphosphonate therapy may be initiated (See
Gentle physical and occupational therapy to maintain mobility and strength. Aggressive therapy can cause further joint damage.
Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
Baseline ophthalmologic examination
Hearing screen for evidence of conductive hearing loss secondary to recurrent otitis media
Baseline developmental assessment
Consultation with a clinical geneticist and/or genetic counselor
Supportive and symptomatic management is indicated.
Stretching exercises are ineffective and painful.
The unknowing therapist may cause damage to the surrounding joint capsule and adjacent tendons with subsequent soft tissue calcification.
Therapies that are "low impact" concerning joint and tendon strain, including short sessions of aqua therapy, are usually well tolerated. Instead of exercises of passive motion, often the child can be motivated to imitate active motion in joints despite the inherent limited range of motion.
Supportive and symptomatic management is indicated.
Management of pain in the hips during and following walking requires attention from late childhood or early adolescence.
Carpal tunnel signs may require tendon release procedures for at least temporary relief. The procedure is repeated several time in some individuals.
Later in the disease course more general bone pain of variable intensity, unrelated to physical exercise or motion, is present.
Bisphosphonates decrease osteoclastic activity; when on therapy, some (but not all) individuals with ML IIIα/β experience decreased pain and associated increased mobility. Bone densitometry is improved in affected individuals and in animal models [
Bilateral hip replacement has been successful in older adolescents and adults with milder ML IIIα/β [
See
Search
• Radiographic skeletal survey, if not performed or incomplete in the diagnostic evaluation. Such survey in early infancy is important for comparison with similar radiographs in the third year of life.
• Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
• Pulmonary radiographs to monitor interstitial lung disease in any serious lower respiratory infection. Chest CT may better show fibrotic changes in the lungs. It is doubtful that the child with ML II can cooperate sufficiently to achieve reliable pulmonary function tests, by which restrictive respiratory deficiency could be documented more objectively.
• Feeding problems concern parents as the affected child consumes fewer calories than expected. Poor suck, which may contribute to feeding difficulties early on, generally resolves quickly. Caloric need is less than that of an unaffected sib.
• Baseline ophthalmologic examination in a neonate with ML II is useful, but significant visual impairment is not a usual issue. An ophthalmologic evaluation between six and 12 months is recommended: Slit lamp examination will reveal corneal haziness, apparently without clinical implication; fundoscopic examination will show no specific retinal abnormalities.
• Hearing screen for conductive hearing loss secondary to recurrent otitis media. Hearing may be normal during the first year, but should be checked at least once after age six months. In the second year, some conductive hearing loss may be present, even without – but certainly following – upper airway infections.
• Developmental assessment to help establish appropriate expectations for the child’s developmental progress
• Consultation with a clinical geneticist and/or genetic counselor
• Radiographic skeletal survey if either not performed or incomplete in the diagnostic evaluation
• Baseline evaluations with an orthopedic surgeon and a metabolic bone specialist to better determine if/when surgical interventions or bisphosphonate therapy may be initiated (See
• Gentle physical and occupational therapy to maintain mobility and strength. Aggressive therapy can cause further joint damage.
• Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
• Baseline ophthalmologic examination
• Hearing screen for evidence of conductive hearing loss secondary to recurrent otitis media
• Baseline developmental assessment
• Consultation with a clinical geneticist and/or genetic counselor
• Stretching exercises are ineffective and painful.
• The unknowing therapist may cause damage to the surrounding joint capsule and adjacent tendons with subsequent soft tissue calcification.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with a
Radiographic skeletal survey, if not performed or incomplete in the diagnostic evaluation. Such survey in early infancy is important for comparison with similar radiographs in the third year of life.
Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
Pulmonary radiographs to monitor interstitial lung disease in any serious lower respiratory infection. Chest CT may better show fibrotic changes in the lungs. It is doubtful that the child with ML II can cooperate sufficiently to achieve reliable pulmonary function tests, by which restrictive respiratory deficiency could be documented more objectively.
Feeding problems concern parents as the affected child consumes fewer calories than expected. Poor suck, which may contribute to feeding difficulties early on, generally resolves quickly. Caloric need is less than that of an unaffected sib.
Baseline ophthalmologic examination in a neonate with ML II is useful, but significant visual impairment is not a usual issue. An ophthalmologic evaluation between six and 12 months is recommended: Slit lamp examination will reveal corneal haziness, apparently without clinical implication; fundoscopic examination will show no specific retinal abnormalities.
Hearing screen for conductive hearing loss secondary to recurrent otitis media. Hearing may be normal during the first year, but should be checked at least once after age six months. In the second year, some conductive hearing loss may be present, even without – but certainly following – upper airway infections.
Developmental assessment to help establish appropriate expectations for the child’s developmental progress
Consultation with a clinical geneticist and/or genetic counselor
Radiographic skeletal survey if either not performed or incomplete in the diagnostic evaluation
Baseline evaluations with an orthopedic surgeon and a metabolic bone specialist to better determine if/when surgical interventions or bisphosphonate therapy may be initiated (See
Gentle physical and occupational therapy to maintain mobility and strength. Aggressive therapy can cause further joint damage.
Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
Baseline ophthalmologic examination
Hearing screen for evidence of conductive hearing loss secondary to recurrent otitis media
Baseline developmental assessment
Consultation with a clinical geneticist and/or genetic counselor
• Radiographic skeletal survey, if not performed or incomplete in the diagnostic evaluation. Such survey in early infancy is important for comparison with similar radiographs in the third year of life.
• Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
• Pulmonary radiographs to monitor interstitial lung disease in any serious lower respiratory infection. Chest CT may better show fibrotic changes in the lungs. It is doubtful that the child with ML II can cooperate sufficiently to achieve reliable pulmonary function tests, by which restrictive respiratory deficiency could be documented more objectively.
• Feeding problems concern parents as the affected child consumes fewer calories than expected. Poor suck, which may contribute to feeding difficulties early on, generally resolves quickly. Caloric need is less than that of an unaffected sib.
• Baseline ophthalmologic examination in a neonate with ML II is useful, but significant visual impairment is not a usual issue. An ophthalmologic evaluation between six and 12 months is recommended: Slit lamp examination will reveal corneal haziness, apparently without clinical implication; fundoscopic examination will show no specific retinal abnormalities.
• Hearing screen for conductive hearing loss secondary to recurrent otitis media. Hearing may be normal during the first year, but should be checked at least once after age six months. In the second year, some conductive hearing loss may be present, even without – but certainly following – upper airway infections.
• Developmental assessment to help establish appropriate expectations for the child’s developmental progress
• Consultation with a clinical geneticist and/or genetic counselor
• Radiographic skeletal survey if either not performed or incomplete in the diagnostic evaluation
• Baseline evaluations with an orthopedic surgeon and a metabolic bone specialist to better determine if/when surgical interventions or bisphosphonate therapy may be initiated (See
• Gentle physical and occupational therapy to maintain mobility and strength. Aggressive therapy can cause further joint damage.
• Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
• Baseline ophthalmologic examination
• Hearing screen for evidence of conductive hearing loss secondary to recurrent otitis media
• Baseline developmental assessment
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Supportive and symptomatic management is indicated.
Stretching exercises are ineffective and painful.
The unknowing therapist may cause damage to the surrounding joint capsule and adjacent tendons with subsequent soft tissue calcification.
Therapies that are "low impact" concerning joint and tendon strain, including short sessions of aqua therapy, are usually well tolerated. Instead of exercises of passive motion, often the child can be motivated to imitate active motion in joints despite the inherent limited range of motion.
Supportive and symptomatic management is indicated.
Management of pain in the hips during and following walking requires attention from late childhood or early adolescence.
Carpal tunnel signs may require tendon release procedures for at least temporary relief. The procedure is repeated several time in some individuals.
Later in the disease course more general bone pain of variable intensity, unrelated to physical exercise or motion, is present.
Bisphosphonates decrease osteoclastic activity; when on therapy, some (but not all) individuals with ML IIIα/β experience decreased pain and associated increased mobility. Bone densitometry is improved in affected individuals and in animal models [
Bilateral hip replacement has been successful in older adolescents and adults with milder ML IIIα/β [
• Stretching exercises are ineffective and painful.
• The unknowing therapist may cause damage to the surrounding joint capsule and adjacent tendons with subsequent soft tissue calcification.
## Mucolipidosis II
Supportive and symptomatic management is indicated.
Stretching exercises are ineffective and painful.
The unknowing therapist may cause damage to the surrounding joint capsule and adjacent tendons with subsequent soft tissue calcification.
Therapies that are "low impact" concerning joint and tendon strain, including short sessions of aqua therapy, are usually well tolerated. Instead of exercises of passive motion, often the child can be motivated to imitate active motion in joints despite the inherent limited range of motion.
• Stretching exercises are ineffective and painful.
• The unknowing therapist may cause damage to the surrounding joint capsule and adjacent tendons with subsequent soft tissue calcification.
## Mucolipidosis IIIα/β
Supportive and symptomatic management is indicated.
Management of pain in the hips during and following walking requires attention from late childhood or early adolescence.
Carpal tunnel signs may require tendon release procedures for at least temporary relief. The procedure is repeated several time in some individuals.
Later in the disease course more general bone pain of variable intensity, unrelated to physical exercise or motion, is present.
Bisphosphonates decrease osteoclastic activity; when on therapy, some (but not all) individuals with ML IIIα/β experience decreased pain and associated increased mobility. Bone densitometry is improved in affected individuals and in animal models [
Bilateral hip replacement has been successful in older adolescents and adults with milder ML IIIα/β [
## Surveillance
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with ML II do not reproduce.
Individuals with ML IIIα/β do not commonly reproduce but fertility is not known to be impaired.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with ML II do not reproduce.
• Individuals with ML IIIα/β do not commonly reproduce but fertility is not known to be impaired.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with ML II do not reproduce.
Individuals with ML IIIα/β do not commonly reproduce but fertility is not known to be impaired.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with ML II do not reproduce.
• Individuals with ML IIIα/β do not commonly reproduce but fertility is not known to be impaired.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
No specific resources for
## Molecular Genetics
GNPTAB-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GNPTAB-Related Disorders (
Click
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Click
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
29 August 2019 (bp) Comprehensive update posted live; this update combines
10 May 2012 (me) Comprehensive update posted live
26 August 2008 (cg) Review posted live
16 June 2008 (jgl) Original submission
• 29 August 2019 (bp) Comprehensive update posted live; this update combines
• 10 May 2012 (me) Comprehensive update posted live
• 26 August 2008 (cg) Review posted live
• 16 June 2008 (jgl) Original submission
## Revision History
29 August 2019 (bp) Comprehensive update posted live; this update combines
10 May 2012 (me) Comprehensive update posted live
26 August 2008 (cg) Review posted live
16 June 2008 (jgl) Original submission
• 29 August 2019 (bp) Comprehensive update posted live; this update combines
• 10 May 2012 (me) Comprehensive update posted live
• 26 August 2008 (cg) Review posted live
• 16 June 2008 (jgl) Original submission
## References
## Literature Cited
Female age three years with ML II
Female age 19 years with ML IIIα/β
Phase-contrast microscopic view of "I-cells" in culture
Living culture of skin fibroblasts derived from a person with ML IIIα/β viewed by contrast light microscope. The cytoplasm is filled with dense granular inclusions that consistently spare a juxtanuclear zone that represents the endoplasmic reticulum and the Golgi apparatus. Electron microscopic study shows that the inclusions are swollen lysosomes bound by a unit membrane and filled with heterogeneous material of varying texture, shape, and electron density. The fibroblasts were originally called inclusion cells (I-cells) and the disorder associated with this in vitro phenotype "I-cell disease." No morphologic differences are observed between fibroblasts derived from an individual with ML II and an individual with ML IIIα/β.
|
[] |
26/8/2008
|
29/8/2019
|
7/7/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
ml3a
|
ml3a
|
[
"Mucolipidosis IIIA",
"Pseudo-Hurler Polydystrophy",
"Pseudo-Hurler Polydystrophy",
"N-acetylglucosamine-1-phosphotransferase subunits alpha/beta",
"GNPTAB",
"Mucolipidosis III Alpha/Beta"
] |
Mucolipidosis III Alpha/Beta – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Jules G Leroy, Sara S Cathey, Michael J Friez
|
Summary Mucolipidosis alpha/beta (ML III alpha/beta; pseudo-Hurler polydystrophy), a slowly progressive disorder with clinical onset at approximately age three years, is characterized by slow growth rate and subnormal stature; radiographic evidence of mild to moderate dysostosis multiplex; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. If present, organomegaly is mild. Pain from osteoporosis that is clinically and radiologically apparent in childhood becomes more severe from adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. In ML III alpha/beta the activity of nearly all lysosomal hydrolases is up to tenfold higher in plasma and other body fluids than in normal controls because of inadequate targeting to lysosomes. Urinary excretion of oligosaccharides (OSs), a nonspecific finding, is often excessive. Significant deficiency (1%-10% of normal) of the activity of the enzyme UDP- ML III alpha/beta is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
|
## Diagnosis
The following clinical features contribute to early diagnosis of mucolipidosis III alpha/beta (ML III alpha/beta) [
Average age at which features are recognized as distinctive: three years (range: late infancy to late childhood)
Slow growth rate that gradually decreases
Frequent upper respiratory infection and/or otitis media (variably present)
Joint stiffness initially in the shoulders, hips, and fingers
Joint pain that is exacerbated by strenuous exercise or physical therapy
Gradual mild coarsening of facial features
Slight corneal cloudiness, noticeable only by slit-lamp examination (variably present)
Absent to mild organomegaly
Inconsistently, mild to moderate kyphoscoliosis
Normal to mildly impaired cognitive development
Osteoporosis associated with pain; clinically and radiologically apparent in childhood and more adversely affecting gait and range of motion in large joints in older individuals
In infancy and early childhood skeletal radiographs reveal mild to moderate dysostosis multiplex [
In late childhood or adolescence skeletal radiographs reveal the following:
The following lysosomal hydrolases are of most interest as their increased activity is relevant in the
β-D-hexosaminidase (EC 3.2.1.52)
β-D-glucuronidase (EC 3.2.1.31)
β-D-galactosidase (EC 3.2.1.23)
α-D-mannosidase (EC 3.2.1.24)
Note: The acid hydrolases are improperly targeted to the lysosomes but not quantitatively deficient in leukocytes in ML III alpha/beta. In contrast to storage disorders resulting from deficiency of a single lysosomal enzyme, ML III alpha/beta cannot be diagnosed by assay of acid hydrolases in leukocytes.
Molecular Genetic Testing Used in Mucolipidosis III Alpha/Beta
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Bidirectional sequencing of the entire
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
Variant detection rate is unknown and may be very low.
Identification of characteristic clinical and radiographic findings
Assay of oligosaccharides (OS)
Assay of several acid hydrolases
β-D-hexosaminidase (EC 3.2.1.52)
β-D-glucuronidase (EC 3.2.1.31)
β-D-galactosidase (EC 3.2.1.23)
α-D-mannosidase (EC 3.2.1.24)
Arylsulfatase A (EC 3.1.6.1)
Note: (1) In ML III, specific activity of lysosomal enzymes is elevated in plasma, deficient in fibroblasts, and normal in leukocytes. (2) The specific activity of lysosomal hydrolytic enzymes in leukocytes is useful in the differential diagnosis of other late-onset lysosomal disorders but is of no value in the diagnosis of ML III alpha/beta itself.
Sequence analysis of
Deletion/duplication analysis of
Only one clearly pathogenic alteration can be identified by sequencing in a proband who has been clinically/biochemically diagnosed; OR
A proband appears homozygous for a pathogenic alteration but only one parent is identified to be a carrier of the alteration.
Note: Assessment of enzyme activity cannot reliably identify heterozygous individuals.
• Average age at which features are recognized as distinctive: three years (range: late infancy to late childhood)
• Slow growth rate that gradually decreases
• Frequent upper respiratory infection and/or otitis media (variably present)
• Joint stiffness initially in the shoulders, hips, and fingers
• Joint pain that is exacerbated by strenuous exercise or physical therapy
• Gradual mild coarsening of facial features
• Slight corneal cloudiness, noticeable only by slit-lamp examination (variably present)
• Absent to mild organomegaly
• Inconsistently, mild to moderate kyphoscoliosis
• Normal to mildly impaired cognitive development
• Osteoporosis associated with pain; clinically and radiologically apparent in childhood and more adversely affecting gait and range of motion in large joints in older individuals
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
• Identification of characteristic clinical and radiographic findings
• Assay of oligosaccharides (OS)
• Assay of several acid hydrolases
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
• Arylsulfatase A (EC 3.1.6.1)
• Note: (1) In ML III, specific activity of lysosomal enzymes is elevated in plasma, deficient in fibroblasts, and normal in leukocytes. (2) The specific activity of lysosomal hydrolytic enzymes in leukocytes is useful in the differential diagnosis of other late-onset lysosomal disorders but is of no value in the diagnosis of ML III alpha/beta itself.
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
• Arylsulfatase A (EC 3.1.6.1)
• Sequence analysis of
• Deletion/duplication analysis of
• Only one clearly pathogenic alteration can be identified by sequencing in a proband who has been clinically/biochemically diagnosed; OR
• A proband appears homozygous for a pathogenic alteration but only one parent is identified to be a carrier of the alteration.
• Only one clearly pathogenic alteration can be identified by sequencing in a proband who has been clinically/biochemically diagnosed; OR
• A proband appears homozygous for a pathogenic alteration but only one parent is identified to be a carrier of the alteration.
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
• Arylsulfatase A (EC 3.1.6.1)
• Only one clearly pathogenic alteration can be identified by sequencing in a proband who has been clinically/biochemically diagnosed; OR
• A proband appears homozygous for a pathogenic alteration but only one parent is identified to be a carrier of the alteration.
## Clinical Diagnosis
The following clinical features contribute to early diagnosis of mucolipidosis III alpha/beta (ML III alpha/beta) [
Average age at which features are recognized as distinctive: three years (range: late infancy to late childhood)
Slow growth rate that gradually decreases
Frequent upper respiratory infection and/or otitis media (variably present)
Joint stiffness initially in the shoulders, hips, and fingers
Joint pain that is exacerbated by strenuous exercise or physical therapy
Gradual mild coarsening of facial features
Slight corneal cloudiness, noticeable only by slit-lamp examination (variably present)
Absent to mild organomegaly
Inconsistently, mild to moderate kyphoscoliosis
Normal to mildly impaired cognitive development
Osteoporosis associated with pain; clinically and radiologically apparent in childhood and more adversely affecting gait and range of motion in large joints in older individuals
In infancy and early childhood skeletal radiographs reveal mild to moderate dysostosis multiplex [
In late childhood or adolescence skeletal radiographs reveal the following:
• Average age at which features are recognized as distinctive: three years (range: late infancy to late childhood)
• Slow growth rate that gradually decreases
• Frequent upper respiratory infection and/or otitis media (variably present)
• Joint stiffness initially in the shoulders, hips, and fingers
• Joint pain that is exacerbated by strenuous exercise or physical therapy
• Gradual mild coarsening of facial features
• Slight corneal cloudiness, noticeable only by slit-lamp examination (variably present)
• Absent to mild organomegaly
• Inconsistently, mild to moderate kyphoscoliosis
• Normal to mildly impaired cognitive development
• Osteoporosis associated with pain; clinically and radiologically apparent in childhood and more adversely affecting gait and range of motion in large joints in older individuals
## Testing
The following lysosomal hydrolases are of most interest as their increased activity is relevant in the
β-D-hexosaminidase (EC 3.2.1.52)
β-D-glucuronidase (EC 3.2.1.31)
β-D-galactosidase (EC 3.2.1.23)
α-D-mannosidase (EC 3.2.1.24)
Note: The acid hydrolases are improperly targeted to the lysosomes but not quantitatively deficient in leukocytes in ML III alpha/beta. In contrast to storage disorders resulting from deficiency of a single lysosomal enzyme, ML III alpha/beta cannot be diagnosed by assay of acid hydrolases in leukocytes.
Molecular Genetic Testing Used in Mucolipidosis III Alpha/Beta
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Bidirectional sequencing of the entire
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
Variant detection rate is unknown and may be very low.
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
## Biochemical Testing
The following lysosomal hydrolases are of most interest as their increased activity is relevant in the
β-D-hexosaminidase (EC 3.2.1.52)
β-D-glucuronidase (EC 3.2.1.31)
β-D-galactosidase (EC 3.2.1.23)
α-D-mannosidase (EC 3.2.1.24)
Note: The acid hydrolases are improperly targeted to the lysosomes but not quantitatively deficient in leukocytes in ML III alpha/beta. In contrast to storage disorders resulting from deficiency of a single lysosomal enzyme, ML III alpha/beta cannot be diagnosed by assay of acid hydrolases in leukocytes.
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
## Molecular Genetic Testing
Molecular Genetic Testing Used in Mucolipidosis III Alpha/Beta
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Bidirectional sequencing of the entire
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
Variant detection rate is unknown and may be very low.
## Testing Strategy
Identification of characteristic clinical and radiographic findings
Assay of oligosaccharides (OS)
Assay of several acid hydrolases
β-D-hexosaminidase (EC 3.2.1.52)
β-D-glucuronidase (EC 3.2.1.31)
β-D-galactosidase (EC 3.2.1.23)
α-D-mannosidase (EC 3.2.1.24)
Arylsulfatase A (EC 3.1.6.1)
Note: (1) In ML III, specific activity of lysosomal enzymes is elevated in plasma, deficient in fibroblasts, and normal in leukocytes. (2) The specific activity of lysosomal hydrolytic enzymes in leukocytes is useful in the differential diagnosis of other late-onset lysosomal disorders but is of no value in the diagnosis of ML III alpha/beta itself.
Sequence analysis of
Deletion/duplication analysis of
Only one clearly pathogenic alteration can be identified by sequencing in a proband who has been clinically/biochemically diagnosed; OR
A proband appears homozygous for a pathogenic alteration but only one parent is identified to be a carrier of the alteration.
Note: Assessment of enzyme activity cannot reliably identify heterozygous individuals.
• Identification of characteristic clinical and radiographic findings
• Assay of oligosaccharides (OS)
• Assay of several acid hydrolases
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
• Arylsulfatase A (EC 3.1.6.1)
• Note: (1) In ML III, specific activity of lysosomal enzymes is elevated in plasma, deficient in fibroblasts, and normal in leukocytes. (2) The specific activity of lysosomal hydrolytic enzymes in leukocytes is useful in the differential diagnosis of other late-onset lysosomal disorders but is of no value in the diagnosis of ML III alpha/beta itself.
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
• Arylsulfatase A (EC 3.1.6.1)
• Sequence analysis of
• Deletion/duplication analysis of
• Only one clearly pathogenic alteration can be identified by sequencing in a proband who has been clinically/biochemically diagnosed; OR
• A proband appears homozygous for a pathogenic alteration but only one parent is identified to be a carrier of the alteration.
• Only one clearly pathogenic alteration can be identified by sequencing in a proband who has been clinically/biochemically diagnosed; OR
• A proband appears homozygous for a pathogenic alteration but only one parent is identified to be a carrier of the alteration.
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
• Arylsulfatase A (EC 3.1.6.1)
• Only one clearly pathogenic alteration can be identified by sequencing in a proband who has been clinically/biochemically diagnosed; OR
• A proband appears homozygous for a pathogenic alteration but only one parent is identified to be a carrier of the alteration.
## Clinical Characteristics
Mucolipidosis III alpha/beta (ML III alpha/beta; pseudo-Hurler polydystrophy) is a slowly progressive inborn error of metabolism with clinical onset at approximately age three years and fatal outcome in early to middle adulthood [
Adults exhibit restrictive lung disease caused by stiffening of the thoracic cage, slowly progressive sclerosis of bronchi, and hardening and thickening of the interstitial tissue (extracellular matrix) in lung parenchyma.
Left and/or right ventricular hypertrophy is often documented on echocardiography in older individuals. Pulmonary hypertension may occur in some older individuals, but at present is still insufficiently documented.
Rapid progression of cardiac disease is rarely observed in ML III alpha/beta.
Pneumonia may compound mild cardiac insufficiency. Death in early adulthood is often from cardiopulmonary causes, even without complicating factors such as pneumonia.
Limited range of motion in the hips and knees explains the slow gait and inability of children to run effectively. Flexion contractures in the hips and knees cause the squatting standing posture, most apparent in lateral view (see
Secondary but severe arthritic changes in the hips that can lead to destruction of the proximal femoral epiphyses make walking increasingly difficult and painful. Significant hardening of the surrounding soft tissues contributes to hip dysfunction. Many affected individuals become wheelchair bound before or during early adulthood.
Range of motion in the wrists and ankles is less adversely affected, than in the other large joints. Dupuytren-type palmar contractures may appear from late childhood onward and exacerbate the moderate to severe claw-like flexion deformity of the fingers associated with recurrent swelling and progressive stiffness. Neuropathic carpal tunnel signs can become severe in some individuals.
In ML III alpha/beta the hands and fingers are usually of near-normal length in contrast to the severely affected hands in ML II.
Before the appropriate diagnosis is made, many individuals with ML III alpha/beta have been evaluated for a rheumatologic disorder.
Osteoporosis affects the entire skeleton. Bone pain becomes the most distressing symptom in Ml III alpha/beta, even in individuals with limited ambulation. Osteolytic bone lesions also are associated with significant bone pain in those who are non-ambulatory.
Note: On electron microscopy (EM) the mesenchymal cells in any tissue reveal large numbers of cytoplasmic vacuoles comprising swollen lysosomes bound by a unit membrane. The contents are pleomorphic, but not dense. This phenomenon is specific to ML II and ML III alpha/beta and is not observed in any lysosomal storage disorder.
The activity of lysosomal enzymes is severely reduced in I-cells, but significantly increased in the corresponding culture media.
The cytologic and enzymatic findings in cell culture cannot distinguish between ML II (I-cell disease) and ML III alpha/beta (see
Clearly, some children have phenotypes clinically intermediate between the reference phenotypes delineated ML II and ML III alpha/beta [
At present it is not known whether the interesting but rarely available post-mortem pathology studies in ML III alpha/beta [
Although mucolipidosis is a clinically useful name, biochemists consider it a misnomer because "mucolipids" do not exist in nature. The term mucolipidosis has been used in four different inborn errors of metabolism; only ML II and ML III alpha/beta are
The enzyme GNPT is the product of two genes, one encoding the alpha and beta subunits, and the other encoding the gamma subunit [
Pathogenic variants in
Pathogenic variants in
Estimates of the prevalence of ML III alpha/beta based on objective data are not available. It is, however, likely that the prevalence is of the same order of magnitude as that of ML II and hence estimated to range between 2.5x10
Consequently, the carrier rate is estimated at between 1:158 and 1:316 (see
• Pathogenic variants in
• Pathogenic variants in
## Clinical Description
Mucolipidosis III alpha/beta (ML III alpha/beta; pseudo-Hurler polydystrophy) is a slowly progressive inborn error of metabolism with clinical onset at approximately age three years and fatal outcome in early to middle adulthood [
Adults exhibit restrictive lung disease caused by stiffening of the thoracic cage, slowly progressive sclerosis of bronchi, and hardening and thickening of the interstitial tissue (extracellular matrix) in lung parenchyma.
Left and/or right ventricular hypertrophy is often documented on echocardiography in older individuals. Pulmonary hypertension may occur in some older individuals, but at present is still insufficiently documented.
Rapid progression of cardiac disease is rarely observed in ML III alpha/beta.
Pneumonia may compound mild cardiac insufficiency. Death in early adulthood is often from cardiopulmonary causes, even without complicating factors such as pneumonia.
Limited range of motion in the hips and knees explains the slow gait and inability of children to run effectively. Flexion contractures in the hips and knees cause the squatting standing posture, most apparent in lateral view (see
Secondary but severe arthritic changes in the hips that can lead to destruction of the proximal femoral epiphyses make walking increasingly difficult and painful. Significant hardening of the surrounding soft tissues contributes to hip dysfunction. Many affected individuals become wheelchair bound before or during early adulthood.
Range of motion in the wrists and ankles is less adversely affected, than in the other large joints. Dupuytren-type palmar contractures may appear from late childhood onward and exacerbate the moderate to severe claw-like flexion deformity of the fingers associated with recurrent swelling and progressive stiffness. Neuropathic carpal tunnel signs can become severe in some individuals.
In ML III alpha/beta the hands and fingers are usually of near-normal length in contrast to the severely affected hands in ML II.
Before the appropriate diagnosis is made, many individuals with ML III alpha/beta have been evaluated for a rheumatologic disorder.
Osteoporosis affects the entire skeleton. Bone pain becomes the most distressing symptom in Ml III alpha/beta, even in individuals with limited ambulation. Osteolytic bone lesions also are associated with significant bone pain in those who are non-ambulatory.
Note: On electron microscopy (EM) the mesenchymal cells in any tissue reveal large numbers of cytoplasmic vacuoles comprising swollen lysosomes bound by a unit membrane. The contents are pleomorphic, but not dense. This phenomenon is specific to ML II and ML III alpha/beta and is not observed in any lysosomal storage disorder.
The activity of lysosomal enzymes is severely reduced in I-cells, but significantly increased in the corresponding culture media.
The cytologic and enzymatic findings in cell culture cannot distinguish between ML II (I-cell disease) and ML III alpha/beta (see
## Genotype-Phenotype Correlations
Clearly, some children have phenotypes clinically intermediate between the reference phenotypes delineated ML II and ML III alpha/beta [
At present it is not known whether the interesting but rarely available post-mortem pathology studies in ML III alpha/beta [
## Nomenclature
Although mucolipidosis is a clinically useful name, biochemists consider it a misnomer because "mucolipids" do not exist in nature. The term mucolipidosis has been used in four different inborn errors of metabolism; only ML II and ML III alpha/beta are
The enzyme GNPT is the product of two genes, one encoding the alpha and beta subunits, and the other encoding the gamma subunit [
Pathogenic variants in
Pathogenic variants in
• Pathogenic variants in
• Pathogenic variants in
## Prevalence
Estimates of the prevalence of ML III alpha/beta based on objective data are not available. It is, however, likely that the prevalence is of the same order of magnitude as that of ML II and hence estimated to range between 2.5x10
Consequently, the carrier rate is estimated at between 1:158 and 1:316 (see
## Genetically Related (Allelic) Disorders
The clinical phenotypes of the disorders caused by pathogenic variants in
Note:
## Differential Diagnosis
See
Attenuated
Attenuated
Morquio disease type B (
Maroteaux-Lamy disease type B (MPS VI B)
Sly disease type B (MPS VII B)
While sharing several clinical aspects of dysostosis multiplex, the entities mentioned are associated with evidence of more severe storage on physical examination. In all the MPSs, the size of the head is enlarged, a finding not present in ML III alpha/beta. Biochemical testing distinguishes the MPSs.
Among the group of
Autosomal dominant precocious osteoarthrosis, a late-manifesting type II collagenopathy; genetically heterogeneous
Progressive pseudorheumatoid chondrodysplasia; autosomal recessive
Multiple epiphyseal dysplasia (see
• Attenuated
• Attenuated
• Morquio disease type B (
• Maroteaux-Lamy disease type B (MPS VI B)
• Sly disease type B (MPS VII B)
• Autosomal dominant precocious osteoarthrosis, a late-manifesting type II collagenopathy; genetically heterogeneous
• Progressive pseudorheumatoid chondrodysplasia; autosomal recessive
• Multiple epiphyseal dysplasia (see
## Management
To establish the extent of disease in an individual diagnosed with mucolipidosis III alpha/beta (ML III alpha/beta), the following evaluations are recommended:
Radiographic skeletal survey if either not performed or incomplete in the diagnostic evaluation
Baseline evaluations with an orthopedic surgeon and a metabolic bone specialist to better determine if/when surgical interventions or bisphosphonate therapy may be initiated (see
Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
Baseline ophthalmologic examination
Hearing screen
Developmental assessment to help establish appropriate expectations for the child’s developmental progress
Consultation with a clinical geneticist and/or genetic counselor
Supportive and symptomatic management is indicated.
Stretching exercises are ineffective and painful.
The unknowing therapist may inflict damage to the surrounding joint capsule and adjacent tendons and cause subsequent soft tissue calcification.
Therapies that are "low impact" in regard to joint and tendon strain, including short sessions of aqua therapy, are usually well tolerated.
Management of pain in the hips during and following walking requires attention from late childhood or early adolescence.
Carpal tunnel signs may require tendon release procedures for temporary relief.
Later in the disease course more general bone pain of variable intensity is present.
Encouraging results have been obtained in several individuals with ML III alpha/beta with monthly IV administration of pamidronate, a biphosphonate. The recommended dose is 1 mg/kg monthly. The protocol under development is different from that applied to individuals with
Several remarks need to be made regarding this symptomatic treatment:
Parents and affected individuals must keep in mind that this treatment does not cure the disorder. It neither represses the slow process of bone resorption nor alters its course.
The long-term effect(s) are unknown.
The end point to the treatment regimen remains incompletely defined [
Not all affected individuals benefit from bisphosphonate treatment. The use of bisphosphonates in ML III alpha/beta and other bone diseases is an area of active clinical research worldwide.
In older adolescents and adults with milder phenotypic variants of ML III alpha/beta, bilateral hip replacement has been successful.
Because of concerns about airway management, surgical intervention should be avoided as much as possible and undertaken only in tertiary care settings with pediatric anesthesiologists and intensivists. Individuals with ML III alpha/beta are small and have a narrow airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a much smaller endotracheal tube than for age- and size-matched controls is necessary. Fiberoptic intubation must be available.
Poor compliance of the thoracic cage and the progressively sclerotic lung parenchyma further complicate airway management, especially in older individuals. Functional decline of lung parenchyma is likely due at least in part to slowly progressive degeneration of soft connective tissue in the extracellular matrix, a phenomenon insufficiently studied but concomitant to the osteopenia in bone. As subclinical cardiac failure may become overt during anesthesia, any surgical intervention should be preceded by a thorough cardiologic evaluation Extubation may also be a challenge.
Young children with ML III alpha/beta and their families benefit from outpatient clinic visits about twice a year.
From age six years similar follow-up visits are recommended on a yearly basis unless bone pain and deteriorating ambulation become major handicaps and/or cardiac and respiratory monitoring need more frequent attention.
See
Preliminary results suggest that IV bisphosphonate may alleviate bone pain in some affected individuals; however, such treatment is still considered investigational.
Search
• Radiographic skeletal survey if either not performed or incomplete in the diagnostic evaluation
• Baseline evaluations with an orthopedic surgeon and a metabolic bone specialist to better determine if/when surgical interventions or bisphosphonate therapy may be initiated (see
• Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
• Baseline ophthalmologic examination
• Hearing screen
• Developmental assessment to help establish appropriate expectations for the child’s developmental progress
• Consultation with a clinical geneticist and/or genetic counselor
• Stretching exercises are ineffective and painful.
• The unknowing therapist may inflict damage to the surrounding joint capsule and adjacent tendons and cause subsequent soft tissue calcification.
• Parents and affected individuals must keep in mind that this treatment does not cure the disorder. It neither represses the slow process of bone resorption nor alters its course.
• The long-term effect(s) are unknown.
• The end point to the treatment regimen remains incompletely defined [
• Not all affected individuals benefit from bisphosphonate treatment. The use of bisphosphonates in ML III alpha/beta and other bone diseases is an area of active clinical research worldwide.
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with mucolipidosis III alpha/beta (ML III alpha/beta), the following evaluations are recommended:
Radiographic skeletal survey if either not performed or incomplete in the diagnostic evaluation
Baseline evaluations with an orthopedic surgeon and a metabolic bone specialist to better determine if/when surgical interventions or bisphosphonate therapy may be initiated (see
Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
Baseline ophthalmologic examination
Hearing screen
Developmental assessment to help establish appropriate expectations for the child’s developmental progress
Consultation with a clinical geneticist and/or genetic counselor
• Radiographic skeletal survey if either not performed or incomplete in the diagnostic evaluation
• Baseline evaluations with an orthopedic surgeon and a metabolic bone specialist to better determine if/when surgical interventions or bisphosphonate therapy may be initiated (see
• Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
• Baseline ophthalmologic examination
• Hearing screen
• Developmental assessment to help establish appropriate expectations for the child’s developmental progress
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Supportive and symptomatic management is indicated.
Stretching exercises are ineffective and painful.
The unknowing therapist may inflict damage to the surrounding joint capsule and adjacent tendons and cause subsequent soft tissue calcification.
Therapies that are "low impact" in regard to joint and tendon strain, including short sessions of aqua therapy, are usually well tolerated.
Management of pain in the hips during and following walking requires attention from late childhood or early adolescence.
Carpal tunnel signs may require tendon release procedures for temporary relief.
Later in the disease course more general bone pain of variable intensity is present.
Encouraging results have been obtained in several individuals with ML III alpha/beta with monthly IV administration of pamidronate, a biphosphonate. The recommended dose is 1 mg/kg monthly. The protocol under development is different from that applied to individuals with
Several remarks need to be made regarding this symptomatic treatment:
Parents and affected individuals must keep in mind that this treatment does not cure the disorder. It neither represses the slow process of bone resorption nor alters its course.
The long-term effect(s) are unknown.
The end point to the treatment regimen remains incompletely defined [
Not all affected individuals benefit from bisphosphonate treatment. The use of bisphosphonates in ML III alpha/beta and other bone diseases is an area of active clinical research worldwide.
In older adolescents and adults with milder phenotypic variants of ML III alpha/beta, bilateral hip replacement has been successful.
• Stretching exercises are ineffective and painful.
• The unknowing therapist may inflict damage to the surrounding joint capsule and adjacent tendons and cause subsequent soft tissue calcification.
• Parents and affected individuals must keep in mind that this treatment does not cure the disorder. It neither represses the slow process of bone resorption nor alters its course.
• The long-term effect(s) are unknown.
• The end point to the treatment regimen remains incompletely defined [
• Not all affected individuals benefit from bisphosphonate treatment. The use of bisphosphonates in ML III alpha/beta and other bone diseases is an area of active clinical research worldwide.
## Prevention of Secondary Complications
Because of concerns about airway management, surgical intervention should be avoided as much as possible and undertaken only in tertiary care settings with pediatric anesthesiologists and intensivists. Individuals with ML III alpha/beta are small and have a narrow airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a much smaller endotracheal tube than for age- and size-matched controls is necessary. Fiberoptic intubation must be available.
Poor compliance of the thoracic cage and the progressively sclerotic lung parenchyma further complicate airway management, especially in older individuals. Functional decline of lung parenchyma is likely due at least in part to slowly progressive degeneration of soft connective tissue in the extracellular matrix, a phenomenon insufficiently studied but concomitant to the osteopenia in bone. As subclinical cardiac failure may become overt during anesthesia, any surgical intervention should be preceded by a thorough cardiologic evaluation Extubation may also be a challenge.
## Surveillance
Young children with ML III alpha/beta and their families benefit from outpatient clinic visits about twice a year.
From age six years similar follow-up visits are recommended on a yearly basis unless bone pain and deteriorating ambulation become major handicaps and/or cardiac and respiratory monitoring need more frequent attention.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Preliminary results suggest that IV bisphosphonate may alleviate bone pain in some affected individuals; however, such treatment is still considered investigational.
Search
## Genetic Counseling
Mucolipidosis III alpha/beta (ML III alpha/beta) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
• The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Mucolipidosis III alpha/beta (ML III alpha/beta) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
• The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
## Carrier (Heterozygote) Detection
Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Diagnosis
Once the
## Resources
3921 Country Club Drive
Lakewood CA 90712
PO Box 14686
Durham NC 27709-4686
MPS House Repton Place
White Lion Road
Amersham Buckinghamshire HP7 9LP
United Kingdom
•
• 3921 Country Club Drive
• Lakewood CA 90712
•
•
• PO Box 14686
• Durham NC 27709-4686
•
•
• MPS House Repton Place
• White Lion Road
• Amersham Buckinghamshire HP7 9LP
• United Kingdom
•
## Molecular Genetics
Mucolipidosis III Alpha/Beta: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Mucolipidosis III Alpha/Beta (
The partial inactivation of UDP-
N-linked glycosylation of lysosomal hydrolases occurs in the endocytoplasmic reticulum, which is also the site of the preceding stepwise build-up of OSs and of their "en bloc" transfer from the dolicholpyrophosphoryl-OS-precursor carrier to some of the asparagine residues in the nascent hydrolase proteins.
As the newly formed glycoproteins traverse the Golgi cisterns, sequential enzymatic modification of the N-linked OSs occurs along two different pathways: one pathway modifies the N-linked OSs into complex type glycan side chains, whereas the other, quantitatively the more important pathway at least in mesenchymal tissues, converts the precursor glycans into oligomannosyl-type OS side chains. Specific phosphorylation alone is adversely affected by biallelic inactivating
Normal formation of the M6P recognition marker is a two-step process. The first step is catalyzed by UDP-
Following its translation this alpha/beta precursor polypeptide undergoes proteolytic cleavage at the lysine (residue 928) - asparagine (residue 929) peptide bond. This bond is enzymatically released by site-1 protease (S1P). Cells deficient in S1P failed to activate the alpha/beta precursor and exhibited the I-cell phenotype in vitro [
## Molecular Pathogenesis
The partial inactivation of UDP-
N-linked glycosylation of lysosomal hydrolases occurs in the endocytoplasmic reticulum, which is also the site of the preceding stepwise build-up of OSs and of their "en bloc" transfer from the dolicholpyrophosphoryl-OS-precursor carrier to some of the asparagine residues in the nascent hydrolase proteins.
As the newly formed glycoproteins traverse the Golgi cisterns, sequential enzymatic modification of the N-linked OSs occurs along two different pathways: one pathway modifies the N-linked OSs into complex type glycan side chains, whereas the other, quantitatively the more important pathway at least in mesenchymal tissues, converts the precursor glycans into oligomannosyl-type OS side chains. Specific phosphorylation alone is adversely affected by biallelic inactivating
Normal formation of the M6P recognition marker is a two-step process. The first step is catalyzed by UDP-
Following its translation this alpha/beta precursor polypeptide undergoes proteolytic cleavage at the lysine (residue 928) - asparagine (residue 929) peptide bond. This bond is enzymatically released by site-1 protease (S1P). Cells deficient in S1P failed to activate the alpha/beta precursor and exhibited the I-cell phenotype in vitro [
## References
## Literature Cited
## Chapter Notes
29 August 2019 (ma) Chapter retired: Covered in
10 May 2012 (me) Comprehensive update posted live
7 July 2009 (cd) Revision: deletion/duplication analysis available clinically for
26 August 2008 (cg) Review posted live
16 June 2008 (jgl) Original submission
• 29 August 2019 (ma) Chapter retired: Covered in
• 10 May 2012 (me) Comprehensive update posted live
• 7 July 2009 (cd) Revision: deletion/duplication analysis available clinically for
• 26 August 2008 (cg) Review posted live
• 16 June 2008 (jgl) Original submission
## Revision History
29 August 2019 (ma) Chapter retired: Covered in
10 May 2012 (me) Comprehensive update posted live
7 July 2009 (cd) Revision: deletion/duplication analysis available clinically for
26 August 2008 (cg) Review posted live
16 June 2008 (jgl) Original submission
• 29 August 2019 (ma) Chapter retired: Covered in
• 10 May 2012 (me) Comprehensive update posted live
• 7 July 2009 (cd) Revision: deletion/duplication analysis available clinically for
• 26 August 2008 (cg) Review posted live
• 16 June 2008 (jgl) Original submission
Girl (age 9.5 yrs) on the right has mucolipidosis type III alpha/beta. Boy (age 3 yrs) on the left has mucolipidosis II. Hands in the two children are significantly different: short, broad with claw-like in ML II and rather long in ML III alpha/beta. Linear growth is minimal in ML II and is progressively deficient in ML III. Although frank dwarfing does not occur in ML III alpha/beta, stature often remains under the 3rd centile.
A. Deficient linear growth in ML III alpha/beta is illustrated by the difference in stature in dizygotic twin girls. The affected twin is shown on the right.
B. Growth of the affected twin (solid circles) and her healthy twin (open circles) plotted on anthropometric growth charts (Stuart type). Note: No length measurements were available before age 3.5 yrs.
Reprinted with permission from March of Dimes.
Same patient with ML III alpha/beta as in
Living culture of skin fibroblasts derived from a person with ML III alpha/beta viewed by the contrast light microscope. The cytoplasm is filled with dense granular inclusions that consistently spare a juxtanuclear zone that represents the endoplasmic reticulum and the Golgi apparatus. Electron microscopic study shows that the inclusions are swollen lysosomes bound by a unit membrane and filled with heterogeneous material of varying texture, shape, and electron density. The fibroblasts were originally called inclusion cells (I-cells) and the disorder associated with this in vitro phenotype "I-cell disease." No morphologic differences are observed between fibroblasts derived from an individual with ML II and an individual with ML III alpha/beta.
|
[
"R Bargal, M Zeigler, B Abu-Libdeh, V Zuri, H Mandel, Z Ben Neriah, F Stewart, N Elcioglu, T Hindi, M Le Merrer, G Bach, A Raas-Rothschild. When mucolipidosis III meets mucolipidosis II: GNPTA gene mutations in 24 patients.. Mol Genet Metab 2006;88:359-63",
"M Bao, JL Booth, BJ Elmendorf, WM Canfield. Bovine UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase. I. Purification and subunit structure.. J Biol Chem. 1996;271:31437-45",
"SS Cathey, M Kudo, S Tiede, A Raas-Rothschild, T Braulke, M Beck, HA Taylor, WM Canfield, JG Leroy, EF Neufeld, VA McKusick. Molecular order in mucolipidosis II and III nomenclature.. Am J Med Genet 2008;146A:512-3",
"SS Cathey, JG Leroy, T Wood, K Eaves, RJ Simensen, M Kudo, RE Stevenson, MJ Friez. Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands.. J Med Genet. 2010;47:38-48",
"GK Cury, RV Velho, T Alegra, U Matte, O Artigalas, M Burin, EM Ribeiro, CM Lourenço, CA Kim, ER Valadares, DSCG Miguel, AX Acosta, MF Galera, IVD Schwartz. Mucolipidoses type II and III: molecular analysis of the GNPTAB and GNPTG genes in 15 Brazilian patients.. J Inherit Metab Dis 2011;34:S206",
"G David-Vizcarra, J Briody, J Ault, M Fietz, J Fletcher, R Savarirayan, M Wilson, J McGill, M Edwards, C Munns, M Alcausin, S Cathey, D Sillence. The natural history and osteodystrophy of mucolipidosis types II and III.. J Paediatr Child Health. 2010;46:316-22",
"M Encarnação, L Lacerda, R Costa, MJ Prata, MF Coutinho, H Ribeiro, L Lopes, M Pineda, J Ignatius, H Galvez, A Mustonen, P Vieira, MR Lima, S Alves. Molecular analysis of the GNPTAB and GNPTG genes in 13 patients with mucolipidosis type II or type III - identification of eight novel mutations.. Clin Genet. 2009;76:76-84",
"DA Kerr, VA Memoli, SS Cathey, BT Harris. Mucolipidosis type III α/β: the first characterization of this rare disease by autopsy.. Arch Pathol Lab Med. 2011;135:503-10",
"H Kobayashi, J Takahashi-Fujigasaki, T Fukuda, K Sakurai, Y Shimada, K Nomura, M Ariga, T Ohashi, Y Eto, T Otomo, N Sakai, H Ida. Pathology of the first autopsy case diagnosed as mucolipidosis type III α/β suggesting autophagic dysfunction.. Mol Genet Metab. 2011;102:170-5",
"M Kudo, M Bao, A D’Sousa, F Ying, H Pan, BA Roe, WM Canfield. The α- and β-subunits of the human UDP-N-acetylglucosamine: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase [corrected] are encoded by a single cDNA.. J Biol Chem 2005;280:36141-9",
"M Kudo, MS Brem, WM Canfield. Mucolipidosis II (I-cell disease) and Mucolipidosis III (classical pseudo-Hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene.. Am J Hum Genet 2006;78:451-63",
"K Marschner, K Kollmann, M Schweizer, T Braulke, S Pohl. A key enzyme in the biogenesis of lysosomes is a protease that regulates cholesterol metabolism.. Science. 2011;333:87-90",
"T Otomo, T Muramatsu, T Yorifuji, T Okuyama, H Nakabayashi, T Fukao, T Ohura, M Yoshino, A Tanaka, N Okamoto, K Inui, K Ozono, N Sakai. Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype-phenotype correlation.. J Hum Genet. 2009;54:145-51",
"KH Paik, SM Song, CS Ki, HW Yu, JS Kim, KH Min, SH Chang, EJ Yoo, IJ Lee, EK Kwan, SJ Han, DK Jin. Identification of mutations in the GNPTA (MFGC4170) gene coding for GlcNAc-phosphotransferase alpha/beta subunits in Korean patients with mucolipidosis type II and type IIIA.. Hum Mut 2005;26:308-14",
"A Raas-Rothschild, R Bargal, O Goldman, E Ben-Asher, JE Groener, A Toutain, E Stemmer, Z Ben-Neriah, H Flusser, FA Beemer, M Penttinen, T Olender, AJ Rein, G Bach, M Zeigler. Genomic organization of the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTAG) and its mutations in mucolipidosis III.. J Med Genet 2004;41",
"A Raas-Rothschild, V Cormier-Daire, M Bao, E Genin, R Salomon, K Brewer, M Zeigler, H Mandel, S Toth, B Roe, A Munnich, WM Canfield. Molecular basis of variant pseudo-hurler polydystrophy (mucolipidosis IIIC).. J Clin Invest 2000;105:673-81",
"C Robinson, N Baker, J Noble, A King, G David, D Sillence, P Hofman, T Cundy. The osteodystrophy of mucolipidosis type III and the effects of intravenous pamidronate treatment.. J Inherit Metab Dis 2002;25:681-93",
"RA Steet, R Hullin, M Kudo, M Martinelli, NU Bosshard, T Schaffner, S Kornfeld, B Steinmann. A splicing mutation in the alpha/beta GlcNAc-1-phosphotransferase gene results in an adult onset form of mucolipidosis III associated with sensory neuropathy and cardiomyopathy.. Am J Med Genet A 2005;132A:369-75",
"B Tappino, NA Chuzhanova, S Regis, A Dardis, F Corsolini, M Stroppiano, E Tonoli, T Beccari, C Rosano, J Mucha, M Blanco, M Szlago, M Di Rocco, DN Cooper, M Filocamo. Molecular characterization of 22 novel UDP-N-acetylglucosamine-1-phosphate transferase alpha- and beta-subunit (GNPTAB) gene mutations causing mucolipidosis types IIalpha/beta and IIIalpha/beta in 46 patients.. Hum Mutat. 2009;30:E956-73",
"S Tiede, N Muschol, G Reutter, M Cantz, K Ullrich, T Braulke. Missense mutations in N-acetylglucosamine-1-phosphotransferase alpha/beta subunit gene in a patient with mucolipidosis III and a mild clinical phenotype.. Am J Med Genet A 2005;137A:235-40",
"M Zarghooni, SS Dittakavi. Molecular analysis of cell lines from patients with mucolipidosis II and mucolipidosis III.. Am J Med Genet A. 2009;149A:2753-61"
] |
26/8/2008
|
10/5/2012
|
7/7/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
ml3c
|
ml3c
|
[
"N-acetylglucosamine-1-phosphotransferase subunit gamma",
"GNPTG",
"Mucolipidosis III Gamma"
] |
Mucolipidosis III Gamma
|
Annick Raas-Rothschild, Ronen Spiegel
|
Summary Mucolipidosis III gamma (ML IIIγ) is a slowly progressive inborn error of metabolism mainly affecting skeletal, joint, and connective tissues. Clinical onset is in early childhood; the progressive course results in severe functional impairment and significant morbidity from chronic pain. Cardiorespiratory complications (restrictive lung disease from thoracic involvement, and thickening and insufficiency of the mitral and aortic valves) are rarely clinically significant. A few (probably <10%) affected individuals display mild cognitive impairment. The diagnosis of ML IIIγ is established in a proband with suggestive clinical and radiographic findings and biallelic pathogenic variants in ML IIIγ is inherited in an autosomal recessive manner. If both parents are known to be carriers of one
|
## Diagnosis
Formal diagnostic criteria for mucolipidosis III gamma have not been established.
Mucolipidosis III gamma (ML IIIγ)
Growth rate deceleration
Joint stiffness of the fingers, shoulders, and hips
Gradual mild coarsening of facial features
Genu valgum
Spinal deformities including scoliosis and hyperlordosis
No organomegaly
In late childhood or adolescence, the changes on skeletal radiographs worsen with the development of generalized osteopenia.
The diagnosis of ML IIIγ
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucolipidosis III Gamma
See
See
Data from
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Two intronic deletions reported are of a size detectable by sequencing but could be missed due to their location [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The following lysosomal hydrolases are of most interest as their increased activity in serum and other body fluids is relevant in the differential diagnosis of ML III and lysosomal storage disorders:
β-D-hexosaminidase (EC 3.2.1.52)
β-D-glucuronidase (EC 3.2.1.31)
β-D-galactosidase (EC 3.2.1.23)
α-D-mannosidase (EC 3.2.1.24)
Note: (1) The intracellular lysosomal hydrolase activity in cultured cells, such as skin fibroblasts, is low compared to control cells and permits support of the diagnosis as well. (2) ML IIIγ cannot be diagnosed by assay of acid hydrolases in leukocytes. (In ML II, specific activity of lysosomal enzymes is elevated in plasma, deficient in fibroblasts, and normal in leukocytes.) (3) Biochemical testing (measurement of lysosomal hydrolase activity) does not distinguish ML III alpha/beta from ML IIIγ. (4) Biochemical testing cannot be used to identify heterozygotes.
• Growth rate deceleration
• Joint stiffness of the fingers, shoulders, and hips
• Gradual mild coarsening of facial features
• Genu valgum
• Spinal deformities including scoliosis and hyperlordosis
• No organomegaly
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
## Suggestive Findings
Mucolipidosis III gamma (ML IIIγ)
Growth rate deceleration
Joint stiffness of the fingers, shoulders, and hips
Gradual mild coarsening of facial features
Genu valgum
Spinal deformities including scoliosis and hyperlordosis
No organomegaly
In late childhood or adolescence, the changes on skeletal radiographs worsen with the development of generalized osteopenia.
• Growth rate deceleration
• Joint stiffness of the fingers, shoulders, and hips
• Gradual mild coarsening of facial features
• Genu valgum
• Spinal deformities including scoliosis and hyperlordosis
• No organomegaly
## Establishing the Diagnosis
The diagnosis of ML IIIγ
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucolipidosis III Gamma
See
See
Data from
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Two intronic deletions reported are of a size detectable by sequencing but could be missed due to their location [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The following lysosomal hydrolases are of most interest as their increased activity in serum and other body fluids is relevant in the differential diagnosis of ML III and lysosomal storage disorders:
β-D-hexosaminidase (EC 3.2.1.52)
β-D-glucuronidase (EC 3.2.1.31)
β-D-galactosidase (EC 3.2.1.23)
α-D-mannosidase (EC 3.2.1.24)
Note: (1) The intracellular lysosomal hydrolase activity in cultured cells, such as skin fibroblasts, is low compared to control cells and permits support of the diagnosis as well. (2) ML IIIγ cannot be diagnosed by assay of acid hydrolases in leukocytes. (In ML II, specific activity of lysosomal enzymes is elevated in plasma, deficient in fibroblasts, and normal in leukocytes.) (3) Biochemical testing (measurement of lysosomal hydrolase activity) does not distinguish ML III alpha/beta from ML IIIγ. (4) Biochemical testing cannot be used to identify heterozygotes.
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
## Molecular Genetic Testing
Approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucolipidosis III Gamma
See
See
Data from
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Two intronic deletions reported are of a size detectable by sequencing but could be missed due to their location [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Supportive Biochemical Findings
The following lysosomal hydrolases are of most interest as their increased activity in serum and other body fluids is relevant in the differential diagnosis of ML III and lysosomal storage disorders:
β-D-hexosaminidase (EC 3.2.1.52)
β-D-glucuronidase (EC 3.2.1.31)
β-D-galactosidase (EC 3.2.1.23)
α-D-mannosidase (EC 3.2.1.24)
Note: (1) The intracellular lysosomal hydrolase activity in cultured cells, such as skin fibroblasts, is low compared to control cells and permits support of the diagnosis as well. (2) ML IIIγ cannot be diagnosed by assay of acid hydrolases in leukocytes. (In ML II, specific activity of lysosomal enzymes is elevated in plasma, deficient in fibroblasts, and normal in leukocytes.) (3) Biochemical testing (measurement of lysosomal hydrolase activity) does not distinguish ML III alpha/beta from ML IIIγ. (4) Biochemical testing cannot be used to identify heterozygotes.
• β-D-hexosaminidase (EC 3.2.1.52)
• β-D-glucuronidase (EC 3.2.1.31)
• β-D-galactosidase (EC 3.2.1.23)
• α-D-mannosidase (EC 3.2.1.24)
## Clinical Characteristics
Mucolipidosis III gamma (ML IIIγ) is a slowly progressive inborn error of metabolism mainly affecting skeletal, joint, and connective tissues. Clinical onset is in early childhood and the progressive course, including mild cardiac involvement, results in severe functional impairment and significant morbidity. A few (probably <10%) affected individuals may display mild cognitive impairment [
The initial manifestation in most affected individuals is joint stiffness in fingers as early as age 18 months [
Worsening hip and knee contractures add to the poor growth rate. While frank dwarfism does not occur, the height of individuals with ML IIIγ is often below the tenth centile on standard growth curves.
Hip involvement usually develops during the end of adolescence in ML IIIγ (earlier in ML IIIα/β). Hip involvement progresses over years, finally resulting in destruction of the proximal femoral epiphyses. Limited hip mobility and lower-limb pain can be significant and may result in waddling gait with age.
Carpal tunnel syndrome develops in most affected individuals and may be clinically significant in the second and third decade [
Spinal deformities develop over time and include scoliosis and hyperlordosis. In one individual atlantoaxial instability required corrective surgery; however, this complication is very uncommon in ML IIIγ [
Short neck reported in several individuals had no clinical significance [
Chronic pain syndrome significantly impairs the quality of life. It is common and mainly involves the hips, knees, and entire legs and sometimes the hands. Chronic pain syndrome is attributed to skeletal and connective tissue disease. In some affected individuals spinal cord compression due to spinal stenosis (decreased diameter of the spinal canal) and vertebral osteoarthritic changes may also contribute to the chronic pain syndrome.
Osteopenia, confirmed by reduced bone mineral densitometry measured by dual-energy x-ray absorptiometry (DXA), is common.
To date no correlation between severity of disease and type of
UDP-
The trivial name of this enzyme is UDPGlcNAc 1-P-transferase; thus, the three ML phenotypes can be considered "UDPGlcNAc 1-P-transferase deficiency disorders" [
ML IIIγ was previously referred to as variant pseudo-Hurler polydystrophy* or mucolipidosis IIIC [
* "Pseudo-Hurler polydystrophy" was the term used from 1966 by Maroteaux and Lamy when they first delineated ML III. They used this term because of the resemblance of ML III to Hurler disease, or mucopolysaccharidosis I (MPS I) [
The worldwide estimated incidence of ML II, ML IIIα/β, and ML IIIγ varies between 2.5 and 10 cases per 1,000,000 live births [
Most individuals with ML IIIγ known to the authors originated from the Mediterranean region [
## Clinical Description
Mucolipidosis III gamma (ML IIIγ) is a slowly progressive inborn error of metabolism mainly affecting skeletal, joint, and connective tissues. Clinical onset is in early childhood and the progressive course, including mild cardiac involvement, results in severe functional impairment and significant morbidity. A few (probably <10%) affected individuals may display mild cognitive impairment [
The initial manifestation in most affected individuals is joint stiffness in fingers as early as age 18 months [
Worsening hip and knee contractures add to the poor growth rate. While frank dwarfism does not occur, the height of individuals with ML IIIγ is often below the tenth centile on standard growth curves.
Hip involvement usually develops during the end of adolescence in ML IIIγ (earlier in ML IIIα/β). Hip involvement progresses over years, finally resulting in destruction of the proximal femoral epiphyses. Limited hip mobility and lower-limb pain can be significant and may result in waddling gait with age.
Carpal tunnel syndrome develops in most affected individuals and may be clinically significant in the second and third decade [
Spinal deformities develop over time and include scoliosis and hyperlordosis. In one individual atlantoaxial instability required corrective surgery; however, this complication is very uncommon in ML IIIγ [
Short neck reported in several individuals had no clinical significance [
Chronic pain syndrome significantly impairs the quality of life. It is common and mainly involves the hips, knees, and entire legs and sometimes the hands. Chronic pain syndrome is attributed to skeletal and connective tissue disease. In some affected individuals spinal cord compression due to spinal stenosis (decreased diameter of the spinal canal) and vertebral osteoarthritic changes may also contribute to the chronic pain syndrome.
Osteopenia, confirmed by reduced bone mineral densitometry measured by dual-energy x-ray absorptiometry (DXA), is common.
## Genotype-Phenotype Correlations
To date no correlation between severity of disease and type of
## Nomenclature
UDP-
The trivial name of this enzyme is UDPGlcNAc 1-P-transferase; thus, the three ML phenotypes can be considered "UDPGlcNAc 1-P-transferase deficiency disorders" [
ML IIIγ was previously referred to as variant pseudo-Hurler polydystrophy* or mucolipidosis IIIC [
* "Pseudo-Hurler polydystrophy" was the term used from 1966 by Maroteaux and Lamy when they first delineated ML III. They used this term because of the resemblance of ML III to Hurler disease, or mucopolysaccharidosis I (MPS I) [
## Prevalence
The worldwide estimated incidence of ML II, ML IIIα/β, and ML IIIγ varies between 2.5 and 10 cases per 1,000,000 live births [
Most individuals with ML IIIγ known to the authors originated from the Mediterranean region [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Mucolipidosis II (ML II), ML IIIα/β, and ML IIIγ are all UDPGlcNAc 1-P-transferase deficiency disorders (see
See
Genes to Consider in the Differential Diagnosis of Mucolipidosis III Gamma (ML IIIγ)
Joint stiffness & osteoarthritis
Spinal involvement (kyphoscoliosis, platyspondyly)
Claw hands
Absence of dysostosis multiplex
Disease course less progressive
Normal level of serum hydrolases
Joint stiffness & osteoarthritis
Mild short stature
Absence of dysostosis multiplex
Disease course less progressive
Normal level of serum hydrolases
Joint stiffness
Corneal clouding
Cardiac abnormalities
Facial coarseness
Dysostosis multiplex
Organomegaly
Normal level of serum hydrolases
↑ urinary oligosaccharides
Joint stiffness
Corneal clouding
Cardiac abnormalities
Normal intelligence
Short stature usually more severe (frank dwarfism)
Absence of dysostosis multiplex
Normal level of serum hydrolases
Dysostosis multiplex
Spinal deformities (kyphoscoliosis)
Coarse facies
Corneal opacities
Cardiac involvement
Normal level of serum hydrolases
Joint stiffness
Corneal clouding
Cardiac abnormalities
Facial coarseness
Dysostosis multiplex
Organomegaly
Cognitive impairment
Hearing impairment
Normal level of serum hydrolases
Joint stiffness
Corneal clouding
Cardiac abnormalities
Facial coarseness
Dysostosis multiplex
Organomegaly
Cognitive impairment
Hearing impairment
Normal level of serum hydrolases
Facial coarseness
Dysostosis multiplex
Organomegaly
Cognitive impairment
Hearing impairment
Normal level of serum hydrolases
Facial coarseness
Skeletal abnormalities
Organomegaly
Cognitive impairment
Neurologic abnormalities
Normal level of serum hydrolases
Joint stiffness
Corneal clouding
Cardiac abnormalities
Facial coarseness
Dysostosis multiplex
Organomegaly
Neurologic abnormalities
Cognitive impairment
Normal level of serum hydrolases
AD = autosomal dominant; AR = autosomal recessive; ML = mucolipidosis; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked
Also referred to as pseudo-Hurler polydystrophy
Most individuals with ML IIIγ known to the authors originated from the Mediterranean region [
Also referred to as Morquio syndrome type B
Also referred to as Sly disease type B
Also referred to as Hunter syndrome
Also referred to as Hurler-Scheie syndrome or Scheie syndrome
• Joint stiffness & osteoarthritis
• Spinal involvement (kyphoscoliosis, platyspondyly)
• Claw hands
• Absence of dysostosis multiplex
• Disease course less progressive
• Normal level of serum hydrolases
• Joint stiffness & osteoarthritis
• Mild short stature
• Absence of dysostosis multiplex
• Disease course less progressive
• Normal level of serum hydrolases
• Joint stiffness
• Corneal clouding
• Cardiac abnormalities
• Facial coarseness
• Dysostosis multiplex
• Organomegaly
• Normal level of serum hydrolases
• ↑ urinary oligosaccharides
• Joint stiffness
• Corneal clouding
• Cardiac abnormalities
• Normal intelligence
• Short stature usually more severe (frank dwarfism)
• Absence of dysostosis multiplex
• Normal level of serum hydrolases
• Dysostosis multiplex
• Spinal deformities (kyphoscoliosis)
• Coarse facies
• Corneal opacities
• Cardiac involvement
• Normal level of serum hydrolases
• Joint stiffness
• Corneal clouding
• Cardiac abnormalities
• Facial coarseness
• Dysostosis multiplex
• Organomegaly
• Cognitive impairment
• Hearing impairment
• Normal level of serum hydrolases
• Joint stiffness
• Corneal clouding
• Cardiac abnormalities
• Facial coarseness
• Dysostosis multiplex
• Organomegaly
• Cognitive impairment
• Hearing impairment
• Normal level of serum hydrolases
• Facial coarseness
• Dysostosis multiplex
• Organomegaly
• Cognitive impairment
• Hearing impairment
• Normal level of serum hydrolases
• Facial coarseness
• Skeletal abnormalities
• Organomegaly
• Cognitive impairment
• Neurologic abnormalities
• Normal level of serum hydrolases
• Joint stiffness
• Corneal clouding
• Cardiac abnormalities
• Facial coarseness
• Dysostosis multiplex
• Organomegaly
• Neurologic abnormalities
• Cognitive impairment
• Normal level of serum hydrolases
## Management
To establish the extent of disease and needs in an individual diagnosed with mucolipidosis III gamma (ML IIIγ), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mucolipidosis IIIγ
Lower limb pain (can be significant)
Gross motor & fine motor skills
Hip, knee contractures
Limited range of motion of shoulders
Stiffness of finger joints & Dupuytren-like palmar contractures (starting in late childhood)
Carpal tunnel syndrome
Odontoid dysplasia & risk of atlanto-axial dislocation
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Children age >5 yrs
Adults at time of diagnosis
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support.
ADL = activities of daily living; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
Supportive and symptomatic management is indicated.
No measures are known to be effective in treating the progressive limitation of motion in large and small joints. Physiotherapy intervention programs need to be adapted to the affected individual's needs. Short sessions of aqua therapy that are "low impact" in regard to joint and tendon strain are usually well tolerated.
Later in the disease course, bone pain of variable intensity may become frequent. Management of pain in the hips is required. In older adolescents and adults, bilateral hip replacement has been successful. In individuals with progressive knee involvement, knee replacement has been successful.
Casts (especially of the hands) during the night hours are usually well tolerated and appear to improve daily functions.
Carpal tunnel signs, and rarely tarsal tunnel symptoms, may require surgical tendon release procedures for temporary relief [
In cases with severe spinal deformities with or without spinal cord compression, spinal surgical procedures should be considered.
Routine pain assessment and consultation with a pain specialist should be performed as required.
Of note, in individuals with significant skeletal disease and considerable decrease in bone mineral densitometry (z score<-2.5), bisphosphonates (oral or intravenous) should be highly considered [
When significant valvular dysfunction disrupts ventricular function, valve replacement should be seriously considered. However, such complications are rare in ML IIIγ.
Antibiotic prophylaxis before minor and major surgical procedures (including dental procedures) is appropriate to prevent bacterial endocarditis.
Psychosocial support of affected individuals and their families is recommended.
As with all storage diseases, anesthesia for individuals with ML IIIγ must be well planned. Because of concerns about airway management, surgical intervention should be undertaken only in tertiary care settings with pediatric anesthesiologists and intensive care physicians.
The anesthetic team should be aware of the following issues:
Persons with ML IIIγ are small and have a small airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a smaller endotracheal tube than for age- and size-matched controls is necessary.
Fiberoptic intubation must be available.
Persons with ML IIIγ have short necks, and atlanto-axial instability has been reported [
Jaw and neck movement can be limited.
Abnormalities of the spine and ribs can limit the individual's capacity to breathe and fully expand the lungs.
Recommended Surveillance for Individuals with Mucolipidosis IIIγ
Children: 5-yr intervals after baseline study
Adults w/normal studies: 3-yr intervals
Adolescents & adults w/↓ densitometry: 2-yr intervals
ADL = activities of daily living; DXA = dual-energy x-ray absorptiometry; OT = occupational therapist; PT = physical therapist
Vigorous stretching exercises are not recommended because they are ineffective, painful, and may damage the surrounding joint capsule and adjacent tendons.
See
Search
• Lower limb pain (can be significant)
• Gross motor & fine motor skills
• Hip, knee contractures
• Limited range of motion of shoulders
• Stiffness of finger joints & Dupuytren-like palmar contractures (starting in late childhood)
• Carpal tunnel syndrome
• Odontoid dysplasia & risk of atlanto-axial dislocation
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Children age >5 yrs
• Adults at time of diagnosis
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support.
• Persons with ML IIIγ are small and have a small airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a smaller endotracheal tube than for age- and size-matched controls is necessary.
• Fiberoptic intubation must be available.
• Persons with ML IIIγ have short necks, and atlanto-axial instability has been reported [
• Jaw and neck movement can be limited.
• Abnormalities of the spine and ribs can limit the individual's capacity to breathe and fully expand the lungs.
• Children: 5-yr intervals after baseline study
• Adults w/normal studies: 3-yr intervals
• Adolescents & adults w/↓ densitometry: 2-yr intervals
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with mucolipidosis III gamma (ML IIIγ), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mucolipidosis IIIγ
Lower limb pain (can be significant)
Gross motor & fine motor skills
Hip, knee contractures
Limited range of motion of shoulders
Stiffness of finger joints & Dupuytren-like palmar contractures (starting in late childhood)
Carpal tunnel syndrome
Odontoid dysplasia & risk of atlanto-axial dislocation
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Children age >5 yrs
Adults at time of diagnosis
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support.
ADL = activities of daily living; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
• Lower limb pain (can be significant)
• Gross motor & fine motor skills
• Hip, knee contractures
• Limited range of motion of shoulders
• Stiffness of finger joints & Dupuytren-like palmar contractures (starting in late childhood)
• Carpal tunnel syndrome
• Odontoid dysplasia & risk of atlanto-axial dislocation
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Children age >5 yrs
• Adults at time of diagnosis
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Supportive and symptomatic management is indicated.
No measures are known to be effective in treating the progressive limitation of motion in large and small joints. Physiotherapy intervention programs need to be adapted to the affected individual's needs. Short sessions of aqua therapy that are "low impact" in regard to joint and tendon strain are usually well tolerated.
Later in the disease course, bone pain of variable intensity may become frequent. Management of pain in the hips is required. In older adolescents and adults, bilateral hip replacement has been successful. In individuals with progressive knee involvement, knee replacement has been successful.
Casts (especially of the hands) during the night hours are usually well tolerated and appear to improve daily functions.
Carpal tunnel signs, and rarely tarsal tunnel symptoms, may require surgical tendon release procedures for temporary relief [
In cases with severe spinal deformities with or without spinal cord compression, spinal surgical procedures should be considered.
Routine pain assessment and consultation with a pain specialist should be performed as required.
Of note, in individuals with significant skeletal disease and considerable decrease in bone mineral densitometry (z score<-2.5), bisphosphonates (oral or intravenous) should be highly considered [
When significant valvular dysfunction disrupts ventricular function, valve replacement should be seriously considered. However, such complications are rare in ML IIIγ.
Antibiotic prophylaxis before minor and major surgical procedures (including dental procedures) is appropriate to prevent bacterial endocarditis.
Psychosocial support of affected individuals and their families is recommended.
As with all storage diseases, anesthesia for individuals with ML IIIγ must be well planned. Because of concerns about airway management, surgical intervention should be undertaken only in tertiary care settings with pediatric anesthesiologists and intensive care physicians.
The anesthetic team should be aware of the following issues:
Persons with ML IIIγ are small and have a small airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a smaller endotracheal tube than for age- and size-matched controls is necessary.
Fiberoptic intubation must be available.
Persons with ML IIIγ have short necks, and atlanto-axial instability has been reported [
Jaw and neck movement can be limited.
Abnormalities of the spine and ribs can limit the individual's capacity to breathe and fully expand the lungs.
• Persons with ML IIIγ are small and have a small airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a smaller endotracheal tube than for age- and size-matched controls is necessary.
• Fiberoptic intubation must be available.
• Persons with ML IIIγ have short necks, and atlanto-axial instability has been reported [
• Jaw and neck movement can be limited.
• Abnormalities of the spine and ribs can limit the individual's capacity to breathe and fully expand the lungs.
## Musculoskeletal
No measures are known to be effective in treating the progressive limitation of motion in large and small joints. Physiotherapy intervention programs need to be adapted to the affected individual's needs. Short sessions of aqua therapy that are "low impact" in regard to joint and tendon strain are usually well tolerated.
Later in the disease course, bone pain of variable intensity may become frequent. Management of pain in the hips is required. In older adolescents and adults, bilateral hip replacement has been successful. In individuals with progressive knee involvement, knee replacement has been successful.
Casts (especially of the hands) during the night hours are usually well tolerated and appear to improve daily functions.
Carpal tunnel signs, and rarely tarsal tunnel symptoms, may require surgical tendon release procedures for temporary relief [
In cases with severe spinal deformities with or without spinal cord compression, spinal surgical procedures should be considered.
Routine pain assessment and consultation with a pain specialist should be performed as required.
Of note, in individuals with significant skeletal disease and considerable decrease in bone mineral densitometry (z score<-2.5), bisphosphonates (oral or intravenous) should be highly considered [
## Cardiac
When significant valvular dysfunction disrupts ventricular function, valve replacement should be seriously considered. However, such complications are rare in ML IIIγ.
Antibiotic prophylaxis before minor and major surgical procedures (including dental procedures) is appropriate to prevent bacterial endocarditis.
Psychosocial support of affected individuals and their families is recommended.
## Anesthesia
As with all storage diseases, anesthesia for individuals with ML IIIγ must be well planned. Because of concerns about airway management, surgical intervention should be undertaken only in tertiary care settings with pediatric anesthesiologists and intensive care physicians.
The anesthetic team should be aware of the following issues:
Persons with ML IIIγ are small and have a small airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a smaller endotracheal tube than for age- and size-matched controls is necessary.
Fiberoptic intubation must be available.
Persons with ML IIIγ have short necks, and atlanto-axial instability has been reported [
Jaw and neck movement can be limited.
Abnormalities of the spine and ribs can limit the individual's capacity to breathe and fully expand the lungs.
• Persons with ML IIIγ are small and have a small airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a smaller endotracheal tube than for age- and size-matched controls is necessary.
• Fiberoptic intubation must be available.
• Persons with ML IIIγ have short necks, and atlanto-axial instability has been reported [
• Jaw and neck movement can be limited.
• Abnormalities of the spine and ribs can limit the individual's capacity to breathe and fully expand the lungs.
## Surveillance
Recommended Surveillance for Individuals with Mucolipidosis IIIγ
Children: 5-yr intervals after baseline study
Adults w/normal studies: 3-yr intervals
Adolescents & adults w/↓ densitometry: 2-yr intervals
ADL = activities of daily living; DXA = dual-energy x-ray absorptiometry; OT = occupational therapist; PT = physical therapist
• Children: 5-yr intervals after baseline study
• Adults w/normal studies: 3-yr intervals
• Adolescents & adults w/↓ densitometry: 2-yr intervals
## Agents/Circumstances to Avoid
Vigorous stretching exercises are not recommended because they are ineffective, painful, and may damage the surrounding joint capsule and adjacent tendons.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Mucolipidosis III gamma (ML IIIγ) is inherited in an autosomal recessive manner.
The parents of an affected child are typically heterozygotes (i.e., carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
In one family, only the father of the proband was heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be a carrier of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Note: Biochemical testing cannot be used to identify heterozygotes.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are typically heterozygotes (i.e., carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• In one family, only the father of the proband was heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be a carrier of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Mucolipidosis III gamma (ML IIIγ) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are typically heterozygotes (i.e., carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
In one family, only the father of the proband was heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be a carrier of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are typically heterozygotes (i.e., carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• In one family, only the father of the proband was heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be a carrier of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier (Heterozygote) Detection
Note: Biochemical testing cannot be used to identify heterozygotes.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
2 Ter Avenue De France
Massy 91300
France
United Kingdom
•
•
•
• 2 Ter Avenue De France
• Massy 91300
• France
•
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
Mucolipidosis III Gamma: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Mucolipidosis III Gamma (
N-acetylglucosamine-1-phosphotransferase is a hexameric enzyme complex composed of two alpha, two beta, and two gamma subunits. The membrane-bound alpha and beta subunits are synthesized as a common alpha/beta precursor encoded by
In the Golgi apparatus the gamma subunit directly binds to the alpha subunit and enhances N-acetylglucosamine-1-phosphotransferase activity for mannose-6-phosphate (M6P) modification of specific lysosomal enzymes. Once modified with M6P, the lysosomal hydrolases can attach to the M6P receptor and be targeted to the mature lysosome.
Notable
Variants listed in the table have been reported in more than one publication and in more than one population, reflecting a possible hot spot.
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
N-acetylglucosamine-1-phosphotransferase is a hexameric enzyme complex composed of two alpha, two beta, and two gamma subunits. The membrane-bound alpha and beta subunits are synthesized as a common alpha/beta precursor encoded by
In the Golgi apparatus the gamma subunit directly binds to the alpha subunit and enhances N-acetylglucosamine-1-phosphotransferase activity for mannose-6-phosphate (M6P) modification of specific lysosomal enzymes. Once modified with M6P, the lysosomal hydrolases can attach to the M6P receptor and be targeted to the mature lysosome.
Notable
Variants listed in the table have been reported in more than one publication and in more than one population, reflecting a possible hot spot.
Variants listed in the table have been provided by the authors.
## Chapter Notes
We thank the "Vaincre les Maladies Lysosomales" association for their continuous support and for the research grants for our research projects on ML III gamma and ML II.
We thank the families for their cooperation.
21 November 2019 (bp) Comprehensive update posted live
5 July 2012 (me) Comprehensive update posted live
28 January 2010 (me) Review posted live
28 August 2009 (arr) Original submission
• 21 November 2019 (bp) Comprehensive update posted live
• 5 July 2012 (me) Comprehensive update posted live
• 28 January 2010 (me) Review posted live
• 28 August 2009 (arr) Original submission
## Acknowledgments
We thank the "Vaincre les Maladies Lysosomales" association for their continuous support and for the research grants for our research projects on ML III gamma and ML II.
We thank the families for their cooperation.
## Revision History
21 November 2019 (bp) Comprehensive update posted live
5 July 2012 (me) Comprehensive update posted live
28 January 2010 (me) Review posted live
28 August 2009 (arr) Original submission
• 21 November 2019 (bp) Comprehensive update posted live
• 5 July 2012 (me) Comprehensive update posted live
• 28 January 2010 (me) Review posted live
• 28 August 2009 (arr) Original submission
## References
## Literature Cited
|
[] |
28/1/2010
|
21/11/2019
|
29/9/2011
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
ml4
|
ml4
|
[
"Mucolipin-1",
"MCOLN1",
"Mucolipidosis IV"
] |
Mucolipidosis IV
|
Albert Misko, Yulia Grishchuk, Ehud Goldin, Raphael Schiffmann
|
Summary Mucolipidosis IV (MLIV) is an ultra-rare lysosomal storage disorder characterized by severe psychomotor delay, progressive visual impairment, and achlorhydria. Individuals with MLIV typically present by the end of the first year of life with delayed developmental milestones (due to a developmental brain abnormality) and impaired vision (resulting from a combination of corneal clouding and retinal degeneration). By adolescence, all individuals with MLIV have severe visual impairment. A neurodegenerative component of MLIV has become more widely appreciated, with the majority of individuals demonstrating progressive spastic quadriparesis and loss of psychomotor skills starting in the second decade of life. About 5% of individuals have atypical MLIV, manifesting with less severe psychomotor impairment, but still exhibiting progressive retinal degeneration and achlorhydria. MLIV is suspected in individuals with typical clinical findings and elevated plasma gastrin concentration or polymorphic lysosomal inclusions in skin or conjunctival biopsy. Identification of biallelic pathogenic variants in MLIV is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the
|
## Diagnosis
Mucolipidosis IV (MLIV)
Early onset of developmental delay whether static, as in cerebral palsy, or progressively declining with loss of previously acquired cognitive and motor abilities [
Dystrophic retinopathy with or without corneal clouding [
Elevated plasma gastrin concentration (due to achlorhydria) in virtually all individuals with MLIV (mean: 1507 pg/mL; range: 400-4100 pg/mL; normal: 0-200 pg/mL) [
Achlorhydria
The diagnosis of MLIV
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: (1) Targeted analysis for pathogenic variant
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay, c
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucolipidosis IV
See
See
For
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Cannot detect
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Required to detect the common 6.4-kb deletion observed in persons of Ashkenazi Jewish heritage and other novel (multi)exon deletions. Note that other genotyping assays specifically designed to detect the 6.4-kb deletion (e.g., breakpoint PCR or allele-specific primer extension) may be employed.
No data on detection rate of non-6.4-kb deletion gene-targeted deletion/duplication analysis are available.
• Early onset of developmental delay whether static, as in cerebral palsy, or progressively declining with loss of previously acquired cognitive and motor abilities [
• Dystrophic retinopathy with or without corneal clouding [
• Elevated plasma gastrin concentration (due to achlorhydria) in virtually all individuals with MLIV (mean: 1507 pg/mL; range: 400-4100 pg/mL; normal: 0-200 pg/mL) [
• Achlorhydria
## Suggestive Findings
Mucolipidosis IV (MLIV)
Early onset of developmental delay whether static, as in cerebral palsy, or progressively declining with loss of previously acquired cognitive and motor abilities [
Dystrophic retinopathy with or without corneal clouding [
Elevated plasma gastrin concentration (due to achlorhydria) in virtually all individuals with MLIV (mean: 1507 pg/mL; range: 400-4100 pg/mL; normal: 0-200 pg/mL) [
Achlorhydria
• Early onset of developmental delay whether static, as in cerebral palsy, or progressively declining with loss of previously acquired cognitive and motor abilities [
• Dystrophic retinopathy with or without corneal clouding [
• Elevated plasma gastrin concentration (due to achlorhydria) in virtually all individuals with MLIV (mean: 1507 pg/mL; range: 400-4100 pg/mL; normal: 0-200 pg/mL) [
• Achlorhydria
## Establishing the Diagnosis
The diagnosis of MLIV
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: (1) Targeted analysis for pathogenic variant
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay, c
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucolipidosis IV
See
See
For
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Cannot detect
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Required to detect the common 6.4-kb deletion observed in persons of Ashkenazi Jewish heritage and other novel (multi)exon deletions. Note that other genotyping assays specifically designed to detect the 6.4-kb deletion (e.g., breakpoint PCR or allele-specific primer extension) may be employed.
No data on detection rate of non-6.4-kb deletion gene-targeted deletion/duplication analysis are available.
## Molecular Genetic Testing
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: (1) Targeted analysis for pathogenic variant
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay, c
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucolipidosis IV
See
See
For
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Cannot detect
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Required to detect the common 6.4-kb deletion observed in persons of Ashkenazi Jewish heritage and other novel (multi)exon deletions. Note that other genotyping assays specifically designed to detect the 6.4-kb deletion (e.g., breakpoint PCR or allele-specific primer extension) may be employed.
No data on detection rate of non-6.4-kb deletion gene-targeted deletion/duplication analysis are available.
## Other Testing
## Clinical Characteristics
Mucolipidosis IV (MLIV) is a neurodevelopmental disorder with a gradual, late-onset neurodegenerative component. The phenotype in affected individuals can be either typical/severe (~95% of individuals) or atypical/mild (~5% of individuals) [
Individuals commonly present in the first year of life with axial hypotonia, delayed motor milestones, and/or corneal clouding. Because the combination of hypotonia and developmental delay are nonspecific, individuals with MLIV are frequently assigned a provisional diagnosis of cerebral palsy during their diagnostic odyssey. Corneal clouding is a more specific disease feature and identification by an ophthalmologist on slit lamp examination often leads to diagnosis by targeted genetic testing.
Pyramidal and extrapyramidal tract signs manifest early in the course of disease. In the first decade of life, individuals exhibit a mixture of spasticity and rigidity with cogwheel or oppositional qualities. Dystonic posturing in the extremities is frequently observed. Hypertonicity is present in the upper and lower extremities and is generally symmetric. Decreased force on volitional activation of the extremities is consistent with upper motor neuron weakness, but worsening muscular hypertonicity suggests relative preservation of muscle and neuromuscular junction integrity.
Receptive language is better than expressive language; some individuals have used up to 50 signs to communicate. Individuals uniformly demonstrate intact social development with strong social engagement, a friendly disposition, and an enjoyment of music [
Individuals typically exhibit dysarthria or anarthria, slow chewing, and restricted lateral tongue movement. Few individuals experience aspiration in the first decade of life and swallow studies are normal. Aspiration may emerge later in life requiring a tracheostomy or gastric tube placement [
While individuals make some developmental gains in the first decade of life, caregivers consistently report worsening hypertonicity and weakness. By early adolescence, loss of psychomotor skills becomes apparent. Though previously described as mainly a static neurodevelopmental condition [
Typical brain MRI abnormalities in individuals with MLIV include hypoplasia of the corpus callosum with absent rostrum and a dysplastic or absent splenium, signal abnormalities in the white matter on T
Epileptiform discharges on EEG are common but are infrequently associated with clinical seizures [
Vision may be close to normal at a young age. Over the first decade of life, progressive retinal degeneration with varying degrees of vascular attenuation, retinal pigment epithelial changes, and optic nerve pallor result in further decrease in vision [
Painful episodes consistent with corneal erosions are common, but appear to decrease in frequency and severity with age.
Other ocular findings are strabismus (>50% of individuals), nystagmus, ptosis, and cataract [
Affected individuals do not have hepatosplenomegaly or specific skeletal abnormalities.
Individuals with atypical MLIV are less severely affected than individuals with typical MLIV or have one organ system disproportionately affected [
Some individuals attain the ability to walk independently or have isolated dystrophic retinopathy without neurologic dysfunction [
Some present with a congenital myopathy with significant generalized hypotonia and elevated serum muscle creatine kinase concentration. Others present with static (non-progressive) motor and cognitive delay and minimal ocular abnormalities.
Individuals of Ashkenazi Jewish ancestry usually have the severe form of MLIV.
A pathogenic variant that creates a new preferred splice site of
The typical, rather severe presentation associated with the
MLIV was classified as a mucolipidosis because of the initial impression of simultaneous storage of lipids and water-soluble substances.
The combined carrier frequency of the two pathogenic variants common in persons of Ashkenazi Jewish descent ranges from 1:100 to 1:127 [
The splice pathogenic variant (
The 6.4-kb deletion is particularly rare in the Israeli population (1:2,000) in comparison to its frequency in the New York metropolitan area (1:406) [
Prior to the availability of molecular diagnosis of MLIV, individuals with atypical MLIV were thought to have cerebral palsy or isolated retinal dystrophy, suggesting that MLIV is underdiagnosed.
• The splice pathogenic variant (
• The 6.4-kb deletion is particularly rare in the Israeli population (1:2,000) in comparison to its frequency in the New York metropolitan area (1:406) [
## Clinical Description
Mucolipidosis IV (MLIV) is a neurodevelopmental disorder with a gradual, late-onset neurodegenerative component. The phenotype in affected individuals can be either typical/severe (~95% of individuals) or atypical/mild (~5% of individuals) [
Individuals commonly present in the first year of life with axial hypotonia, delayed motor milestones, and/or corneal clouding. Because the combination of hypotonia and developmental delay are nonspecific, individuals with MLIV are frequently assigned a provisional diagnosis of cerebral palsy during their diagnostic odyssey. Corneal clouding is a more specific disease feature and identification by an ophthalmologist on slit lamp examination often leads to diagnosis by targeted genetic testing.
Pyramidal and extrapyramidal tract signs manifest early in the course of disease. In the first decade of life, individuals exhibit a mixture of spasticity and rigidity with cogwheel or oppositional qualities. Dystonic posturing in the extremities is frequently observed. Hypertonicity is present in the upper and lower extremities and is generally symmetric. Decreased force on volitional activation of the extremities is consistent with upper motor neuron weakness, but worsening muscular hypertonicity suggests relative preservation of muscle and neuromuscular junction integrity.
Receptive language is better than expressive language; some individuals have used up to 50 signs to communicate. Individuals uniformly demonstrate intact social development with strong social engagement, a friendly disposition, and an enjoyment of music [
Individuals typically exhibit dysarthria or anarthria, slow chewing, and restricted lateral tongue movement. Few individuals experience aspiration in the first decade of life and swallow studies are normal. Aspiration may emerge later in life requiring a tracheostomy or gastric tube placement [
While individuals make some developmental gains in the first decade of life, caregivers consistently report worsening hypertonicity and weakness. By early adolescence, loss of psychomotor skills becomes apparent. Though previously described as mainly a static neurodevelopmental condition [
Typical brain MRI abnormalities in individuals with MLIV include hypoplasia of the corpus callosum with absent rostrum and a dysplastic or absent splenium, signal abnormalities in the white matter on T
Epileptiform discharges on EEG are common but are infrequently associated with clinical seizures [
Vision may be close to normal at a young age. Over the first decade of life, progressive retinal degeneration with varying degrees of vascular attenuation, retinal pigment epithelial changes, and optic nerve pallor result in further decrease in vision [
Painful episodes consistent with corneal erosions are common, but appear to decrease in frequency and severity with age.
Other ocular findings are strabismus (>50% of individuals), nystagmus, ptosis, and cataract [
Affected individuals do not have hepatosplenomegaly or specific skeletal abnormalities.
Individuals with atypical MLIV are less severely affected than individuals with typical MLIV or have one organ system disproportionately affected [
Some individuals attain the ability to walk independently or have isolated dystrophic retinopathy without neurologic dysfunction [
Some present with a congenital myopathy with significant generalized hypotonia and elevated serum muscle creatine kinase concentration. Others present with static (non-progressive) motor and cognitive delay and minimal ocular abnormalities.
## Typical MLIV
Individuals commonly present in the first year of life with axial hypotonia, delayed motor milestones, and/or corneal clouding. Because the combination of hypotonia and developmental delay are nonspecific, individuals with MLIV are frequently assigned a provisional diagnosis of cerebral palsy during their diagnostic odyssey. Corneal clouding is a more specific disease feature and identification by an ophthalmologist on slit lamp examination often leads to diagnosis by targeted genetic testing.
Pyramidal and extrapyramidal tract signs manifest early in the course of disease. In the first decade of life, individuals exhibit a mixture of spasticity and rigidity with cogwheel or oppositional qualities. Dystonic posturing in the extremities is frequently observed. Hypertonicity is present in the upper and lower extremities and is generally symmetric. Decreased force on volitional activation of the extremities is consistent with upper motor neuron weakness, but worsening muscular hypertonicity suggests relative preservation of muscle and neuromuscular junction integrity.
Receptive language is better than expressive language; some individuals have used up to 50 signs to communicate. Individuals uniformly demonstrate intact social development with strong social engagement, a friendly disposition, and an enjoyment of music [
Individuals typically exhibit dysarthria or anarthria, slow chewing, and restricted lateral tongue movement. Few individuals experience aspiration in the first decade of life and swallow studies are normal. Aspiration may emerge later in life requiring a tracheostomy or gastric tube placement [
While individuals make some developmental gains in the first decade of life, caregivers consistently report worsening hypertonicity and weakness. By early adolescence, loss of psychomotor skills becomes apparent. Though previously described as mainly a static neurodevelopmental condition [
Typical brain MRI abnormalities in individuals with MLIV include hypoplasia of the corpus callosum with absent rostrum and a dysplastic or absent splenium, signal abnormalities in the white matter on T
Epileptiform discharges on EEG are common but are infrequently associated with clinical seizures [
Vision may be close to normal at a young age. Over the first decade of life, progressive retinal degeneration with varying degrees of vascular attenuation, retinal pigment epithelial changes, and optic nerve pallor result in further decrease in vision [
Painful episodes consistent with corneal erosions are common, but appear to decrease in frequency and severity with age.
Other ocular findings are strabismus (>50% of individuals), nystagmus, ptosis, and cataract [
Affected individuals do not have hepatosplenomegaly or specific skeletal abnormalities.
## Atypical MLIV
Individuals with atypical MLIV are less severely affected than individuals with typical MLIV or have one organ system disproportionately affected [
Some individuals attain the ability to walk independently or have isolated dystrophic retinopathy without neurologic dysfunction [
Some present with a congenital myopathy with significant generalized hypotonia and elevated serum muscle creatine kinase concentration. Others present with static (non-progressive) motor and cognitive delay and minimal ocular abnormalities.
## Genotype-Phenotype Correlations
Individuals of Ashkenazi Jewish ancestry usually have the severe form of MLIV.
A pathogenic variant that creates a new preferred splice site of
The typical, rather severe presentation associated with the
## Nomenclature
MLIV was classified as a mucolipidosis because of the initial impression of simultaneous storage of lipids and water-soluble substances.
## Prevalence
The combined carrier frequency of the two pathogenic variants common in persons of Ashkenazi Jewish descent ranges from 1:100 to 1:127 [
The splice pathogenic variant (
The 6.4-kb deletion is particularly rare in the Israeli population (1:2,000) in comparison to its frequency in the New York metropolitan area (1:406) [
Prior to the availability of molecular diagnosis of MLIV, individuals with atypical MLIV were thought to have cerebral palsy or isolated retinal dystrophy, suggesting that MLIV is underdiagnosed.
• The splice pathogenic variant (
• The 6.4-kb deletion is particularly rare in the Israeli population (1:2,000) in comparison to its frequency in the New York metropolitan area (1:406) [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The earliest signs of mucolipidosis IV (MLIV) include axial hypotonia, developmental delay, and strabismus, which are nonspecific and often lead to a provisional diagnosis of cerebral palsy. However, the finding of corneal clouding in combination with these neurologic features is relatively specific and should trigger further workup for MLIV.
Disorders with Eye Findings of Interest in the Differential Diagnosis of Mucolipidosis IV
AD = autosomal dominant; AR = autosomal recessive; ML = mucolipidosis; MOI = mode of inheritance; MPS = mucopolysaccharidoses; XL = X-linked
Listed genes represent the most commonly associated genes; at least 19 genes are associated with Bardet-Biedl syndrome (see
Because MLIV initially presents with impaired neurodevelopment in the absence of progressive features till later in life, individuals considered to have "cerebral palsy" should be evaluated for MLIV.
The neurologic abnormalities and the finding of widespread storage material in tissue biopsy could suggest other lysosomal storage disorders including mucolipidosis type I (OMIM
The finding of white matter abnormalities and a thin dysplastic corpus callosum could suggest other inherited hypomyelinating leukodystrophies such as sialic acid storage disease (Salla disease). (See
## Eye Findings
Disorders with Eye Findings of Interest in the Differential Diagnosis of Mucolipidosis IV
AD = autosomal dominant; AR = autosomal recessive; ML = mucolipidosis; MOI = mode of inheritance; MPS = mucopolysaccharidoses; XL = X-linked
Listed genes represent the most commonly associated genes; at least 19 genes are associated with Bardet-Biedl syndrome (see
## Neurologic Findings
Because MLIV initially presents with impaired neurodevelopment in the absence of progressive features till later in life, individuals considered to have "cerebral palsy" should be evaluated for MLIV.
The neurologic abnormalities and the finding of widespread storage material in tissue biopsy could suggest other lysosomal storage disorders including mucolipidosis type I (OMIM
The finding of white matter abnormalities and a thin dysplastic corpus callosum could suggest other inherited hypomyelinating leukodystrophies such as sialic acid storage disease (Salla disease). (See
## Management
No clinical practice guidelines for mucolipidosis IV (MLIV) have been published.
To establish the extent of disease and needs in an individual diagnosed with MLIV, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mucolipidosis IV
To incl brain MRI
Consider EEG if seizures a concern.
To incl motor, adaptive, cognitive, & speech/language eval by neuropsychologist
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
CBC
Iron studies
Use of online family community established by the ML4 Foundation;
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
ADL = activities of daily living; CBC = complete blood count; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations in Individuals with Mucolipidosis IV
Orthopedics / physical medicine & rehab / PT/OT incl stretching to help avoid contractures & falls
Intramuscular botulinum toxin injections or oral medications for muscle spasticity & rigidity
PT & rehab can help prevent permanent joint contractures.
Consider need for positioning & mobility devices, disability parking placard.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Surgical correction of strabismus
High-contrast black & white materials for those w/visual impairment
Community vision services through early intervention or school district
Note: Corneal transplantation or scraping has not been successful because the donor corneal epithelium is eventually replaced by the abnormal host epithelium or the affected person's epithelium regrows.
Use preservative-free drops only.
Consult ophthalmologist before treatment.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists such as a physical medicine and rehabilitation physician to aid in management of baclofen, tizanidine, Botox
Recommended Surveillance for Individuals with Mucolipidosis IV
Monitor those w/seizures as clinically indicated.
Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
Annually, or more frequently if active renal compromise is identified
Note: Creatinine levels are not sufficient to monitor renal function as muscle atrophy in MLIV will ↓ baseline levels.
CBC
Iron studies
CBC = complete blood count; OT = occupational therapy/therapist; PT = physical therapy/therapist
Chloroquine may be contraindicated, based on published research in cultured skin fibroblasts from affected individuals [
See
Search
• To incl brain MRI
• Consider EEG if seizures a concern.
• To incl motor, adaptive, cognitive, & speech/language eval by neuropsychologist
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
• CBC
• Iron studies
• Use of online family community established by the ML4 Foundation;
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
• Orthopedics / physical medicine & rehab / PT/OT incl stretching to help avoid contractures & falls
• Intramuscular botulinum toxin injections or oral medications for muscle spasticity & rigidity
• PT & rehab can help prevent permanent joint contractures.
• Consider need for positioning & mobility devices, disability parking placard.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Surgical correction of strabismus
• High-contrast black & white materials for those w/visual impairment
• Community vision services through early intervention or school district
• Note: Corneal transplantation or scraping has not been successful because the donor corneal epithelium is eventually replaced by the abnormal host epithelium or the affected person's epithelium regrows.
• Use preservative-free drops only.
• Consult ophthalmologist before treatment.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists such as a physical medicine and rehabilitation physician to aid in management of baclofen, tizanidine, Botox
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
• Annually, or more frequently if active renal compromise is identified
• Note: Creatinine levels are not sufficient to monitor renal function as muscle atrophy in MLIV will ↓ baseline levels.
• CBC
• Iron studies
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MLIV, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mucolipidosis IV
To incl brain MRI
Consider EEG if seizures a concern.
To incl motor, adaptive, cognitive, & speech/language eval by neuropsychologist
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
CBC
Iron studies
Use of online family community established by the ML4 Foundation;
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
ADL = activities of daily living; CBC = complete blood count; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• To incl brain MRI
• Consider EEG if seizures a concern.
• To incl motor, adaptive, cognitive, & speech/language eval by neuropsychologist
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
• CBC
• Iron studies
• Use of online family community established by the ML4 Foundation;
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Mucolipidosis IV
Orthopedics / physical medicine & rehab / PT/OT incl stretching to help avoid contractures & falls
Intramuscular botulinum toxin injections or oral medications for muscle spasticity & rigidity
PT & rehab can help prevent permanent joint contractures.
Consider need for positioning & mobility devices, disability parking placard.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Surgical correction of strabismus
High-contrast black & white materials for those w/visual impairment
Community vision services through early intervention or school district
Note: Corneal transplantation or scraping has not been successful because the donor corneal epithelium is eventually replaced by the abnormal host epithelium or the affected person's epithelium regrows.
Use preservative-free drops only.
Consult ophthalmologist before treatment.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists such as a physical medicine and rehabilitation physician to aid in management of baclofen, tizanidine, Botox
• Orthopedics / physical medicine & rehab / PT/OT incl stretching to help avoid contractures & falls
• Intramuscular botulinum toxin injections or oral medications for muscle spasticity & rigidity
• PT & rehab can help prevent permanent joint contractures.
• Consider need for positioning & mobility devices, disability parking placard.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Surgical correction of strabismus
• High-contrast black & white materials for those w/visual impairment
• Community vision services through early intervention or school district
• Note: Corneal transplantation or scraping has not been successful because the donor corneal epithelium is eventually replaced by the abnormal host epithelium or the affected person's epithelium regrows.
• Use preservative-free drops only.
• Consult ophthalmologist before treatment.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists such as a physical medicine and rehabilitation physician to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists such as a physical medicine and rehabilitation physician to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists such as a physical medicine and rehabilitation physician to aid in management of baclofen, tizanidine, Botox
## Surveillance
Recommended Surveillance for Individuals with Mucolipidosis IV
Monitor those w/seizures as clinically indicated.
Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
Annually, or more frequently if active renal compromise is identified
Note: Creatinine levels are not sufficient to monitor renal function as muscle atrophy in MLIV will ↓ baseline levels.
CBC
Iron studies
CBC = complete blood count; OT = occupational therapy/therapist; PT = physical therapy/therapist
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
• Annually, or more frequently if active renal compromise is identified
• Note: Creatinine levels are not sufficient to monitor renal function as muscle atrophy in MLIV will ↓ baseline levels.
• CBC
• Iron studies
## Agents/Circumstances to Avoid
Chloroquine may be contraindicated, based on published research in cultured skin fibroblasts from affected individuals [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Mucolipidosis IV (MLIV) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with MLIV are not known to reproduce.
No information is available regarding the ability of individuals with mild disease to reproduce.
Carrier testing for at-risk relatives requires prior identification of the
See
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with MLIV are not known to reproduce.
• No information is available regarding the ability of individuals with mild disease to reproduce.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
Mucolipidosis IV (MLIV) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with MLIV are not known to reproduce.
No information is available regarding the ability of individuals with mild disease to reproduce.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with MLIV are not known to reproduce.
• No information is available regarding the ability of individuals with mild disease to reproduce.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
See
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
3500 Piedmont Road
Suite 500
Atlanta GA 30305
•
• United Kingdom
•
•
• 3500 Piedmont Road
• Suite 500
• Atlanta GA 30305
•
•
•
•
•
## Molecular Genetics
Mucolipidosis IV: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Mucolipidosis IV (
The lysosomal storage of lipids and water-soluble substances in mucolipidosis IV (MLIV) is attributed to a transport defect in the late steps of endocytosis resulting from abnormal membrane components of endosomes. Endosomes shuttle lipids and proteins between the plasma membrane and the various cellular organelles. Nutrients bound to lysosomes for processing would be retained in these transition vesicles. Alternatively, it could indicate an increased rate of membrane recycling resulting from rapid degradation of malfunctioning protein complexes at the plasma membrane. Inability of cells to compensate for the missing cation channel function causes the defect in organization of white matter in the brain and reduces maintenance of cells in the retina and optic nerve. Inability to secrete gastric acid may be directly related to a defect in the operation of the acid-secreting H
Notable
Variants listed in the table have been provided by the authors.
Deletion of exons 1 through 5 and part of exon 6; to date, only one individual homozygous for the 6.4-kb deletion has been identified [
Approximately 60% of individuals with MLIV of Ashkenazi Jewish heritage in the US are homozygotes for the c.406-2A>G intronic acceptor splice site pathogenic variant. An estimated 33% are compound heterozygotes for this variant and the 6.4-kb deletion [
Base pair transition creates a new preferred splice acceptor site that results in a frameshift.
Variant designation that does not conform to current naming conventions
Near the donor site of intron 13; creates an alternative donor splice site that results in a frameshift [
## Molecular Pathogenesis
The lysosomal storage of lipids and water-soluble substances in mucolipidosis IV (MLIV) is attributed to a transport defect in the late steps of endocytosis resulting from abnormal membrane components of endosomes. Endosomes shuttle lipids and proteins between the plasma membrane and the various cellular organelles. Nutrients bound to lysosomes for processing would be retained in these transition vesicles. Alternatively, it could indicate an increased rate of membrane recycling resulting from rapid degradation of malfunctioning protein complexes at the plasma membrane. Inability of cells to compensate for the missing cation channel function causes the defect in organization of white matter in the brain and reduces maintenance of cells in the retina and optic nerve. Inability to secrete gastric acid may be directly related to a defect in the operation of the acid-secreting H
Notable
Variants listed in the table have been provided by the authors.
Deletion of exons 1 through 5 and part of exon 6; to date, only one individual homozygous for the 6.4-kb deletion has been identified [
Approximately 60% of individuals with MLIV of Ashkenazi Jewish heritage in the US are homozygotes for the c.406-2A>G intronic acceptor splice site pathogenic variant. An estimated 33% are compound heterozygotes for this variant and the 6.4-kb deletion [
Base pair transition creates a new preferred splice acceptor site that results in a frameshift.
Variant designation that does not conform to current naming conventions
Near the donor site of intron 13; creates an alternative donor splice site that results in a frameshift [
## Chapter Notes
Albert Misko is a pediatric neurologist at Massachusetts General Hospital who specializes in the care of patients with neurometabolic disorders. His research program aims to accelerate the development of genetic and small molecule therapies that mitigate neurologic damage and correct inherited metabolic deficiencies.Website:
Yulia Grishchuk obtained her PhD in Molecular Biology from Engelhardt Institute of Molecular Biology in Moscow, Russia. During her postdoctoral training at the Brain Mind Institute, EPFL, and University of Lausanne in Switzerland, she studied endocytosis and autophagy in neurotoxicity and neurodegeneration. She then joined Dr Slaugenhaupt's laboratory at Massachusetts General Hospital, where she continued her research of lysosomal dysfunction in neurodegeneration. Dr Grishchuk leads a laboratory working on therapy development for mucolipidosis IV. Website:
Raphael Schiffmann is the Director of the Institute of Metabolic Disease at the Baylor Research Institute, Dallas, Texas. His research focuses on elucidating the pathophysiology of lysosomal storage and evaluating enzyme replacement therapy and other novel therapeutic modalities. Website:
We would like to recognize funding from the UPenn Million Dollar Bike Ride Grant Program (2017D007934 and MDBR-20-124-ML4) and the NIH/Lysosomal Disease Network (U54NS065768) that has made much of our work on the natural history of MLIV possible.
We would also like to thank Dr Sue Slaugenhaupt for her mentorship and many contributions to our understanding of mucolipidosis IV.
Ehud Goldin, PhD (2004-present)Yulia Grishchuk, PhD (2015-present)Albert Misko, MD, PhD (2021-present)Raphael Schiffmann, MD, MHSc (2004-present)Susan A Slaugenhaupt, PhD; Harvard Medical School (2004-2015)Janine Smith, MD; National Institutes of Health (2004-2015)
11 February 2021 (sw) Comprehensive update posted live
30 July 2015 (me) Comprehensive update posted live
20 July 2010 (me) Comprehensive update posted live
6 June 2007 (me) Comprehensive update posted live
1 December 2005 (rs) Revision: sequence analysis no longer clinically available
28 January 2005 (me) Review posted live
16 August 2004 (rs) Original submission
• 11 February 2021 (sw) Comprehensive update posted live
• 30 July 2015 (me) Comprehensive update posted live
• 20 July 2010 (me) Comprehensive update posted live
• 6 June 2007 (me) Comprehensive update posted live
• 1 December 2005 (rs) Revision: sequence analysis no longer clinically available
• 28 January 2005 (me) Review posted live
• 16 August 2004 (rs) Original submission
## Author Notes
Albert Misko is a pediatric neurologist at Massachusetts General Hospital who specializes in the care of patients with neurometabolic disorders. His research program aims to accelerate the development of genetic and small molecule therapies that mitigate neurologic damage and correct inherited metabolic deficiencies.Website:
Yulia Grishchuk obtained her PhD in Molecular Biology from Engelhardt Institute of Molecular Biology in Moscow, Russia. During her postdoctoral training at the Brain Mind Institute, EPFL, and University of Lausanne in Switzerland, she studied endocytosis and autophagy in neurotoxicity and neurodegeneration. She then joined Dr Slaugenhaupt's laboratory at Massachusetts General Hospital, where she continued her research of lysosomal dysfunction in neurodegeneration. Dr Grishchuk leads a laboratory working on therapy development for mucolipidosis IV. Website:
Raphael Schiffmann is the Director of the Institute of Metabolic Disease at the Baylor Research Institute, Dallas, Texas. His research focuses on elucidating the pathophysiology of lysosomal storage and evaluating enzyme replacement therapy and other novel therapeutic modalities. Website:
## Acknowledgments
We would like to recognize funding from the UPenn Million Dollar Bike Ride Grant Program (2017D007934 and MDBR-20-124-ML4) and the NIH/Lysosomal Disease Network (U54NS065768) that has made much of our work on the natural history of MLIV possible.
We would also like to thank Dr Sue Slaugenhaupt for her mentorship and many contributions to our understanding of mucolipidosis IV.
## Author History
Ehud Goldin, PhD (2004-present)Yulia Grishchuk, PhD (2015-present)Albert Misko, MD, PhD (2021-present)Raphael Schiffmann, MD, MHSc (2004-present)Susan A Slaugenhaupt, PhD; Harvard Medical School (2004-2015)Janine Smith, MD; National Institutes of Health (2004-2015)
## Revision History
11 February 2021 (sw) Comprehensive update posted live
30 July 2015 (me) Comprehensive update posted live
20 July 2010 (me) Comprehensive update posted live
6 June 2007 (me) Comprehensive update posted live
1 December 2005 (rs) Revision: sequence analysis no longer clinically available
28 January 2005 (me) Review posted live
16 August 2004 (rs) Original submission
• 11 February 2021 (sw) Comprehensive update posted live
• 30 July 2015 (me) Comprehensive update posted live
• 20 July 2010 (me) Comprehensive update posted live
• 6 June 2007 (me) Comprehensive update posted live
• 1 December 2005 (rs) Revision: sequence analysis no longer clinically available
• 28 January 2005 (me) Review posted live
• 16 August 2004 (rs) Original submission
## References
## Literature Cited
|
[
"G Altarescu, M Sun, DF Moore, JA Smith, EA Wiggs, BI Solomon, NJ Patronas, KP Frei, S Gupta, CR Kaneski, OW Quarrell, SA Slaugenhaupt, E Goldin, R Schiffmann. The neurogenetics of mucolipidosis type IV.. Neurology 2002;59:306-13",
"N Amir, J Zlotogora, B Gideon. Mucolipidosis type IV: clinical spectrum and natural history.. Pediatrics 1987;79:953-959",
"G Bach. Mucolipidosis type IV.. Mol Genet Metab 2001;73:197-203",
"R Bargal, N Avidan, E Ben-Asher, Z Olender, M Zeigler, A Frumkin, A Raas-Rothschild, G Glusman, D Lancet, G Bach. Identification of the gene causing mucolipidosis type IV.. Nat Genet 2000;26:118-23",
"R Bargal, N Avidan, T Olender, E Ben Asher, M Zeigler, A Raas-Rothschild, A Frumkin, O Ben-Yoseph, Y Friedlender, D Lancet, G Bach. Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population.. Hum Mutat 2001;17:397-402",
"R Bargal, HH Goebel, E Latta, G Bach. Mucolipidosis IV: novel mutation and diverse ultrastructural spectrum in the skin.. Neuropediatrics 2002;33:199-202",
"MT Bassi, M Manzoni, E Monti, MT Pizzo, A Ballabio, G Borsani. Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV.. Am J Hum Genet 2000;67:1110-20",
"M Chandra, H Zhou, Q Li, S Muallem, S Hofmann, A Soyombo. A role for the calcium channel TRPML1 in gastric acid secretion, based on anaylsis of knockout mice.. Gastroenterology 2011;140:857-67",
"R Dobrovolny, P Liskova, J Ledvinova, H Poupetova, B Asfaw, M Filipec, K Jirsova, J Kraus, M Elleder. Mucolipidosis IV: report of a case with ocular restricted phenotype caused by leaky splice mutation.. Am J Ophthalmol 2007;143:663-71",
"L Edelmann, J Dong, RJ Desnick, R Kornreich. Carrier screening for mucolipidosis type IV in the American Ashkenazi Jewish population.. Am J Hum Genet 2002;70:1023-7",
"KP Frei, NJ Patronas, KE Crutchfield, G Altarescu, R Schiffmann. Mucolipidosis type IV: characteristic MRI findings.. Neurology 1998;51:565-9",
"E Goldin, RC Caruso, W Benko, CR Kaneski, S Stahl, R Schiffmann. Isolated ocular disease is associated with decreased mucolipin-1 channel conductance.. Invest Ophthalmol Vis Sci. 2008;49:3134-42",
"E Goldin, A Cooney, CR Kaneski, RO Brady, R Schiffmann. Mucolipidosis IV consists of one complementation group.. Proc Natl Acad Sci U S A. 1999;96:8562-6",
"E Goldin, S Stahl, AM Cooney, CR Kaneski, S Gupta, RO Brady, JR Ellis, R Schiffmann. Transfer of a mitochondrial DNA fragment to MCOLN1 causes an inherited case of mucolipidosis IV.. Hum Mutat 2004a;24:460-5",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"M Manzoni, E Monti, R Bresciani, A Bozzato, S Barlati, MT Bassi, G Borsani. Overexpression of wild-type and mutant mucolipin proteins in mammalian cells: effects on the late endocytic compartment organization.. FEBS Lett 2004;567:219-24",
"B Pode-Shakked, Y Finezilber, Y Levi, S Liber, N Fleischer, L Greenbaum, A Raas-Rothschild. Shared facial phenotype of patients with mucolipidosis type IV: a clinical observation reaffirmed by next generation phenotyping.. Eur J Med Genet 2020;63",
"SM Pradhan, LO Atchaneeyasakul, B Appukuttan, RN Mixon, TJ McFarland, AM Billingslea, DJ Wilson, JT Stout, RG Weleber. Electronegative electroretinogram in mucolipidosis IV.. Arch Ophthalmol 2002;120:45-50",
"MK Raychowdhury, S González-Perrett, N Montalbetti, GA Timpanaro, B Chasan, WH Goldmann, S Stahl, A Cooney, E Goldin, HF Cantiello. Molecular pathophysiology of mucolipidosis type IV: pH dysregulation of the mucolipin-1 cation channel.. Hum Mol Genet 2004;13:617-27",
"R Schiffmann, NK Dwyer, IA Lubensky, M Tsokos, VE Sutliff, JS Latimer, KP Frei, RO Brady, NW Barton, EJ Blanchette-Mackie, E Goldin. Constitutive achlorhydria in mucolipidosis type IV.. Proc Natl Acad Sci U S A 1998;95:1207-12",
"R Schiffmann, J Mayfield, C Swift, I Nestrasil. Quantitative neuroimaging in mucolipidosis type IV.. Mol Genet Metab. 2014;111:147-51",
"P Segal, B Pode-Shakkaed, A Raas-Rothschild. Elucidating the behavioral phenotype of patients affected with mucolipidosis type IV: what can we learn from the parents?. Eur J Med Genet 2017;60:340-344",
"H Siegel, K Frei, J Greenfield, R Schiffmann, S Sato. Electroencephalographic findings in patients with mucolipidosis type IV.. Electroencephalogr Clin Neurophysiol 1998;106:400-3",
"JA Smith, CC Chan, E Goldin, R Schiffmann. Noninvasive diagnosis and ophthalmic features of mucolipidosis type IV.. Ophthalmology 2002;109:588-94",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"M Sun, E Goldin, S Stahl, JL Falardeau, JC Kennedy, JS Acierno, C Bove, CR Kaneski, J Nagle, MC Bromley, M Colman, R Schiffmann, SA Slaugenhaupt. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel.. Hum Mol Genet 2000;9:2471-8",
"ZH Wang, B Zeng, GM Pastores, N Raksadawan, E Ong, EH Kolodny. Rapid detection of the two common mutations in Ashkenazi Jewish patients with mucolipidosis type IV.. Genet Test 2001;5:87-92"
] |
28/1/2005
|
11/2/2021
|
1/12/2005
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mlc
|
mlc
|
[
"Van der Knaap Disease",
"Van der Knaap Disease",
"Improving Megalencephalic Leukoencephalopathy with Subcortical Cysts (Improving MLC)",
"Classic Megalencephalic Leukoencephalopathy with Subcortical Cysts (Classic MLC)",
"Aquaporin-4",
"G-protein coupled receptor family C group 5 member B",
"Hepatic and glial cell adhesion molecule",
"Membrane protein MLC1",
"AQP4",
"GPRC5B",
"HEPACAM",
"MLC1",
"Megalencephalic Leukoencephalopathy with Subcortical Cysts"
] |
Megalencephalic Leukoencephalopathy with Subcortical Cysts
|
Rogier Min, Truus EM Abbink, Marjo S van der Knaap
|
Summary Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by two phenotypes: classic MLC and improving MLC. Individuals with Individuals with The diagnosis of classic MLC is established in individuals with suggestive clinical findings and characteristic abnormalities identified on brain MRI examination, including abnormal and swollen cerebral hemispheric white matter and subcortical cysts in the anterior temporal and often frontoparietal regions; and/or biallelic loss-of-function variants in The diagnosis of improving MLC is established in individuals with suggestive clinical findings and a heterozygous gain-of-function variant in MLC is inherited in an autosomal recessive or an autosomal dominant manner. Once the MLC-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for MLC are possible.
|
Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC): Included Phenotypes
Similar initial presentation followed by stabilization, sometimes improvement, & no secondary decline
Brain MRI changes typically improve or normalize; no delayed-onset neurologic decline
AD = autosomal dominant; AR = autosomal recessive; MLC = megalencephalic leukoencephalopathy with subcortical cysts; MOI = mode of inheritance
For synonyms and outdated names, see
Genes are listed in alphabetic order by phenotype.
• Similar initial presentation followed by stabilization, sometimes improvement, & no secondary decline
• Brain MRI changes typically improve or normalize; no delayed-onset neurologic decline
## Diagnosis
Two phenotypes are observed in megalencephalic leukoencephalopathy with subcortical cysts (MLC): classic MLC and improving MLC.
Classic MLC should be suspected in individuals with the following clinical and brain imaging findings and family history.
Macrocephaly with onset that is either congenital or within the first year of life
Normal or mildly delayed early development
Slow deterioration of motor functions with cerebellar ataxia and mild spasticity
Seizures
Dysarthria
Decline in cognitive function (occurs later and is typically milder than motor decline)
Behavioral problems in some individuals
Temporary exacerbation of signs and symptoms after minor head trauma
Diffusely abnormal and mildly swollen cerebral hemispheric white matter
Subcortical cysts are almost invariably present in the anterior temporal region and often in the frontoparietal regions.
Over time, white matter swelling decreases and cerebral atrophy ensues. The subcortical cysts may increase in size and number. In some individuals, the cysts become very large, occupying a large part of the frontoparietal white matter. In others, the white matter abnormalities decrease over time, and signal intensities become less abnormal.
Diffusion-weighted imaging reveals increased diffusivity of abnormal white matter [
Improving MLC should be suspected in individuals with the following clinical and brain imaging findings and family history.
Macrocephaly with onset that is either congenital or within the first year of life; macrocephaly may persist or head size may be in the normal range in older individuals
Normal or mildly delayed early development
Motor function improves after the first year of life (clumsiness and hypotonia may persist)
Seizures in some individuals
Intellectual disability (with or without autism spectrum disorder) or normal cognitive function
No regression of mental or motor functions
Brain MRI abnormalities within the first year of life are similar to those seen in the classic MLC phenotype, but cerebellar white matter is usually normal.
Striking improvement occurs over time. Brain MRI may appear normal within a few years and no longer diagnostic of MLC. In some individuals, minor frontal and temporal subcortical white matter abnormalities and anterior temporal cysts persist.
The clinical diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC) can be
The molecular diagnosis of
The molecular diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: If no pathogenic variant(s) are identified in any of the genes listed in
For an introduction to multigene panels click
When the phenotype is similar to many other inherited disorders characterized by macrocephaly and white matter abnormalities,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Megalencephalic Leukoencephalopathy with Subcortical Cysts
AD = autosomal dominant; AR = autosomal recessive; MLC = megalencephalic leukoencephalopathy with subcortical cysts; MOI = mode of inheritance; NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (as seen with
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A fraction of these variants are in a splice junction (most are within the canonical splice site, although deep intronic variants have also been reported).
No large intragenic deletions/duplications have been reported in individuals with
Including multiexon deletions [
In some individuals with clinical and brain MRI findings of MLC, pathogenic variants in
• Macrocephaly with onset that is either congenital or within the first year of life
• Normal or mildly delayed early development
• Slow deterioration of motor functions with cerebellar ataxia and mild spasticity
• Seizures
• Dysarthria
• Decline in cognitive function (occurs later and is typically milder than motor decline)
• Behavioral problems in some individuals
• Temporary exacerbation of signs and symptoms after minor head trauma
• Diffusely abnormal and mildly swollen cerebral hemispheric white matter
• Subcortical cysts are almost invariably present in the anterior temporal region and often in the frontoparietal regions.
• Over time, white matter swelling decreases and cerebral atrophy ensues. The subcortical cysts may increase in size and number. In some individuals, the cysts become very large, occupying a large part of the frontoparietal white matter. In others, the white matter abnormalities decrease over time, and signal intensities become less abnormal.
• Diffusion-weighted imaging reveals increased diffusivity of abnormal white matter [
• Macrocephaly with onset that is either congenital or within the first year of life; macrocephaly may persist or head size may be in the normal range in older individuals
• Normal or mildly delayed early development
• Motor function improves after the first year of life (clumsiness and hypotonia may persist)
• Seizures in some individuals
• Intellectual disability (with or without autism spectrum disorder) or normal cognitive function
• No regression of mental or motor functions
• Brain MRI abnormalities within the first year of life are similar to those seen in the classic MLC phenotype, but cerebellar white matter is usually normal.
• Striking improvement occurs over time. Brain MRI may appear normal within a few years and no longer diagnostic of MLC. In some individuals, minor frontal and temporal subcortical white matter abnormalities and anterior temporal cysts persist.
## Suggestive Findings
Two phenotypes are observed in megalencephalic leukoencephalopathy with subcortical cysts (MLC): classic MLC and improving MLC.
Classic MLC should be suspected in individuals with the following clinical and brain imaging findings and family history.
Macrocephaly with onset that is either congenital or within the first year of life
Normal or mildly delayed early development
Slow deterioration of motor functions with cerebellar ataxia and mild spasticity
Seizures
Dysarthria
Decline in cognitive function (occurs later and is typically milder than motor decline)
Behavioral problems in some individuals
Temporary exacerbation of signs and symptoms after minor head trauma
Diffusely abnormal and mildly swollen cerebral hemispheric white matter
Subcortical cysts are almost invariably present in the anterior temporal region and often in the frontoparietal regions.
Over time, white matter swelling decreases and cerebral atrophy ensues. The subcortical cysts may increase in size and number. In some individuals, the cysts become very large, occupying a large part of the frontoparietal white matter. In others, the white matter abnormalities decrease over time, and signal intensities become less abnormal.
Diffusion-weighted imaging reveals increased diffusivity of abnormal white matter [
Improving MLC should be suspected in individuals with the following clinical and brain imaging findings and family history.
Macrocephaly with onset that is either congenital or within the first year of life; macrocephaly may persist or head size may be in the normal range in older individuals
Normal or mildly delayed early development
Motor function improves after the first year of life (clumsiness and hypotonia may persist)
Seizures in some individuals
Intellectual disability (with or without autism spectrum disorder) or normal cognitive function
No regression of mental or motor functions
Brain MRI abnormalities within the first year of life are similar to those seen in the classic MLC phenotype, but cerebellar white matter is usually normal.
Striking improvement occurs over time. Brain MRI may appear normal within a few years and no longer diagnostic of MLC. In some individuals, minor frontal and temporal subcortical white matter abnormalities and anterior temporal cysts persist.
• Macrocephaly with onset that is either congenital or within the first year of life
• Normal or mildly delayed early development
• Slow deterioration of motor functions with cerebellar ataxia and mild spasticity
• Seizures
• Dysarthria
• Decline in cognitive function (occurs later and is typically milder than motor decline)
• Behavioral problems in some individuals
• Temporary exacerbation of signs and symptoms after minor head trauma
• Diffusely abnormal and mildly swollen cerebral hemispheric white matter
• Subcortical cysts are almost invariably present in the anterior temporal region and often in the frontoparietal regions.
• Over time, white matter swelling decreases and cerebral atrophy ensues. The subcortical cysts may increase in size and number. In some individuals, the cysts become very large, occupying a large part of the frontoparietal white matter. In others, the white matter abnormalities decrease over time, and signal intensities become less abnormal.
• Diffusion-weighted imaging reveals increased diffusivity of abnormal white matter [
• Macrocephaly with onset that is either congenital or within the first year of life; macrocephaly may persist or head size may be in the normal range in older individuals
• Normal or mildly delayed early development
• Motor function improves after the first year of life (clumsiness and hypotonia may persist)
• Seizures in some individuals
• Intellectual disability (with or without autism spectrum disorder) or normal cognitive function
• No regression of mental or motor functions
• Brain MRI abnormalities within the first year of life are similar to those seen in the classic MLC phenotype, but cerebellar white matter is usually normal.
• Striking improvement occurs over time. Brain MRI may appear normal within a few years and no longer diagnostic of MLC. In some individuals, minor frontal and temporal subcortical white matter abnormalities and anterior temporal cysts persist.
## Classic MLC
Classic MLC should be suspected in individuals with the following clinical and brain imaging findings and family history.
Macrocephaly with onset that is either congenital or within the first year of life
Normal or mildly delayed early development
Slow deterioration of motor functions with cerebellar ataxia and mild spasticity
Seizures
Dysarthria
Decline in cognitive function (occurs later and is typically milder than motor decline)
Behavioral problems in some individuals
Temporary exacerbation of signs and symptoms after minor head trauma
Diffusely abnormal and mildly swollen cerebral hemispheric white matter
Subcortical cysts are almost invariably present in the anterior temporal region and often in the frontoparietal regions.
Over time, white matter swelling decreases and cerebral atrophy ensues. The subcortical cysts may increase in size and number. In some individuals, the cysts become very large, occupying a large part of the frontoparietal white matter. In others, the white matter abnormalities decrease over time, and signal intensities become less abnormal.
Diffusion-weighted imaging reveals increased diffusivity of abnormal white matter [
• Macrocephaly with onset that is either congenital or within the first year of life
• Normal or mildly delayed early development
• Slow deterioration of motor functions with cerebellar ataxia and mild spasticity
• Seizures
• Dysarthria
• Decline in cognitive function (occurs later and is typically milder than motor decline)
• Behavioral problems in some individuals
• Temporary exacerbation of signs and symptoms after minor head trauma
• Diffusely abnormal and mildly swollen cerebral hemispheric white matter
• Subcortical cysts are almost invariably present in the anterior temporal region and often in the frontoparietal regions.
• Over time, white matter swelling decreases and cerebral atrophy ensues. The subcortical cysts may increase in size and number. In some individuals, the cysts become very large, occupying a large part of the frontoparietal white matter. In others, the white matter abnormalities decrease over time, and signal intensities become less abnormal.
• Diffusion-weighted imaging reveals increased diffusivity of abnormal white matter [
## Improving MLC
Improving MLC should be suspected in individuals with the following clinical and brain imaging findings and family history.
Macrocephaly with onset that is either congenital or within the first year of life; macrocephaly may persist or head size may be in the normal range in older individuals
Normal or mildly delayed early development
Motor function improves after the first year of life (clumsiness and hypotonia may persist)
Seizures in some individuals
Intellectual disability (with or without autism spectrum disorder) or normal cognitive function
No regression of mental or motor functions
Brain MRI abnormalities within the first year of life are similar to those seen in the classic MLC phenotype, but cerebellar white matter is usually normal.
Striking improvement occurs over time. Brain MRI may appear normal within a few years and no longer diagnostic of MLC. In some individuals, minor frontal and temporal subcortical white matter abnormalities and anterior temporal cysts persist.
• Macrocephaly with onset that is either congenital or within the first year of life; macrocephaly may persist or head size may be in the normal range in older individuals
• Normal or mildly delayed early development
• Motor function improves after the first year of life (clumsiness and hypotonia may persist)
• Seizures in some individuals
• Intellectual disability (with or without autism spectrum disorder) or normal cognitive function
• No regression of mental or motor functions
• Brain MRI abnormalities within the first year of life are similar to those seen in the classic MLC phenotype, but cerebellar white matter is usually normal.
• Striking improvement occurs over time. Brain MRI may appear normal within a few years and no longer diagnostic of MLC. In some individuals, minor frontal and temporal subcortical white matter abnormalities and anterior temporal cysts persist.
## Establishing the Diagnosis
The clinical diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC) can be
The molecular diagnosis of
The molecular diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: If no pathogenic variant(s) are identified in any of the genes listed in
For an introduction to multigene panels click
When the phenotype is similar to many other inherited disorders characterized by macrocephaly and white matter abnormalities,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Megalencephalic Leukoencephalopathy with Subcortical Cysts
AD = autosomal dominant; AR = autosomal recessive; MLC = megalencephalic leukoencephalopathy with subcortical cysts; MOI = mode of inheritance; NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (as seen with
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A fraction of these variants are in a splice junction (most are within the canonical splice site, although deep intronic variants have also been reported).
No large intragenic deletions/duplications have been reported in individuals with
Including multiexon deletions [
In some individuals with clinical and brain MRI findings of MLC, pathogenic variants in
## Option 1
Note: If no pathogenic variant(s) are identified in any of the genes listed in
For an introduction to multigene panels click
## Option 2
When the phenotype is similar to many other inherited disorders characterized by macrocephaly and white matter abnormalities,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Megalencephalic Leukoencephalopathy with Subcortical Cysts
AD = autosomal dominant; AR = autosomal recessive; MLC = megalencephalic leukoencephalopathy with subcortical cysts; MOI = mode of inheritance; NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (as seen with
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A fraction of these variants are in a splice junction (most are within the canonical splice site, although deep intronic variants have also been reported).
No large intragenic deletions/duplications have been reported in individuals with
Including multiexon deletions [
In some individuals with clinical and brain MRI findings of MLC, pathogenic variants in
## Clinical Characteristics
The two phenotypes observed in individuals with megalencephalic leukoencephalopathy with subcortical cysts (MLC) are classic MLC and improving MLC.
To date, approximately 500 individuals have been identified with biallelic pathogenic variants in
Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC): Comparison of Phenotypes by Select Features
Data based on
ID = intellectual disability; MLC = megalencephalic leukoencephalopathy with subcortical cysts
Slow deterioration of motor function occurs over years with development of ataxia of the trunk and extremities. Signs of pyramidal dysfunction are late and minor and largely dominated by signs of cerebellar ataxia. Speech becomes increasingly dysarthric and dysphagia may develop. Deep tendon reflexes become brisk and Babinski signs become apparent. Some individuals display extrapyramidal movement abnormalities with dystonia and athetosis. Some individuals also develop tics [
Gradually, the ability to walk independently is lost and many children become completely wheelchair dependent at the end of the first decade or in the second decade of life. Some children have a more severe clinical course and maintain their ability to walk independently for only a few years, or never achieve independent walking. Others maintain the ability to walk independently into the fifth decade of life.
In children diagnosed with improving MLC due to heterozygous gain-of-function variants in
In families with multiple affected individuals in more than one generation, the proband is usually the child and the affected parent is subsequently diagnosed. Parents with a heterozygous pathogenic variant in
Only two sibs have been reported to date with biallelic pathogenic variants in
The three individuals with
In biallelic
Subtypes of megalencephalic leukoencephalopathy with subcortical cysts (MLC) were previously named according to the genetic loci associated with each subtype:
MLC1, associated with biallelic pathogenic variants in
MLC2A, associated with biallelic pathogenic variants in
MLC3, associated with heterozygous pathogenic variants in
MLC2B, associated with heterozygous pathogenic variants in
MLC4, associated with biallelic pathogenic variants in
Other names previously used for MLC:
Leukoencephalopathy with swelling and a discrepantly mild course
Leukoencephalopathy with swelling and cysts
Infantile leukoencephalopathy and megalencephaly
Vacuolating leukoencephalopathy
There are several populations where founder variants in MLC-associated genes have been identified (see
Founder variants in
• In biallelic
•
• MLC1, associated with biallelic pathogenic variants in
• MLC2A, associated with biallelic pathogenic variants in
• MLC3, associated with heterozygous pathogenic variants in
• MLC1, associated with biallelic pathogenic variants in
• MLC2A, associated with biallelic pathogenic variants in
• MLC3, associated with heterozygous pathogenic variants in
•
• MLC2B, associated with heterozygous pathogenic variants in
• MLC4, associated with biallelic pathogenic variants in
• MLC2B, associated with heterozygous pathogenic variants in
• MLC4, associated with biallelic pathogenic variants in
• MLC1, associated with biallelic pathogenic variants in
• MLC2A, associated with biallelic pathogenic variants in
• MLC3, associated with heterozygous pathogenic variants in
• MLC2B, associated with heterozygous pathogenic variants in
• MLC4, associated with biallelic pathogenic variants in
• Leukoencephalopathy with swelling and a discrepantly mild course
• Leukoencephalopathy with swelling and cysts
• Infantile leukoencephalopathy and megalencephaly
• Vacuolating leukoencephalopathy
## Clinical Description
The two phenotypes observed in individuals with megalencephalic leukoencephalopathy with subcortical cysts (MLC) are classic MLC and improving MLC.
To date, approximately 500 individuals have been identified with biallelic pathogenic variants in
Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC): Comparison of Phenotypes by Select Features
Data based on
ID = intellectual disability; MLC = megalencephalic leukoencephalopathy with subcortical cysts
Slow deterioration of motor function occurs over years with development of ataxia of the trunk and extremities. Signs of pyramidal dysfunction are late and minor and largely dominated by signs of cerebellar ataxia. Speech becomes increasingly dysarthric and dysphagia may develop. Deep tendon reflexes become brisk and Babinski signs become apparent. Some individuals display extrapyramidal movement abnormalities with dystonia and athetosis. Some individuals also develop tics [
Gradually, the ability to walk independently is lost and many children become completely wheelchair dependent at the end of the first decade or in the second decade of life. Some children have a more severe clinical course and maintain their ability to walk independently for only a few years, or never achieve independent walking. Others maintain the ability to walk independently into the fifth decade of life.
In children diagnosed with improving MLC due to heterozygous gain-of-function variants in
In families with multiple affected individuals in more than one generation, the proband is usually the child and the affected parent is subsequently diagnosed. Parents with a heterozygous pathogenic variant in
Only two sibs have been reported to date with biallelic pathogenic variants in
## Classic MLC
Slow deterioration of motor function occurs over years with development of ataxia of the trunk and extremities. Signs of pyramidal dysfunction are late and minor and largely dominated by signs of cerebellar ataxia. Speech becomes increasingly dysarthric and dysphagia may develop. Deep tendon reflexes become brisk and Babinski signs become apparent. Some individuals display extrapyramidal movement abnormalities with dystonia and athetosis. Some individuals also develop tics [
Gradually, the ability to walk independently is lost and many children become completely wheelchair dependent at the end of the first decade or in the second decade of life. Some children have a more severe clinical course and maintain their ability to walk independently for only a few years, or never achieve independent walking. Others maintain the ability to walk independently into the fifth decade of life.
## Improving MLC
In children diagnosed with improving MLC due to heterozygous gain-of-function variants in
In families with multiple affected individuals in more than one generation, the proband is usually the child and the affected parent is subsequently diagnosed. Parents with a heterozygous pathogenic variant in
Only two sibs have been reported to date with biallelic pathogenic variants in
## Phenotype Correlations by Gene
The three individuals with
## Genotype-Phenotype Correlations
In biallelic
• In biallelic
## Nomenclature
Subtypes of megalencephalic leukoencephalopathy with subcortical cysts (MLC) were previously named according to the genetic loci associated with each subtype:
MLC1, associated with biallelic pathogenic variants in
MLC2A, associated with biallelic pathogenic variants in
MLC3, associated with heterozygous pathogenic variants in
MLC2B, associated with heterozygous pathogenic variants in
MLC4, associated with biallelic pathogenic variants in
Other names previously used for MLC:
Leukoencephalopathy with swelling and a discrepantly mild course
Leukoencephalopathy with swelling and cysts
Infantile leukoencephalopathy and megalencephaly
Vacuolating leukoencephalopathy
•
• MLC1, associated with biallelic pathogenic variants in
• MLC2A, associated with biallelic pathogenic variants in
• MLC3, associated with heterozygous pathogenic variants in
• MLC1, associated with biallelic pathogenic variants in
• MLC2A, associated with biallelic pathogenic variants in
• MLC3, associated with heterozygous pathogenic variants in
•
• MLC2B, associated with heterozygous pathogenic variants in
• MLC4, associated with biallelic pathogenic variants in
• MLC2B, associated with heterozygous pathogenic variants in
• MLC4, associated with biallelic pathogenic variants in
• MLC1, associated with biallelic pathogenic variants in
• MLC2A, associated with biallelic pathogenic variants in
• MLC3, associated with heterozygous pathogenic variants in
• MLC2B, associated with heterozygous pathogenic variants in
• MLC4, associated with biallelic pathogenic variants in
• Leukoencephalopathy with swelling and a discrepantly mild course
• Leukoencephalopathy with swelling and cysts
• Infantile leukoencephalopathy and megalencephaly
• Vacuolating leukoencephalopathy
## Penetrance
## Prevalence
There are several populations where founder variants in MLC-associated genes have been identified (see
Founder variants in
## Genetically Related (Allelic) Disorders
Associations of
## Differential Diagnosis
The differential diagnosis of macrocephaly and diffuse leukoencephalopathy is limited. Other disorders with white matter disease and swelling of the abnormal white matter are listed in
Note: If the head circumference of an infant is well within the normal limits at age one year, it is highly unlikely that the infant has MLC.
Disorders of Interest in the Differential Diagnosis of Megalencephalic Leukoencephalopathy with Subcortical Cysts
WM abnormalities are limited to the directly subcortical WM in some persons.
MRI typically shows involvement of thalamus & globus pallidus w/relative sparing of bilateral crescent formed by putamen & caudate nucleus (globus pallidus & thalamus are not involved in MLC).
Absence of the typical subcortical cysts seen in MLC
Frontal predominance of MRI abnormalities (predilection for anterior parts of brain is less clear in MLC)
Cysts usually located in deep frontal WM (different from MLC)
Mild signal abnormalities of basal ganglia & thalami (not seen in MLC)
Contrast enhancement of specific brain structures almost invariably seen (not seen in MLC)
Typical involvement of brain stem structures (signal abnormalities, tumor-like structures, atrophy) (not seen in MLC)
Cerebral WM abnormalities are limited to directly subcortical WM in some persons.
Cerebral WM abnormalities are multifocal in some persons (invariably diffuse in MLC).
MRI typically shows involvement of basal nuclei (not seen in MLC).
Dentate nucleus is typically prominently affected (not in MLC).
AD = autosomal dominant; AR = autosomal recessive; MLC = megalencephalic leukoencephalopathy with subcortical cysts; MOI = mode of inheritance; WM = white matter
MDC1A is associated with prominent weakness and hypotonia (features not seen in MLC).
• WM abnormalities are limited to the directly subcortical WM in some persons.
• MRI typically shows involvement of thalamus & globus pallidus w/relative sparing of bilateral crescent formed by putamen & caudate nucleus (globus pallidus & thalamus are not involved in MLC).
• Absence of the typical subcortical cysts seen in MLC
• Frontal predominance of MRI abnormalities (predilection for anterior parts of brain is less clear in MLC)
• Cysts usually located in deep frontal WM (different from MLC)
• Mild signal abnormalities of basal ganglia & thalami (not seen in MLC)
• Contrast enhancement of specific brain structures almost invariably seen (not seen in MLC)
• Typical involvement of brain stem structures (signal abnormalities, tumor-like structures, atrophy) (not seen in MLC)
• Cerebral WM abnormalities are limited to directly subcortical WM in some persons.
• Cerebral WM abnormalities are multifocal in some persons (invariably diffuse in MLC).
• MRI typically shows involvement of basal nuclei (not seen in MLC).
• Dentate nucleus is typically prominently affected (not in MLC).
## Management
To establish the extent of disease and needs in an individual diagnosed with megalencephalic leukoencephalopathy with subcortical cysts (MLC), the evaluations summarized in
Megalencephalic Leukoencephalopathy with Subcortical Cysts: Recommended Evaluations Following Initial Diagnosis
Assess for macrocephaly (esp if progressive).
Brain MRI in those w/megalencephaly to assess white matter & subcortical structures (See
Consider EEG if seizures are a concern.
To incl physical, occupational, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support.
Home nursing referral.
MLC = megalencephalic leukoencephalopathy with subcortical cysts; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for MLC.
Megalencephalic Leukoencephalopathy with Subcortical Cysts: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Megalencephalic Leukoencephalopathy with Subcortical Cysts: Recommended Surveillance
In individuals with classic MLC, minor head trauma may lead to temporary motor deterioration, seizures, or (rarely) coma. For this reason, contact sports and other activities with a high risk of head trauma should be avoided in affected individuals. Wearing a helmet should also be considered for situations associated with increased risk of head trauma.
See
Potential teratogenic effects of anti-seizure medication should be discussed with affected women of childbearing age, ideally prior to conception.
See
Search
• Assess for macrocephaly (esp if progressive).
• Brain MRI in those w/megalencephaly to assess white matter & subcortical structures (See
• Consider EEG if seizures are a concern.
• To incl physical, occupational, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support.
• Home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with megalencephalic leukoencephalopathy with subcortical cysts (MLC), the evaluations summarized in
Megalencephalic Leukoencephalopathy with Subcortical Cysts: Recommended Evaluations Following Initial Diagnosis
Assess for macrocephaly (esp if progressive).
Brain MRI in those w/megalencephaly to assess white matter & subcortical structures (See
Consider EEG if seizures are a concern.
To incl physical, occupational, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support.
Home nursing referral.
MLC = megalencephalic leukoencephalopathy with subcortical cysts; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assess for macrocephaly (esp if progressive).
• Brain MRI in those w/megalencephaly to assess white matter & subcortical structures (See
• Consider EEG if seizures are a concern.
• To incl physical, occupational, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support.
• Home nursing referral.
## Treatment of Manifestations
There is no cure for MLC.
Megalencephalic Leukoencephalopathy with Subcortical Cysts: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Megalencephalic Leukoencephalopathy with Subcortical Cysts: Recommended Surveillance
## Agents/Circumstances to Avoid
In individuals with classic MLC, minor head trauma may lead to temporary motor deterioration, seizures, or (rarely) coma. For this reason, contact sports and other activities with a high risk of head trauma should be avoided in affected individuals. Wearing a helmet should also be considered for situations associated with increased risk of head trauma.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Potential teratogenic effects of anti-seizure medication should be discussed with affected women of childbearing age, ideally prior to conception.
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of a child with autosomal recessive MLC (i.e., a child with
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an autosomal recessive MLC-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Individuals who are heterozygous for an
Individuals who are heterozygous for a
Individuals who are heterozygous for an
If both parents are known to be heterozygous for a pathogenic variant associated with autosomal recessive MLC, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
Intrafamilial variability has been observed in
Individuals who are heterozygous for an
Individuals who are heterozygous for a
Individuals who are heterozygous for an
Carrier testing for at-risk relatives requires prior identification of the MLC-related pathogenic variants in the family.
Many individuals with heterozygous
A proband with heterozygous
In the three individuals reported to date with
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with heterozygous
If a parent of the proband is affected and/or is known to have the autosomal dominant MLC-related pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
If the heterozygous
If the parents have not been tested for the heterozygous
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are carriers (or are at risk of being carriers) of MLC-related pathogenic variants.
Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for MLC are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of a child with autosomal recessive MLC (i.e., a child with
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an autosomal recessive MLC-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for an
• Individuals who are heterozygous for a
• Individuals who are heterozygous for an
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a pathogenic variant associated with autosomal recessive MLC, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Intrafamilial variability has been observed in
• Individuals who are heterozygous for an
• Individuals who are heterozygous for a
• Individuals who are heterozygous for an
• Many individuals with heterozygous
• A proband with heterozygous
• In the three individuals reported to date with
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with heterozygous
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the autosomal dominant MLC-related pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the heterozygous
• If the parents have not been tested for the heterozygous
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are carriers (or are at risk of being carriers) of MLC-related pathogenic variants.
## Mode of Inheritance
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with autosomal recessive MLC (i.e., a child with
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an autosomal recessive MLC-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Individuals who are heterozygous for an
Individuals who are heterozygous for a
Individuals who are heterozygous for an
If both parents are known to be heterozygous for a pathogenic variant associated with autosomal recessive MLC, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
Intrafamilial variability has been observed in
Individuals who are heterozygous for an
Individuals who are heterozygous for a
Individuals who are heterozygous for an
Carrier testing for at-risk relatives requires prior identification of the MLC-related pathogenic variants in the family.
• The parents of a child with autosomal recessive MLC (i.e., a child with
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an autosomal recessive MLC-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for an
• Individuals who are heterozygous for a
• Individuals who are heterozygous for an
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a pathogenic variant associated with autosomal recessive MLC, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Intrafamilial variability has been observed in
• Individuals who are heterozygous for an
• Individuals who are heterozygous for a
• Individuals who are heterozygous for an
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the MLC-related pathogenic variants in the family.
## Autosomal Dominant Inheritance – Risk to Family Members
Many individuals with heterozygous
A proband with heterozygous
In the three individuals reported to date with
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with heterozygous
If a parent of the proband is affected and/or is known to have the autosomal dominant MLC-related pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
If the heterozygous
If the parents have not been tested for the heterozygous
• Many individuals with heterozygous
• A proband with heterozygous
• In the three individuals reported to date with
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with heterozygous
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the autosomal dominant MLC-related pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the heterozygous
• If the parents have not been tested for the heterozygous
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are carriers (or are at risk of being carriers) of MLC-related pathogenic variants.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are carriers (or are at risk of being carriers) of MLC-related pathogenic variants.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for MLC are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Australia
•
•
•
•
•
• Australia
•
•
•
•
•
## Molecular Genetics
Megalencephalic Leukoencephalopathy with Subcortical Cysts: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Megalencephalic Leukoencephalopathy with Subcortical Cysts (
All MLC-causing variants in
The recessive pathogenic variant p.Ala215Thr in aquaporin-4 alters the second of two highly conserved Asn-Pro-Ala (NPA) motifs that form the narrow central part of the water channel. These motifs are crucial for selective water permeability and for localization of the channel to the plasma membrane [
Megalencephalic Leukoencephalopathy with Subcortical Cysts: Gene-Specific Laboratory Considerations
MLC = megalencephalic leukoencephalopathy with subcortical cysts
Genes from
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
MLC = megalencephalic leukoencephalopathy with subcortical cysts; UTR = untranslated region
Genes from
## Molecular Pathogenesis
All MLC-causing variants in
The recessive pathogenic variant p.Ala215Thr in aquaporin-4 alters the second of two highly conserved Asn-Pro-Ala (NPA) motifs that form the narrow central part of the water channel. These motifs are crucial for selective water permeability and for localization of the channel to the plasma membrane [
Megalencephalic Leukoencephalopathy with Subcortical Cysts: Gene-Specific Laboratory Considerations
MLC = megalencephalic leukoencephalopathy with subcortical cysts
Genes from
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
MLC = megalencephalic leukoencephalopathy with subcortical cysts; UTR = untranslated region
Genes from
## Chapter Notes
The authors are happy to offer cDNA analysis of
Truus EM Abbink, PhD (2018-present)
Rogier Min, PhD (2018-present)
JC Pronk, PhD; Vrije Universiteit Medical Center, Amsterdam (2003-2008)
Gert C Scheper, PhD; Vrije Universiteit Medical Center, Amsterdam (2008-2018)
Marjo S van der Knaap, MD, PhD (2003-present)
27 July 2023 (gm) Comprehensive update posted live
29 March 2018 (sw) Comprehensive update posted live
3 November 2011 (me) Comprehensive update posted live
29 July 2008 (me) Comprehensive update posted live
29 November 2005 (me) Comprehensive update posted live
11 August 2003 (me) Review posted live
12 June 2003 (mvdk) Original submission
• 27 July 2023 (gm) Comprehensive update posted live
• 29 March 2018 (sw) Comprehensive update posted live
• 3 November 2011 (me) Comprehensive update posted live
• 29 July 2008 (me) Comprehensive update posted live
• 29 November 2005 (me) Comprehensive update posted live
• 11 August 2003 (me) Review posted live
• 12 June 2003 (mvdk) Original submission
## Author Notes
The authors are happy to offer cDNA analysis of
## Author History
Truus EM Abbink, PhD (2018-present)
Rogier Min, PhD (2018-present)
JC Pronk, PhD; Vrije Universiteit Medical Center, Amsterdam (2003-2008)
Gert C Scheper, PhD; Vrije Universiteit Medical Center, Amsterdam (2008-2018)
Marjo S van der Knaap, MD, PhD (2003-present)
## Revision History
27 July 2023 (gm) Comprehensive update posted live
29 March 2018 (sw) Comprehensive update posted live
3 November 2011 (me) Comprehensive update posted live
29 July 2008 (me) Comprehensive update posted live
29 November 2005 (me) Comprehensive update posted live
11 August 2003 (me) Review posted live
12 June 2003 (mvdk) Original submission
• 27 July 2023 (gm) Comprehensive update posted live
• 29 March 2018 (sw) Comprehensive update posted live
• 3 November 2011 (me) Comprehensive update posted live
• 29 July 2008 (me) Comprehensive update posted live
• 29 November 2005 (me) Comprehensive update posted live
• 11 August 2003 (me) Review posted live
• 12 June 2003 (mvdk) Original submission
## References
## Literature Cited
Brain images of an individual with MLC (A, C) and an unaffected individual (B, D)
A. Transverse T
B. Transverse T
C. Sagittal T
D. Sagittal T
|
[] |
11/8/2003
|
27/7/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mld
|
mld
|
[
"ARSA Deficiency",
"Metachromatic Leukodystrophy",
"Metachromatic Leukodystrophy",
"ARSA Deficiency",
"Arylsulfatase A",
"ARSA",
"Arylsulfatase A Deficiency"
] |
Arylsulfatase A Deficiency
|
Natalia Gomez-Ospina
|
Summary Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile, juvenile, and adult MLD. The age of onset within a family is usually similar. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms. The diagnosis of MLD is established in a proband with the suggestive findings of progressive neurologic dysfunction, brain MRI evidence of leukodystrophy, or arylsulfatase A enzyme deficiency by identification of biallelic MLD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing of at-risk family members and prenatal testing for a pregnancy at increased risk are possible if both
|
## Diagnosis
Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD)
Note: (1) The use of low-temperature assays can minimize interference by other arylsulfatases and lower the baseline level [
Note: For MLD, the term "pseudodeficiency" refers to very low levels of arylsulfatase A enzyme activity in an otherwise healthy individual. The term has been applied to other enzyme deficiency disorders, such as
MLD is among the 14 disorders included in ScreenPlus, a pilot NBS study including 100,000 infants [
The diagnosis of MLD
Identification of biallelic
Identification of increased urinary excretion of sulfatides (See
Identification of metachromatic lipid deposits in nervous system tissue following a nerve or brain biopsy (See
Three classes of
Alleles with two
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by progressive neurologic dysfunction,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Arylsulfatase A Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are undetected. For issues to consider in the interpretation of sequence analysis results, click
This test method also detects the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Complete deletion of
Individuals with all types of MLD excrete abnormally high sulfatides in urine. These can be quantified by high-performance liquid chromatography (HPLC), mass spectrometry, and thin-layer chromatography (TLC). TLC is a semiquantitative method. For HPLC and mass spectrometry, reference and pathologic values vary by laboratory. For sample preparation, it is important to note that wipes containing soaps and lotions should be avoided before collection, as these products may interfere with the accuracy of the test results. Lab specimen collection recommendations also vary. Some require a first morning, random urine specimen, while others may require a 24-hour collection. The samples are stable refrigerated or at ambient temperature for up to 45 days. Samples can also be frozen and remain stable for up to 19 months.
Note: Elevated urine sulfatides and arylsulfatase A enzyme deficiency in the presence of dysmorphic features, dysostosis multiplex, or ichthyosis should prompt evaluation for multiple sulfatase deficiency (see
Sulfatides interact strongly with certain positively charged dyes used to stain tissues, resulting in a shift in the color of the stained tissue termed metachromasia. When frozen tissue sections are treated with acidified cresyl violet (Hirsch-Peiffer stain), sulfatide-rich storage deposits stain a golden brown. The finding of metachromatic lipid deposits in nervous system tissue is pathognomonic for MLD.
Note: (1) Fixing the tissue with alcohol before staining extracts the sulfatides such that the metachromasia is no longer observed. (2) Although still considered by some to be the diagnostic "gold standard" for MLD, this highly invasive approach is now used only in exceptional circumstances (e.g., confirmation of a prenatal diagnosis of MLD following pregnancy termination).
• Note: (1) The use of low-temperature assays can minimize interference by other arylsulfatases and lower the baseline level [
• Identification of biallelic
• Identification of increased urinary excretion of sulfatides (See
• Identification of metachromatic lipid deposits in nervous system tissue following a nerve or brain biopsy (See
• Alleles with two
## Suggestive Findings
Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD)
Note: (1) The use of low-temperature assays can minimize interference by other arylsulfatases and lower the baseline level [
Note: For MLD, the term "pseudodeficiency" refers to very low levels of arylsulfatase A enzyme activity in an otherwise healthy individual. The term has been applied to other enzyme deficiency disorders, such as
MLD is among the 14 disorders included in ScreenPlus, a pilot NBS study including 100,000 infants [
• Note: (1) The use of low-temperature assays can minimize interference by other arylsulfatases and lower the baseline level [
## Establishing the Diagnosis
The diagnosis of MLD
Identification of biallelic
Identification of increased urinary excretion of sulfatides (See
Identification of metachromatic lipid deposits in nervous system tissue following a nerve or brain biopsy (See
Three classes of
Alleles with two
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by progressive neurologic dysfunction,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Arylsulfatase A Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are undetected. For issues to consider in the interpretation of sequence analysis results, click
This test method also detects the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Complete deletion of
Individuals with all types of MLD excrete abnormally high sulfatides in urine. These can be quantified by high-performance liquid chromatography (HPLC), mass spectrometry, and thin-layer chromatography (TLC). TLC is a semiquantitative method. For HPLC and mass spectrometry, reference and pathologic values vary by laboratory. For sample preparation, it is important to note that wipes containing soaps and lotions should be avoided before collection, as these products may interfere with the accuracy of the test results. Lab specimen collection recommendations also vary. Some require a first morning, random urine specimen, while others may require a 24-hour collection. The samples are stable refrigerated or at ambient temperature for up to 45 days. Samples can also be frozen and remain stable for up to 19 months.
Note: Elevated urine sulfatides and arylsulfatase A enzyme deficiency in the presence of dysmorphic features, dysostosis multiplex, or ichthyosis should prompt evaluation for multiple sulfatase deficiency (see
Sulfatides interact strongly with certain positively charged dyes used to stain tissues, resulting in a shift in the color of the stained tissue termed metachromasia. When frozen tissue sections are treated with acidified cresyl violet (Hirsch-Peiffer stain), sulfatide-rich storage deposits stain a golden brown. The finding of metachromatic lipid deposits in nervous system tissue is pathognomonic for MLD.
Note: (1) Fixing the tissue with alcohol before staining extracts the sulfatides such that the metachromasia is no longer observed. (2) Although still considered by some to be the diagnostic "gold standard" for MLD, this highly invasive approach is now used only in exceptional circumstances (e.g., confirmation of a prenatal diagnosis of MLD following pregnancy termination).
• Identification of biallelic
• Identification of increased urinary excretion of sulfatides (See
• Identification of metachromatic lipid deposits in nervous system tissue following a nerve or brain biopsy (See
• Alleles with two
## Molecular Genetic Testing
Three classes of
Alleles with two
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by progressive neurologic dysfunction,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Arylsulfatase A Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are undetected. For issues to consider in the interpretation of sequence analysis results, click
This test method also detects the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Complete deletion of
• Alleles with two
##
For an introduction to multigene panels click
##
When the phenotype is indistinguishable from many other inherited disorders characterized by progressive neurologic dysfunction,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Arylsulfatase A Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are undetected. For issues to consider in the interpretation of sequence analysis results, click
This test method also detects the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Complete deletion of
## Other Testing
Individuals with all types of MLD excrete abnormally high sulfatides in urine. These can be quantified by high-performance liquid chromatography (HPLC), mass spectrometry, and thin-layer chromatography (TLC). TLC is a semiquantitative method. For HPLC and mass spectrometry, reference and pathologic values vary by laboratory. For sample preparation, it is important to note that wipes containing soaps and lotions should be avoided before collection, as these products may interfere with the accuracy of the test results. Lab specimen collection recommendations also vary. Some require a first morning, random urine specimen, while others may require a 24-hour collection. The samples are stable refrigerated or at ambient temperature for up to 45 days. Samples can also be frozen and remain stable for up to 19 months.
Note: Elevated urine sulfatides and arylsulfatase A enzyme deficiency in the presence of dysmorphic features, dysostosis multiplex, or ichthyosis should prompt evaluation for multiple sulfatase deficiency (see
Sulfatides interact strongly with certain positively charged dyes used to stain tissues, resulting in a shift in the color of the stained tissue termed metachromasia. When frozen tissue sections are treated with acidified cresyl violet (Hirsch-Peiffer stain), sulfatide-rich storage deposits stain a golden brown. The finding of metachromatic lipid deposits in nervous system tissue is pathognomonic for MLD.
Note: (1) Fixing the tissue with alcohol before staining extracts the sulfatides such that the metachromasia is no longer observed. (2) Although still considered by some to be the diagnostic "gold standard" for MLD, this highly invasive approach is now used only in exceptional circumstances (e.g., confirmation of a prenatal diagnosis of MLD following pregnancy termination).
##
Individuals with all types of MLD excrete abnormally high sulfatides in urine. These can be quantified by high-performance liquid chromatography (HPLC), mass spectrometry, and thin-layer chromatography (TLC). TLC is a semiquantitative method. For HPLC and mass spectrometry, reference and pathologic values vary by laboratory. For sample preparation, it is important to note that wipes containing soaps and lotions should be avoided before collection, as these products may interfere with the accuracy of the test results. Lab specimen collection recommendations also vary. Some require a first morning, random urine specimen, while others may require a 24-hour collection. The samples are stable refrigerated or at ambient temperature for up to 45 days. Samples can also be frozen and remain stable for up to 19 months.
Note: Elevated urine sulfatides and arylsulfatase A enzyme deficiency in the presence of dysmorphic features, dysostosis multiplex, or ichthyosis should prompt evaluation for multiple sulfatase deficiency (see
##
Sulfatides interact strongly with certain positively charged dyes used to stain tissues, resulting in a shift in the color of the stained tissue termed metachromasia. When frozen tissue sections are treated with acidified cresyl violet (Hirsch-Peiffer stain), sulfatide-rich storage deposits stain a golden brown. The finding of metachromatic lipid deposits in nervous system tissue is pathognomonic for MLD.
Note: (1) Fixing the tissue with alcohol before staining extracts the sulfatides such that the metachromasia is no longer observed. (2) Although still considered by some to be the diagnostic "gold standard" for MLD, this highly invasive approach is now used only in exceptional circumstances (e.g., confirmation of a prenatal diagnosis of MLD following pregnancy termination).
## Clinical Characteristics
The clinical presentation of arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is heterogeneous with respect to the age of onset, the rate of progression, and the initial symptoms. Three clinical subtypes of MLD are primarily distinguished by age of onset:
Late-infantile MLD, comprising 50%-60% of affected individuals
Juvenile MLD, approximately 20%-40%
Adult MLD, approximately 10%-20%
The age of onset within a family is usually similar, but exceptions occur [
As the disease progresses, language, cognitive development, and gross and fine motor skills regress. Peripheral neuropathy can lead to pain in the arms and legs. In one study, individuals with the late-infantile form had lost the ability to sit without support and to move by age three years, and all had lost both trunk and head control by age three years, four months [
Some medical professionals distinguish between early-onset and late-onset juvenile MLD, and recent studies support measurable differences between these two subgroups [
The course is variable. Periods of relative stability may be interspersed with periods of decline. Inappropriate behaviors and poor decision making become problems for the family or other caregivers. Dressing and other self-help skills deteriorate. Eventually, bowel and bladder control are lost. As the disease advances, dystonic movements, spastic quadriparesis, or decorticate posturing occurs. Severe contractures and generalized seizures may occur. The duration of the disease ranges from several years to decades.
MRI of the brain is a powerful tool to investigate the involvement of the central nervous system in this disease. MLD primarily affects the white matter, and its changes during the disease can be seen on T
Several studies have addressed the electrophysiologic findings of peripheral neuropathy in MLD and their progression over time. Studies show that both motor and sensory NCVs show uniform slowing, as is expected for a demyelinating polyneuropathy [
Brain stem auditory evoked responses (BAERs) are frequently found to be abnormal in individuals with late-infantile MLD. When studying the progression of late-infantile MLD, it has been observed that central waves in BAERs tend to disappear early, which is contrary to the expected pattern of progressive shortening of the I-V interpeak latency seen in healthy children during the first years of life, reflecting normal brain stem myelination. However, the use of BAERs is less straightforward in individuals with juvenile and adult MLD. Some individuals may exhibit recordings that are close to normal or maintain stable I-V interpeak latencies despite experiencing psychomotor deterioration [
Sulfatide accumulation has been found outside the central nervous system in other organs. Accumulation n the gallbladder, hyperplastic polyps, hemobilia, and gallbladder carcinoma has been reported [
There are three classes of
Alleles with two
The genotypes
The genotype
The genotype
There are substantial limitations to using these genotype-phenotype correlations in predicting an affected individual's clinical presentation and natural history. The predictive value is best for individuals homozygous for two 0-type alleles. Still, individuals with one or two R-type alleles show considerable phenotypic variability, implicating other genetic and/or environmental factors. Additional variants in the same allele can further affect enzyme function and disease severity [
The polyadenylation site variant
The glycosylation site alteration
The most common
Homozygosity for the c.*96A>G variant (almost always on the same chromosome with p.Asn352Ser) is associated with arylsulfatase A enzyme activity that is approximately 10% of normal controls and could result in diagnostic uncertainty.
Homozygosity for the p.Asn352Ser variant alone results in 50% or more of the mean control arylsulfatase A enzyme activity in leukocytes.
The term "metachromatic leukodystrophy" (
The term "metachromatic leukoencephalopathy" has also been used.
MLD has also been referred to as "Greenfield's disease" after the first report of the late-infantile form of MLD.
The following populations have an increased prevalence of MLD due to the presence of founder variants (figures are approximate; see
1:75 in Habbanite Jewsish population in Israel
1:8,000 in Israeli Arabs
1:2,500 in individuals of Yup'ik ancestry from Alakanuk, Alaska
1: 6,400 in individuals of Navajo ancestry from the western portion of the Navajo Nation in the United States
• Late-infantile MLD, comprising 50%-60% of affected individuals
• Juvenile MLD, approximately 20%-40%
• Adult MLD, approximately 10%-20%
• MRI of the brain is a powerful tool to investigate the involvement of the central nervous system in this disease. MLD primarily affects the white matter, and its changes during the disease can be seen on T
• Several studies have addressed the electrophysiologic findings of peripheral neuropathy in MLD and their progression over time. Studies show that both motor and sensory NCVs show uniform slowing, as is expected for a demyelinating polyneuropathy [
• Brain stem auditory evoked responses (BAERs) are frequently found to be abnormal in individuals with late-infantile MLD. When studying the progression of late-infantile MLD, it has been observed that central waves in BAERs tend to disappear early, which is contrary to the expected pattern of progressive shortening of the I-V interpeak latency seen in healthy children during the first years of life, reflecting normal brain stem myelination. However, the use of BAERs is less straightforward in individuals with juvenile and adult MLD. Some individuals may exhibit recordings that are close to normal or maintain stable I-V interpeak latencies despite experiencing psychomotor deterioration [
• Sulfatide accumulation has been found outside the central nervous system in other organs. Accumulation n the gallbladder, hyperplastic polyps, hemobilia, and gallbladder carcinoma has been reported [
• Alleles with two
• The genotypes
• The genotype
• The genotype
• The polyadenylation site variant
• The glycosylation site alteration
• The most common
• The polyadenylation site variant
• The glycosylation site alteration
• The most common
•
• Homozygosity for the c.*96A>G variant (almost always on the same chromosome with p.Asn352Ser) is associated with arylsulfatase A enzyme activity that is approximately 10% of normal controls and could result in diagnostic uncertainty.
• Homozygosity for the p.Asn352Ser variant alone results in 50% or more of the mean control arylsulfatase A enzyme activity in leukocytes.
• Homozygosity for the c.*96A>G variant (almost always on the same chromosome with p.Asn352Ser) is associated with arylsulfatase A enzyme activity that is approximately 10% of normal controls and could result in diagnostic uncertainty.
• Homozygosity for the p.Asn352Ser variant alone results in 50% or more of the mean control arylsulfatase A enzyme activity in leukocytes.
• The polyadenylation site variant
• The glycosylation site alteration
• The most common
• Homozygosity for the c.*96A>G variant (almost always on the same chromosome with p.Asn352Ser) is associated with arylsulfatase A enzyme activity that is approximately 10% of normal controls and could result in diagnostic uncertainty.
• Homozygosity for the p.Asn352Ser variant alone results in 50% or more of the mean control arylsulfatase A enzyme activity in leukocytes.
• 1:75 in Habbanite Jewsish population in Israel
• 1:8,000 in Israeli Arabs
• 1:2,500 in individuals of Yup'ik ancestry from Alakanuk, Alaska
• 1: 6,400 in individuals of Navajo ancestry from the western portion of the Navajo Nation in the United States
## Clinical Description
The clinical presentation of arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is heterogeneous with respect to the age of onset, the rate of progression, and the initial symptoms. Three clinical subtypes of MLD are primarily distinguished by age of onset:
Late-infantile MLD, comprising 50%-60% of affected individuals
Juvenile MLD, approximately 20%-40%
Adult MLD, approximately 10%-20%
The age of onset within a family is usually similar, but exceptions occur [
As the disease progresses, language, cognitive development, and gross and fine motor skills regress. Peripheral neuropathy can lead to pain in the arms and legs. In one study, individuals with the late-infantile form had lost the ability to sit without support and to move by age three years, and all had lost both trunk and head control by age three years, four months [
Some medical professionals distinguish between early-onset and late-onset juvenile MLD, and recent studies support measurable differences between these two subgroups [
The course is variable. Periods of relative stability may be interspersed with periods of decline. Inappropriate behaviors and poor decision making become problems for the family or other caregivers. Dressing and other self-help skills deteriorate. Eventually, bowel and bladder control are lost. As the disease advances, dystonic movements, spastic quadriparesis, or decorticate posturing occurs. Severe contractures and generalized seizures may occur. The duration of the disease ranges from several years to decades.
MRI of the brain is a powerful tool to investigate the involvement of the central nervous system in this disease. MLD primarily affects the white matter, and its changes during the disease can be seen on T
Several studies have addressed the electrophysiologic findings of peripheral neuropathy in MLD and their progression over time. Studies show that both motor and sensory NCVs show uniform slowing, as is expected for a demyelinating polyneuropathy [
Brain stem auditory evoked responses (BAERs) are frequently found to be abnormal in individuals with late-infantile MLD. When studying the progression of late-infantile MLD, it has been observed that central waves in BAERs tend to disappear early, which is contrary to the expected pattern of progressive shortening of the I-V interpeak latency seen in healthy children during the first years of life, reflecting normal brain stem myelination. However, the use of BAERs is less straightforward in individuals with juvenile and adult MLD. Some individuals may exhibit recordings that are close to normal or maintain stable I-V interpeak latencies despite experiencing psychomotor deterioration [
Sulfatide accumulation has been found outside the central nervous system in other organs. Accumulation n the gallbladder, hyperplastic polyps, hemobilia, and gallbladder carcinoma has been reported [
• Late-infantile MLD, comprising 50%-60% of affected individuals
• Juvenile MLD, approximately 20%-40%
• Adult MLD, approximately 10%-20%
• MRI of the brain is a powerful tool to investigate the involvement of the central nervous system in this disease. MLD primarily affects the white matter, and its changes during the disease can be seen on T
• Several studies have addressed the electrophysiologic findings of peripheral neuropathy in MLD and their progression over time. Studies show that both motor and sensory NCVs show uniform slowing, as is expected for a demyelinating polyneuropathy [
• Brain stem auditory evoked responses (BAERs) are frequently found to be abnormal in individuals with late-infantile MLD. When studying the progression of late-infantile MLD, it has been observed that central waves in BAERs tend to disappear early, which is contrary to the expected pattern of progressive shortening of the I-V interpeak latency seen in healthy children during the first years of life, reflecting normal brain stem myelination. However, the use of BAERs is less straightforward in individuals with juvenile and adult MLD. Some individuals may exhibit recordings that are close to normal or maintain stable I-V interpeak latencies despite experiencing psychomotor deterioration [
• Sulfatide accumulation has been found outside the central nervous system in other organs. Accumulation n the gallbladder, hyperplastic polyps, hemobilia, and gallbladder carcinoma has been reported [
## Genotype-Phenotype Correlations
There are three classes of
Alleles with two
The genotypes
The genotype
The genotype
There are substantial limitations to using these genotype-phenotype correlations in predicting an affected individual's clinical presentation and natural history. The predictive value is best for individuals homozygous for two 0-type alleles. Still, individuals with one or two R-type alleles show considerable phenotypic variability, implicating other genetic and/or environmental factors. Additional variants in the same allele can further affect enzyme function and disease severity [
The polyadenylation site variant
The glycosylation site alteration
The most common
Homozygosity for the c.*96A>G variant (almost always on the same chromosome with p.Asn352Ser) is associated with arylsulfatase A enzyme activity that is approximately 10% of normal controls and could result in diagnostic uncertainty.
Homozygosity for the p.Asn352Ser variant alone results in 50% or more of the mean control arylsulfatase A enzyme activity in leukocytes.
• Alleles with two
• The genotypes
• The genotype
• The genotype
• The polyadenylation site variant
• The glycosylation site alteration
• The most common
• The polyadenylation site variant
• The glycosylation site alteration
• The most common
•
• Homozygosity for the c.*96A>G variant (almost always on the same chromosome with p.Asn352Ser) is associated with arylsulfatase A enzyme activity that is approximately 10% of normal controls and could result in diagnostic uncertainty.
• Homozygosity for the p.Asn352Ser variant alone results in 50% or more of the mean control arylsulfatase A enzyme activity in leukocytes.
• Homozygosity for the c.*96A>G variant (almost always on the same chromosome with p.Asn352Ser) is associated with arylsulfatase A enzyme activity that is approximately 10% of normal controls and could result in diagnostic uncertainty.
• Homozygosity for the p.Asn352Ser variant alone results in 50% or more of the mean control arylsulfatase A enzyme activity in leukocytes.
• The polyadenylation site variant
• The glycosylation site alteration
• The most common
• Homozygosity for the c.*96A>G variant (almost always on the same chromosome with p.Asn352Ser) is associated with arylsulfatase A enzyme activity that is approximately 10% of normal controls and could result in diagnostic uncertainty.
• Homozygosity for the p.Asn352Ser variant alone results in 50% or more of the mean control arylsulfatase A enzyme activity in leukocytes.
## Nomenclature
The term "metachromatic leukodystrophy" (
The term "metachromatic leukoencephalopathy" has also been used.
MLD has also been referred to as "Greenfield's disease" after the first report of the late-infantile form of MLD.
## Prevalence
The following populations have an increased prevalence of MLD due to the presence of founder variants (figures are approximate; see
1:75 in Habbanite Jewsish population in Israel
1:8,000 in Israeli Arabs
1:2,500 in individuals of Yup'ik ancestry from Alakanuk, Alaska
1: 6,400 in individuals of Navajo ancestry from the western portion of the Navajo Nation in the United States
• 1:75 in Habbanite Jewsish population in Israel
• 1:8,000 in Israeli Arabs
• 1:2,500 in individuals of Yup'ik ancestry from Alakanuk, Alaska
• 1: 6,400 in individuals of Navajo ancestry from the western portion of the Navajo Nation in the United States
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Individuals with 22q13.3 deletion syndrome (see
## Differential Diagnosis
Phenotypes That Show Notable Overlap with Arylsulfatase A Deficiency
CSF = cerebrospinal fluid; MLD = metachromatic leukodystrophy; MPS = mucopolysaccharidosis; NCV = nerve conduction velocity
Including arylsulfatase B, arylsulfatase C, galactose-6-sulfatase, glucuronate-2-sulfatase, iduronate sulfatase, heparan-N-sulfamidase, and N-acetylglucosamine-6-sulfatase
Note: Arylsulfatase A enzyme activity is also deficient in many tissues in defects of the phosphomannosyl lysosomal recognition pathway, such as mucolipidosis II (see
Selected Progressive Degenerative Disorders That Manifest After a Period of Normal Development in the Differential Diagnosis of Arylsulfatase A Deficiency
Type 1 is characterized by rapid psychomotor regression & severe neurologic deterioration, usually starting around age 6 mos. Assoc w/↑ sweat sodium chloride levels, & persons may not live beyond a decade.
Type 2 is characterized by milder DD & neurologic symptoms, development of angiokeratoma corporis diffusum, normal salt levels in sweat, & longer life expectancy.
AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; XL = X-linked
Although some mucopolysaccharidoses can have a similar presentation to MLD, the characteristic physical features seen in most mucopolysaccharidoses (e.g., short stature, dysostosis multiplex, coarse facial appearance, corneal clouding, hepatosplenomegaly, pulmonary congestion, and heart problems) are not found in individuals with MLD. The evaluation of appropriate lysosomal enzymes can distinguish the disorders.
• Type 1 is characterized by rapid psychomotor regression & severe neurologic deterioration, usually starting around age 6 mos. Assoc w/↑ sweat sodium chloride levels, & persons may not live beyond a decade.
• Type 2 is characterized by milder DD & neurologic symptoms, development of angiokeratoma corporis diffusum, normal salt levels in sweat, & longer life expectancy.
## Management
Clinical practice guidelines for arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) have been published [
To establish the extent of disease and needs in an individual diagnosed with MLD, the evaluations summarized in
Arylsulfatase A Deficiency: Recommended Evaluations Following Initial Diagnosis
Neurologic eval
Measurement of arylsulfatase A enzyme activity
Measurement of urinary sulfatide excretion
Brain MRI to assess myelin integrity
EEG if concern for seizures
Peripheral nervous system eval, such as nerve conduction studies, can be used to monitor disease progression or responses in therapeutic trials.
BAERs can be used to assess progression in late-infantile MLD.
To assess disease progression
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; BAERs = brain stem auditory evoked responses; EU = European Union; HSCT = hematopoietic stem cell transplantation; MLD = metachromatic leukodystrophy; MOI = mode of inheritance; UK = United Kingdom; US = United States
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
Different types of MLD have shown different responses.
However, in the absence of alternative approaches, HSCT should be discussed with families, particularly with those with slower progressing, late-onset forms of MLD. At-risk relatives diagnosed by biochemical or molecular genetic testing before symptoms occur could benefit most from this intervention. Despite mounting evidence of utility, HSCT is not expected to fully abrogate the manifestations of the disease.
The safety and efficacy of atidarsagene autotemcel were evaluated using data from 37 affected children enrolled in two single-arm, open-label clinical trials and an expanded access program [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in neurology, biochemical genetics, and pediatrics (see
Arylsulfatase A Deficiency: Supportive Treatment of Manifestations
See
Provision of enriched environment to support maintenance of intellectual abilities as long as possible
Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls & maintain neuromuscular function & mobility as long as possible
Aggressive PT is recommended.
Muscle relaxants for contractures
Safety measures for gait or movement limitations
See
Feeding therapy, swallowing aids, suction equipment, & other standard treatments for drooling & swallowing difficulty
Gastrostomy tube placement may be required for persistent feeding issues.
Standard treatments for gastroesophageal reflux & constipation
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Anesthesia (if required) should be administered by experienced anesthesiologist.
Education re likely progression of disorder to facilitate decisions re future care needs
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; MLD = metachromatic leukodystrophy; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Arylsulfatase A Deficiency: Recommended Surveillance
Brain MRI to monitor status of CNS demyelination
MLD brain MRI severity scoring method to monitor progression & response to therapy
Monitor those w/seizures as clinically indicated.
Monitor for disease exacerbations following febrile infections.
Assess for new manifestations such as seizures, contractures, changes in tone, & movement disorders.
Measurement of growth parameters
Eval of nutritional status, safety of oral intake, difficulties w/feeding or swallowing
Assessment of need for gastrostomy tube placement
CNS = central nervous system; GMFM = gross motor function measurement; MLD = metachromatic leukodystrophy; OT = occupational therapy; PT = physical therapy
While environmental factors are thought to influence the onset and severity of MLD manifestations, no specific exacerbating agents are known. Initial symptoms are often noted following a febrile illness or other stress, but it is unclear if a high fever accelerates progression.
Excessive alcohol and drug use are often associated with later-onset MLD, but it is unclear if this is caused by the disease or is simply an attempt at self-medication in the face of increasing cognitive difficulties [
It is appropriate to consider evaluation of apparently asymptomatic sibs of a proband to identify those who could potentially benefit from HSCT and other treatment options. Although substantial risk is involved and long-term effects are unclear, the best clinical outcomes are obtained when HSCT occurs before clinical symptoms have appeared (see
Perform molecular genetic testing if the pathogenic variants in the family are known.
If the pathogenic variants in the family are not known, workup should begin with measurement of urinary excretion of sulfatides.
Measurement of arylsulfatase A enzyme activity in peripheral blood leukocytes or cultured fibroblasts can support the diagnosis but is not sufficient by itself. See
See
Search
• Neurologic eval
• Measurement of arylsulfatase A enzyme activity
• Measurement of urinary sulfatide excretion
• Brain MRI to assess myelin integrity
• EEG if concern for seizures
• Peripheral nervous system eval, such as nerve conduction studies, can be used to monitor disease progression or responses in therapeutic trials.
• BAERs can be used to assess progression in late-infantile MLD.
• To assess disease progression
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support
• Home nursing referral
• Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
• Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
• Different types of MLD have shown different responses.
• However, in the absence of alternative approaches, HSCT should be discussed with families, particularly with those with slower progressing, late-onset forms of MLD. At-risk relatives diagnosed by biochemical or molecular genetic testing before symptoms occur could benefit most from this intervention. Despite mounting evidence of utility, HSCT is not expected to fully abrogate the manifestations of the disease.
• Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
• Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
• Different types of MLD have shown different responses.
• The safety and efficacy of atidarsagene autotemcel were evaluated using data from 37 affected children enrolled in two single-arm, open-label clinical trials and an expanded access program [
• Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
• Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
• Different types of MLD have shown different responses.
• See
• Provision of enriched environment to support maintenance of intellectual abilities as long as possible
• Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls & maintain neuromuscular function & mobility as long as possible
• Aggressive PT is recommended.
• Muscle relaxants for contractures
• Safety measures for gait or movement limitations
• See
• Feeding therapy, swallowing aids, suction equipment, & other standard treatments for drooling & swallowing difficulty
• Gastrostomy tube placement may be required for persistent feeding issues.
• Standard treatments for gastroesophageal reflux & constipation
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Education re likely progression of disorder to facilitate decisions re future care needs
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Brain MRI to monitor status of CNS demyelination
• MLD brain MRI severity scoring method to monitor progression & response to therapy
• Monitor those w/seizures as clinically indicated.
• Monitor for disease exacerbations following febrile infections.
• Assess for new manifestations such as seizures, contractures, changes in tone, & movement disorders.
• Measurement of growth parameters
• Eval of nutritional status, safety of oral intake, difficulties w/feeding or swallowing
• Assessment of need for gastrostomy tube placement
• Perform molecular genetic testing if the pathogenic variants in the family are known.
• If the pathogenic variants in the family are not known, workup should begin with measurement of urinary excretion of sulfatides.
• Measurement of arylsulfatase A enzyme activity in peripheral blood leukocytes or cultured fibroblasts can support the diagnosis but is not sufficient by itself. See
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MLD, the evaluations summarized in
Arylsulfatase A Deficiency: Recommended Evaluations Following Initial Diagnosis
Neurologic eval
Measurement of arylsulfatase A enzyme activity
Measurement of urinary sulfatide excretion
Brain MRI to assess myelin integrity
EEG if concern for seizures
Peripheral nervous system eval, such as nerve conduction studies, can be used to monitor disease progression or responses in therapeutic trials.
BAERs can be used to assess progression in late-infantile MLD.
To assess disease progression
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; BAERs = brain stem auditory evoked responses; EU = European Union; HSCT = hematopoietic stem cell transplantation; MLD = metachromatic leukodystrophy; MOI = mode of inheritance; UK = United Kingdom; US = United States
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Neurologic eval
• Measurement of arylsulfatase A enzyme activity
• Measurement of urinary sulfatide excretion
• Brain MRI to assess myelin integrity
• EEG if concern for seizures
• Peripheral nervous system eval, such as nerve conduction studies, can be used to monitor disease progression or responses in therapeutic trials.
• BAERs can be used to assess progression in late-infantile MLD.
• To assess disease progression
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
Different types of MLD have shown different responses.
However, in the absence of alternative approaches, HSCT should be discussed with families, particularly with those with slower progressing, late-onset forms of MLD. At-risk relatives diagnosed by biochemical or molecular genetic testing before symptoms occur could benefit most from this intervention. Despite mounting evidence of utility, HSCT is not expected to fully abrogate the manifestations of the disease.
The safety and efficacy of atidarsagene autotemcel were evaluated using data from 37 affected children enrolled in two single-arm, open-label clinical trials and an expanded access program [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in neurology, biochemical genetics, and pediatrics (see
Arylsulfatase A Deficiency: Supportive Treatment of Manifestations
See
Provision of enriched environment to support maintenance of intellectual abilities as long as possible
Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls & maintain neuromuscular function & mobility as long as possible
Aggressive PT is recommended.
Muscle relaxants for contractures
Safety measures for gait or movement limitations
See
Feeding therapy, swallowing aids, suction equipment, & other standard treatments for drooling & swallowing difficulty
Gastrostomy tube placement may be required for persistent feeding issues.
Standard treatments for gastroesophageal reflux & constipation
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Anesthesia (if required) should be administered by experienced anesthesiologist.
Education re likely progression of disorder to facilitate decisions re future care needs
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; MLD = metachromatic leukodystrophy; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
• Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
• Different types of MLD have shown different responses.
• However, in the absence of alternative approaches, HSCT should be discussed with families, particularly with those with slower progressing, late-onset forms of MLD. At-risk relatives diagnosed by biochemical or molecular genetic testing before symptoms occur could benefit most from this intervention. Despite mounting evidence of utility, HSCT is not expected to fully abrogate the manifestations of the disease.
• Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
• Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
• Different types of MLD have shown different responses.
• The safety and efficacy of atidarsagene autotemcel were evaluated using data from 37 affected children enrolled in two single-arm, open-label clinical trials and an expanded access program [
• Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
• Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
• Different types of MLD have shown different responses.
• See
• Provision of enriched environment to support maintenance of intellectual abilities as long as possible
• Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls & maintain neuromuscular function & mobility as long as possible
• Aggressive PT is recommended.
• Muscle relaxants for contractures
• Safety measures for gait or movement limitations
• See
• Feeding therapy, swallowing aids, suction equipment, & other standard treatments for drooling & swallowing difficulty
• Gastrostomy tube placement may be required for persistent feeding issues.
• Standard treatments for gastroesophageal reflux & constipation
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Education re likely progression of disorder to facilitate decisions re future care needs
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Targeted Therapy
Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
Different types of MLD have shown different responses.
However, in the absence of alternative approaches, HSCT should be discussed with families, particularly with those with slower progressing, late-onset forms of MLD. At-risk relatives diagnosed by biochemical or molecular genetic testing before symptoms occur could benefit most from this intervention. Despite mounting evidence of utility, HSCT is not expected to fully abrogate the manifestations of the disease.
The safety and efficacy of atidarsagene autotemcel were evaluated using data from 37 affected children enrolled in two single-arm, open-label clinical trials and an expanded access program [
• Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
• Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
• Different types of MLD have shown different responses.
• However, in the absence of alternative approaches, HSCT should be discussed with families, particularly with those with slower progressing, late-onset forms of MLD. At-risk relatives diagnosed by biochemical or molecular genetic testing before symptoms occur could benefit most from this intervention. Despite mounting evidence of utility, HSCT is not expected to fully abrogate the manifestations of the disease.
• Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
• Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
• Different types of MLD have shown different responses.
• The safety and efficacy of atidarsagene autotemcel were evaluated using data from 37 affected children enrolled in two single-arm, open-label clinical trials and an expanded access program [
• Systematic outcome data are limited and difficult to generalize due to the use of different eligibility criteria and transplantation protocols;
• Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen (HLA) typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
• Different types of MLD have shown different responses.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in neurology, biochemical genetics, and pediatrics (see
Arylsulfatase A Deficiency: Supportive Treatment of Manifestations
See
Provision of enriched environment to support maintenance of intellectual abilities as long as possible
Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls & maintain neuromuscular function & mobility as long as possible
Aggressive PT is recommended.
Muscle relaxants for contractures
Safety measures for gait or movement limitations
See
Feeding therapy, swallowing aids, suction equipment, & other standard treatments for drooling & swallowing difficulty
Gastrostomy tube placement may be required for persistent feeding issues.
Standard treatments for gastroesophageal reflux & constipation
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Anesthesia (if required) should be administered by experienced anesthesiologist.
Education re likely progression of disorder to facilitate decisions re future care needs
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; MLD = metachromatic leukodystrophy; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• See
• Provision of enriched environment to support maintenance of intellectual abilities as long as possible
• Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls & maintain neuromuscular function & mobility as long as possible
• Aggressive PT is recommended.
• Muscle relaxants for contractures
• Safety measures for gait or movement limitations
• See
• Feeding therapy, swallowing aids, suction equipment, & other standard treatments for drooling & swallowing difficulty
• Gastrostomy tube placement may be required for persistent feeding issues.
• Standard treatments for gastroesophageal reflux & constipation
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Education re likely progression of disorder to facilitate decisions re future care needs
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
##
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
##
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
##
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Arylsulfatase A Deficiency: Recommended Surveillance
Brain MRI to monitor status of CNS demyelination
MLD brain MRI severity scoring method to monitor progression & response to therapy
Monitor those w/seizures as clinically indicated.
Monitor for disease exacerbations following febrile infections.
Assess for new manifestations such as seizures, contractures, changes in tone, & movement disorders.
Measurement of growth parameters
Eval of nutritional status, safety of oral intake, difficulties w/feeding or swallowing
Assessment of need for gastrostomy tube placement
CNS = central nervous system; GMFM = gross motor function measurement; MLD = metachromatic leukodystrophy; OT = occupational therapy; PT = physical therapy
• Brain MRI to monitor status of CNS demyelination
• MLD brain MRI severity scoring method to monitor progression & response to therapy
• Monitor those w/seizures as clinically indicated.
• Monitor for disease exacerbations following febrile infections.
• Assess for new manifestations such as seizures, contractures, changes in tone, & movement disorders.
• Measurement of growth parameters
• Eval of nutritional status, safety of oral intake, difficulties w/feeding or swallowing
• Assessment of need for gastrostomy tube placement
## Agents/Circumstances to Avoid
While environmental factors are thought to influence the onset and severity of MLD manifestations, no specific exacerbating agents are known. Initial symptoms are often noted following a febrile illness or other stress, but it is unclear if a high fever accelerates progression.
Excessive alcohol and drug use are often associated with later-onset MLD, but it is unclear if this is caused by the disease or is simply an attempt at self-medication in the face of increasing cognitive difficulties [
## Evaluation of Relatives at Risk
It is appropriate to consider evaluation of apparently asymptomatic sibs of a proband to identify those who could potentially benefit from HSCT and other treatment options. Although substantial risk is involved and long-term effects are unclear, the best clinical outcomes are obtained when HSCT occurs before clinical symptoms have appeared (see
Perform molecular genetic testing if the pathogenic variants in the family are known.
If the pathogenic variants in the family are not known, workup should begin with measurement of urinary excretion of sulfatides.
Measurement of arylsulfatase A enzyme activity in peripheral blood leukocytes or cultured fibroblasts can support the diagnosis but is not sufficient by itself. See
See
• Perform molecular genetic testing if the pathogenic variants in the family are known.
• If the pathogenic variants in the family are not known, workup should begin with measurement of urinary excretion of sulfatides.
• Measurement of arylsulfatase A enzyme activity in peripheral blood leukocytes or cultured fibroblasts can support the diagnosis but is not sufficient by itself. See
## Therapies Under Investigation
Search
## Genetic Counseling
Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background.
## Mode of Inheritance
Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 5801
Bethesda MD 20824
Canada
•
•
•
•
•
• PO Box 5801
• Bethesda MD 20824
•
•
• Canada
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Arylsulfatase A Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Arylsulfatase A Deficiency (
In general, alleles with pathogenic splice site variants, insertions, or deletions do not produce any active enzyme (I-type
Between 20% and 25% of the single amino acid changes are associated with a low level (≤1%) of arylsulfatase A enzyme activity (A-type
Pathogenic variant (
Common variant in persons of central & western European ancestry.
Pathogenic variant (
Common variant in persons of central & western European ancestry
Glycosylation site alteration
Common benign variant occurring in 15%-40% of persons.
Pathogenic variant (
Common variant in persons of central & western European ancestry
Pathogenic variant (
Common variant in persons of central & western European ancestry
AK = Alaska; MLD = metachromatic leukodystrophy; PD = pseudodeficiency
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
The most common
• Pathogenic variant (
• Common variant in persons of central & western European ancestry.
• Pathogenic variant (
• Common variant in persons of central & western European ancestry
• Glycosylation site alteration
• Common benign variant occurring in 15%-40% of persons.
• Pathogenic variant (
• Common variant in persons of central & western European ancestry
• Pathogenic variant (
• Common variant in persons of central & western European ancestry
## Molecular Pathogenesis
In general, alleles with pathogenic splice site variants, insertions, or deletions do not produce any active enzyme (I-type
Between 20% and 25% of the single amino acid changes are associated with a low level (≤1%) of arylsulfatase A enzyme activity (A-type
Pathogenic variant (
Common variant in persons of central & western European ancestry.
Pathogenic variant (
Common variant in persons of central & western European ancestry
Glycosylation site alteration
Common benign variant occurring in 15%-40% of persons.
Pathogenic variant (
Common variant in persons of central & western European ancestry
Pathogenic variant (
Common variant in persons of central & western European ancestry
AK = Alaska; MLD = metachromatic leukodystrophy; PD = pseudodeficiency
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
The most common
• Pathogenic variant (
• Common variant in persons of central & western European ancestry.
• Pathogenic variant (
• Common variant in persons of central & western European ancestry
• Glycosylation site alteration
• Common benign variant occurring in 15%-40% of persons.
• Pathogenic variant (
• Common variant in persons of central & western European ancestry
• Pathogenic variant (
• Common variant in persons of central & western European ancestry
## Chapter Notes
Websites:
Email:
We would like to express our heartfelt gratitude to the patient support groups, dedicated individuals, and researchers who have tirelessly contributed to our understanding and treatment of MLD.
Arvan L Fluharty, PhD; University of California, Los Angeles (2006-2017)Natalia Gomez-Ospina, MD, PhD (2017-present)
25 April 2024 (sw) Revision: atidarsagene autotemcel approved by FDA (
8 February 2024 (sw) Comprehensive update posted live
14 December 2017 (sw) Comprehensive update posted live
6 February 2014 (me) Comprehensive update posted live
25 August 2011 (me) Comprehensive update posted live
23 September 2008 (me) Comprehensive update posted live
30 May 2006 (me) Review posted live
15 November 2004 (mf) Original submission
• 25 April 2024 (sw) Revision: atidarsagene autotemcel approved by FDA (
• 8 February 2024 (sw) Comprehensive update posted live
• 14 December 2017 (sw) Comprehensive update posted live
• 6 February 2014 (me) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 23 September 2008 (me) Comprehensive update posted live
• 30 May 2006 (me) Review posted live
• 15 November 2004 (mf) Original submission
## Author Notes
Websites:
Email:
## Acknowledgments
We would like to express our heartfelt gratitude to the patient support groups, dedicated individuals, and researchers who have tirelessly contributed to our understanding and treatment of MLD.
## Author History
Arvan L Fluharty, PhD; University of California, Los Angeles (2006-2017)Natalia Gomez-Ospina, MD, PhD (2017-present)
## Revision History
25 April 2024 (sw) Revision: atidarsagene autotemcel approved by FDA (
8 February 2024 (sw) Comprehensive update posted live
14 December 2017 (sw) Comprehensive update posted live
6 February 2014 (me) Comprehensive update posted live
25 August 2011 (me) Comprehensive update posted live
23 September 2008 (me) Comprehensive update posted live
30 May 2006 (me) Review posted live
15 November 2004 (mf) Original submission
• 25 April 2024 (sw) Revision: atidarsagene autotemcel approved by FDA (
• 8 February 2024 (sw) Comprehensive update posted live
• 14 December 2017 (sw) Comprehensive update posted live
• 6 February 2014 (me) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 23 September 2008 (me) Comprehensive update posted live
• 30 May 2006 (me) Review posted live
• 15 November 2004 (mf) Original submission
## Key Sections in this
## References
Wang RY, Bodamer OA, Watson MS, Wilcox WR; ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. ACMG Standards and Guidelines. Available
• Wang RY, Bodamer OA, Watson MS, Wilcox WR; ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. ACMG Standards and Guidelines. Available
## Published Guidelines / Consensus Statements
Wang RY, Bodamer OA, Watson MS, Wilcox WR; ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. ACMG Standards and Guidelines. Available
• Wang RY, Bodamer OA, Watson MS, Wilcox WR; ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. ACMG Standards and Guidelines. Available
## Literature Cited
|
[] |
30/5/2006
|
8/2/2024
|
25/4/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mlid-maternal
|
mlid-maternal
|
[
"Inactive protein-arginine deiminase type-6",
"KH domain-containing protein 3",
"NACHT, LRR and PYD domains-containing protein 2",
"NACHT, LRR and PYD domains-containing protein 5",
"NACHT, LRR and PYD domains-containing protein 7",
"KHDC3L",
"NLRP2",
"NLRP5",
"NLRP7",
"PADI6",
"Maternal Effect Gene-Related Multi-Locus Imprinting Disturbances",
"Overview"
] |
Maternal Effect Gene-Related Multilocus Imprinting Disturbances
|
Zeynep Tümer, Thomas Eggermann, Saskia Maas, Jet Bliek, Deborah Mackay
|
Summary The purpose of this overview is to: Briefly describe the concept of Briefly review selected well-described Review the Provide an Inform
|
## Genomic Imprinting
For the purposes of this
In humans there are approximately 100 imprinted genomic regions; some of the imprinted loci comprise single genes, while others contain clusters of genes [
In these regions, gene expression is regulated by imprinting centers that are differently epigenetically marked (including differential DNA methylation) in the egg and sperm. Notably, maternally and paternally inherited imprinted regions have divergent DNA methylation at differentially methylated regions (DMRs).
After fertilization, imprinted regions maintain these marks through essentially all subsequent cell divisions in the body.
These changes include DNA methylation disturbance (loss of methylation [LOM] or gain of methylation [GOM]) of imprinted DMRs, segmental or whole-chromosome uniparental disomy (UPD), or pathogenic single-nucleotide variants or copy number variants of genes under imprinted control.
Although each imprinting disorder has a characteristic affected locus, some individuals have DNA methylation disturbance not at a single imprinted locus but at multiple imprinted loci across the genome, a phenomenon termed multilocus imprinting disturbances (MLID) [
Epigenetically, MLID is heterogeneous, meaning it can affect any number and combination of imprinted loci, including those currently known to be associated with recognized imprinting disorders and those not known to have any clinical associations at this time. Different imprinting disorders have different observed frequencies of MLID [
This
Unlike more traditional genetic conditions in which the affected offspring has a pathogenic DNA variant (single-nucleotide pathogenic variant or a pathogenic copy number variant) that leads directly to symptoms, this group of conditions is characterized by biallelic DNA pathogenic variants in the apparently unaffected mother of an offspring that leads to aberrant imprinting in the embryo, which in turn leads to one or more imprinting disorders in the offspring.
Each affected offspring is a carrier for one of the maternal pathogenic variants in the maternal effect gene, which in and of itself does not lead to symptoms, but some of the offspring may have symptoms due to the abnormal imprinting resulting from the maternal inability to properly establish or maintain imprinting in the offspring during embryonic development.
• In humans there are approximately 100 imprinted genomic regions; some of the imprinted loci comprise single genes, while others contain clusters of genes [
• In these regions, gene expression is regulated by imprinting centers that are differently epigenetically marked (including differential DNA methylation) in the egg and sperm. Notably, maternally and paternally inherited imprinted regions have divergent DNA methylation at differentially methylated regions (DMRs).
• After fertilization, imprinted regions maintain these marks through essentially all subsequent cell divisions in the body.
• These changes include DNA methylation disturbance (loss of methylation [LOM] or gain of methylation [GOM]) of imprinted DMRs, segmental or whole-chromosome uniparental disomy (UPD), or pathogenic single-nucleotide variants or copy number variants of genes under imprinted control.
• Although each imprinting disorder has a characteristic affected locus, some individuals have DNA methylation disturbance not at a single imprinted locus but at multiple imprinted loci across the genome, a phenomenon termed multilocus imprinting disturbances (MLID) [
• Epigenetically, MLID is heterogeneous, meaning it can affect any number and combination of imprinted loci, including those currently known to be associated with recognized imprinting disorders and those not known to have any clinical associations at this time. Different imprinting disorders have different observed frequencies of MLID [
• This
• Unlike more traditional genetic conditions in which the affected offspring has a pathogenic DNA variant (single-nucleotide pathogenic variant or a pathogenic copy number variant) that leads directly to symptoms, this group of conditions is characterized by biallelic DNA pathogenic variants in the apparently unaffected mother of an offspring that leads to aberrant imprinting in the embryo, which in turn leads to one or more imprinting disorders in the offspring.
• Each affected offspring is a carrier for one of the maternal pathogenic variants in the maternal effect gene, which in and of itself does not lead to symptoms, but some of the offspring may have symptoms due to the abnormal imprinting resulting from the maternal inability to properly establish or maintain imprinting in the offspring during embryonic development.
## Review of Imprinting Disorders in Which Multilocus Imprinting Disturbances Have Been Observed
Multilocus imprinting disturbances (MLID) are most frequently identified in individuals whose initial features are consistent with
The clinical features of individuals with MLID are not fully predictable from their imprinting disturbance, as MLID can alter the clinical presentation and progression of a classic imprinting disorder [
Some affected individuals have initial symptoms of a classic imprinting disorder such as TNDM or BWSp, but upon further evaluation, features of other imprinting disorders are subsequently noted.
Some affected individuals have phenotypic features typical of a specific imprinting disorder (such as BWSp) that are not apparently altered by the presence of MLID. However, some affected individuals have clinical features of more than one imprinting disorder, features that are a blend of one or more imprinting disorder, or features that do not align with any classic imprinting disorder.
As noted in
Imprinting Disorders in Which MEG-MLID Has Been Observed
Macroglossia
Exomphalos
Lateralized overgrowth
Hyperinsulinism
Multifocal &/or bilateral Wilms tumor or nephroblastomatosis
Resistance to PTH &, in some cases, TSH
Mild features of Albright hereditary osteodystrophy, such as brachydactyly
SGA
Postnatal growth failure
Prominent forehead
Body asymmetry
Feeding difficulties &/or low body mass index
IUGR
Hypotonia
Feeding difficulties in infancy
Truncal obesity
Precocious puberty
Scoliosis
Small hands & feet
Transient neonatal diabetes mellitus
Severe IUGR
DMR = differentially methylated region, also known as an imprinting center (IC); GOM = gain of methylation; ID = intellectual disability; IG = intergenic; IUGR = intrauterine growth restriction; LOM = loss of methylation; MEG = maternal effect gene; MLID = multilocus imprinting disturbances; NR = none reported; PTH = parathyroid hormone; SGA = small for gestational age; TSH = thyroid-stimulating hormone; TSS = transcriptional start site differentially methylated region
Adapted from
Nomenclature from
Frequency of individuals with the specific imprinting disorder who have the imprinting disorder as a result of MLID regardless of the underlying molecular defect.
These genes have biallelic causative variants in the mother of the affected offspring; affected offspring may be heterozygous carriers of a pathogenic variant in one of these genes, but the offspring's symptoms are due to aberrant imprinting and not to the pathogenic variant itself.
This is the only molecular defect in individuals with BWSp for which MLID has been detected. For other disease mechanisms that lead to BWSp, see
This is the only 11p15.5 molecular defect for which MLID has been detected. For other disease mechanisms that lead to SRS,
SGA can involve birth weight and/or length.
Clinical features may overlap with those of BWSp and SRS.
This is the only molecular defect in individuals with Temple syndrome for which MLID has been detected. For other disease mechanisms that lead to Temple syndrome, see
One case has been identified in which the mother had biallelic pathogenic variants in
A subset of individuals with TNDM and MLID have biallelic pathogenic variants in
• The clinical features of individuals with MLID are not fully predictable from their imprinting disturbance, as MLID can alter the clinical presentation and progression of a classic imprinting disorder [
• Some affected individuals have initial symptoms of a classic imprinting disorder such as TNDM or BWSp, but upon further evaluation, features of other imprinting disorders are subsequently noted.
• Some affected individuals have phenotypic features typical of a specific imprinting disorder (such as BWSp) that are not apparently altered by the presence of MLID. However, some affected individuals have clinical features of more than one imprinting disorder, features that are a blend of one or more imprinting disorder, or features that do not align with any classic imprinting disorder.
• Macroglossia
• Exomphalos
• Lateralized overgrowth
• Hyperinsulinism
• Multifocal &/or bilateral Wilms tumor or nephroblastomatosis
• Resistance to PTH &, in some cases, TSH
• Mild features of Albright hereditary osteodystrophy, such as brachydactyly
• SGA
• Postnatal growth failure
• Prominent forehead
• Body asymmetry
• Feeding difficulties &/or low body mass index
• IUGR
• Hypotonia
• Feeding difficulties in infancy
• Truncal obesity
• Precocious puberty
• Scoliosis
• Small hands & feet
• Transient neonatal diabetes mellitus
• Severe IUGR
## Genes of Interest in Maternal Effect Gene-Related Multilocus Imprinting Disturbances
Note: In some instances, a mother is found to be compound heterozygous for a pathogenic variant in a gene listed below and a second pathogenic variant not identified. These instances are not included in
MEG-MLID: Genes and Associated Phenotypes in Offspring
All reported offspring had BWSp.
Maternal infertility due to oocyte/zygote/embryo maturation arrest
Miscarriage
Most offspring had BWSp.
In 1 family, 1 child had BWSp & 1 had SRS.
Features not specific for any classic imprinting disorder
Maternal infertility due to oocyte/zygote/embryo maturation arrest
Miscarriage
Both reported offspring had BWSp.
Hydatidiform mole
Miscarriage
Most offspring had BWSp.
2 offspring had SRS.
Maternal infertility due to oocyte/zygote/embryo maturation arrest
Miscarriage
SRS = Silver-Russell syndrome; BWSp = Beckwith-Wiedemann spectrum
Adapted from
Genes are listed in alphabetic order.
Clinical features may be present in the offspring, but the features in the offspring may not be specific for any classic imprinting disorder.
• All reported offspring had BWSp.
• Maternal infertility due to oocyte/zygote/embryo maturation arrest
• Miscarriage
• Most offspring had BWSp.
• In 1 family, 1 child had BWSp & 1 had SRS.
• Features not specific for any classic imprinting disorder
• Maternal infertility due to oocyte/zygote/embryo maturation arrest
• Miscarriage
• Both reported offspring had BWSp.
• Hydatidiform mole
• Miscarriage
• Most offspring had BWSp.
• 2 offspring had SRS.
• Maternal infertility due to oocyte/zygote/embryo maturation arrest
• Miscarriage
##
Evaluation Strategies to Identify the Genetic Cause of Maternal Effect Gene-Related Multilocus Imprinting Disturbances in a Family
In genetic terms, the "molecular proband" is the mother who has the pathogenic variants but is asymptomatic with regards to clinical features of an imprinting disorder (though may have reproductive issues), while the clinical impact of these variants with regards to imprinting disorders is on the offspring, who is the "clinical proband" (see
Establishing a specific genetic cause of MLID:
Can aid in discussions of recurrence risks (see
Usually involves a medical history, physical examination and (where relevant) laboratory testing of the clinical proband(s), detailed family history, and genomic/genetic testing of the clinical proband(s) and family members, as warranted.
Mothers with biallelic pathogenic variants in a maternal effect gene (MEG) may have offspring with one imprinting disorder, multilocus imprinting disturbances (MLID) (i.e., clinical features of more than one imprinting disorder, features that are a blend of two or more imprinting disorders, or features that do not align with any classic imprinting disorder), or offspring who are clinically healthy; such mothers may also experience reproductive difficulties including pregnancy losses, molar pregnancy, or apparent infertility.
The detection of MLID in more than one child is strongly suggestive of biallelic pathogenic variants in an MEG in the mother. In families with reproductive issues (fertility problems, recurrent miscarriages, or requirement of the use of assisted reproductive technology [ART] to achieve a pregnancy), the birth of a child with features of one or more of the imprinting disorders listed in
Physical examination should not focus solely on the identification of the classic features of each imprinting disorder listed in
A three-generation family history (pedigree) should be taken with specific inquiry about female relatives with infertility, multiple miscarriages, molar pregnancies, offspring with features of one or more imprinting disorders, and multiple different offspring with an imprinting disorder (see
Note: Features in the medical and family history may be suggestive of MEG-MLID even when there is a low clinical suspicion that the offspring has a classic imprinting disorder phenotype; in this scenario, testing the mother for biallelic pathogenic variants in MEGs may be considered [
Because the imprinted loci involved in MEG-MLID are unpredictable and epigenotype-phenotype correlations are variable, all imprinted loci that are known to be associated with an imprinting disorder should be evaluated through testing.
Several methylation-specific (MS) assays are available for clinical MEG-MLID testing (e.g., MLPA, pyrosequencing, long-read sequencing), but diagnostic laboratories should confirm their suitability and that the clinically associated imprinted loci are addressed.
Genome-wide MS assays (e.g., those based on DNA methylation arrays or massively parallel sequencing) may be used to detect MEG-MLID; however, diagnostic laboratories should ensure that they include all clinically associated imprinted loci and must assess their sensitivity to detect mosaic imprinting disturbances.
Note: (1) For genetic testing, the molecular proband is the mother (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Can aid in discussions of recurrence risks (see
• Usually involves a medical history, physical examination and (where relevant) laboratory testing of the clinical proband(s), detailed family history, and genomic/genetic testing of the clinical proband(s) and family members, as warranted.
• Because the imprinted loci involved in MEG-MLID are unpredictable and epigenotype-phenotype correlations are variable, all imprinted loci that are known to be associated with an imprinting disorder should be evaluated through testing.
• Several methylation-specific (MS) assays are available for clinical MEG-MLID testing (e.g., MLPA, pyrosequencing, long-read sequencing), but diagnostic laboratories should confirm their suitability and that the clinically associated imprinted loci are addressed.
• Genome-wide MS assays (e.g., those based on DNA methylation arrays or massively parallel sequencing) may be used to detect MEG-MLID; however, diagnostic laboratories should ensure that they include all clinically associated imprinted loci and must assess their sensitivity to detect mosaic imprinting disturbances.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Medical History
Mothers with biallelic pathogenic variants in a maternal effect gene (MEG) may have offspring with one imprinting disorder, multilocus imprinting disturbances (MLID) (i.e., clinical features of more than one imprinting disorder, features that are a blend of two or more imprinting disorders, or features that do not align with any classic imprinting disorder), or offspring who are clinically healthy; such mothers may also experience reproductive difficulties including pregnancy losses, molar pregnancy, or apparent infertility.
The detection of MLID in more than one child is strongly suggestive of biallelic pathogenic variants in an MEG in the mother. In families with reproductive issues (fertility problems, recurrent miscarriages, or requirement of the use of assisted reproductive technology [ART] to achieve a pregnancy), the birth of a child with features of one or more of the imprinting disorders listed in
## Physical Examination
Physical examination should not focus solely on the identification of the classic features of each imprinting disorder listed in
## Family History
A three-generation family history (pedigree) should be taken with specific inquiry about female relatives with infertility, multiple miscarriages, molar pregnancies, offspring with features of one or more imprinting disorders, and multiple different offspring with an imprinting disorder (see
## Genomic/Genetic Testing
Note: Features in the medical and family history may be suggestive of MEG-MLID even when there is a low clinical suspicion that the offspring has a classic imprinting disorder phenotype; in this scenario, testing the mother for biallelic pathogenic variants in MEGs may be considered [
Because the imprinted loci involved in MEG-MLID are unpredictable and epigenotype-phenotype correlations are variable, all imprinted loci that are known to be associated with an imprinting disorder should be evaluated through testing.
Several methylation-specific (MS) assays are available for clinical MEG-MLID testing (e.g., MLPA, pyrosequencing, long-read sequencing), but diagnostic laboratories should confirm their suitability and that the clinically associated imprinted loci are addressed.
Genome-wide MS assays (e.g., those based on DNA methylation arrays or massively parallel sequencing) may be used to detect MEG-MLID; however, diagnostic laboratories should ensure that they include all clinically associated imprinted loci and must assess their sensitivity to detect mosaic imprinting disturbances.
Note: (1) For genetic testing, the molecular proband is the mother (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Because the imprinted loci involved in MEG-MLID are unpredictable and epigenotype-phenotype correlations are variable, all imprinted loci that are known to be associated with an imprinting disorder should be evaluated through testing.
• Several methylation-specific (MS) assays are available for clinical MEG-MLID testing (e.g., MLPA, pyrosequencing, long-read sequencing), but diagnostic laboratories should confirm their suitability and that the clinically associated imprinted loci are addressed.
• Genome-wide MS assays (e.g., those based on DNA methylation arrays or massively parallel sequencing) may be used to detect MEG-MLID; however, diagnostic laboratories should ensure that they include all clinically associated imprinted loci and must assess their sensitivity to detect mosaic imprinting disturbances.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Genetic Counseling
In genetic terms, the molecular proband in a family with maternal effect gene-related multilocus imprinting disturbances (MEG-MLID) is the mother (see
A female who is a molecular proband will not have features of an imprinting disorder but may have a reproductive history consistent with MEG-MLID (e.g., pregnancy loses, molar pregnancy, or apparent infertility) and/or (multiple) offspring with features of imprinting disorders [
Sibs are presumed to have a 25% chance of having biallelic pathogenic variants, a 50% chance of having one pathogenic variant, and a 25% chance of having neither of the familial pathogenic variants.
Female sibs who inherit biallelic pathogenic variants are at risk of MEG-MLID-related reproductive complications (i.e., pregnancy losses, molar pregnancy, apparent infertility, and affected offspring).
Female sibs who inherit one pathogenic variant are heterozygotes. The risk of MEG-MLID-related reproductive complications is presumed to be low; however, further study is needed to determine if maternal heterozygosity for a pathogenic variant in an MEG may contribute to reproductive complications.
Male sibs who inherit biallelic or heterozygous pathogenic variants in an MEG are not at risk for MEG-MLID-related reproductive problems.
Note: The sibs of a molecular proband are not themselves at increased risk of having features of an imprinting disorder but do have the reproductive risks listed above.
Offspring with features of one or more imprinting disorders.
Note: Each affected offspring is heterozygous for a maternally transmitted pathogenic variant in an MEG. In and of itself, the maternally transmitted pathogenic variant is not currently known to lead to clinical manifestations; offspring have clinical manifestations due to abnormal imprinting resulting from the early embryo's inability to properly establish or maintain imprinting.
Offspring who are clinically healthy.
Note: Each unaffected offspring is also heterozygous for a maternally transmitted pathogenic variant in an MEG (see
The risk that offspring of a clinical proband will have features of imprinting disorders is presumed to be low, but there is insufficient knowledge about the reproductive outcomes of individuals with MLID to assert that the risk is reduced to that of the general population.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most health care professionals would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
There are limited possibilities for prenatal testing in offspring of a female who has biallelic pathogenic variants in an MEG gene. There is no reliable prenatal test for detection of multilocus methylation changes. For prenatal testing for
Preimplantation diagnostic testing is not possible.
• Sibs are presumed to have a 25% chance of having biallelic pathogenic variants, a 50% chance of having one pathogenic variant, and a 25% chance of having neither of the familial pathogenic variants.
• Female sibs who inherit biallelic pathogenic variants are at risk of MEG-MLID-related reproductive complications (i.e., pregnancy losses, molar pregnancy, apparent infertility, and affected offspring).
• Female sibs who inherit one pathogenic variant are heterozygotes. The risk of MEG-MLID-related reproductive complications is presumed to be low; however, further study is needed to determine if maternal heterozygosity for a pathogenic variant in an MEG may contribute to reproductive complications.
• Male sibs who inherit biallelic or heterozygous pathogenic variants in an MEG are not at risk for MEG-MLID-related reproductive problems.
• Offspring with features of one or more imprinting disorders.
• Note: Each affected offspring is heterozygous for a maternally transmitted pathogenic variant in an MEG. In and of itself, the maternally transmitted pathogenic variant is not currently known to lead to clinical manifestations; offspring have clinical manifestations due to abnormal imprinting resulting from the early embryo's inability to properly establish or maintain imprinting.
• Offspring who are clinically healthy.
• Note: Each unaffected offspring is also heterozygous for a maternally transmitted pathogenic variant in an MEG (see
## Risk to Family Members of a Molecular Proband
In genetic terms, the molecular proband in a family with maternal effect gene-related multilocus imprinting disturbances (MEG-MLID) is the mother (see
A female who is a molecular proband will not have features of an imprinting disorder but may have a reproductive history consistent with MEG-MLID (e.g., pregnancy loses, molar pregnancy, or apparent infertility) and/or (multiple) offspring with features of imprinting disorders [
Sibs are presumed to have a 25% chance of having biallelic pathogenic variants, a 50% chance of having one pathogenic variant, and a 25% chance of having neither of the familial pathogenic variants.
Female sibs who inherit biallelic pathogenic variants are at risk of MEG-MLID-related reproductive complications (i.e., pregnancy losses, molar pregnancy, apparent infertility, and affected offspring).
Female sibs who inherit one pathogenic variant are heterozygotes. The risk of MEG-MLID-related reproductive complications is presumed to be low; however, further study is needed to determine if maternal heterozygosity for a pathogenic variant in an MEG may contribute to reproductive complications.
Male sibs who inherit biallelic or heterozygous pathogenic variants in an MEG are not at risk for MEG-MLID-related reproductive problems.
Note: The sibs of a molecular proband are not themselves at increased risk of having features of an imprinting disorder but do have the reproductive risks listed above.
Offspring with features of one or more imprinting disorders.
Note: Each affected offspring is heterozygous for a maternally transmitted pathogenic variant in an MEG. In and of itself, the maternally transmitted pathogenic variant is not currently known to lead to clinical manifestations; offspring have clinical manifestations due to abnormal imprinting resulting from the early embryo's inability to properly establish or maintain imprinting.
Offspring who are clinically healthy.
Note: Each unaffected offspring is also heterozygous for a maternally transmitted pathogenic variant in an MEG (see
• Sibs are presumed to have a 25% chance of having biallelic pathogenic variants, a 50% chance of having one pathogenic variant, and a 25% chance of having neither of the familial pathogenic variants.
• Female sibs who inherit biallelic pathogenic variants are at risk of MEG-MLID-related reproductive complications (i.e., pregnancy losses, molar pregnancy, apparent infertility, and affected offspring).
• Female sibs who inherit one pathogenic variant are heterozygotes. The risk of MEG-MLID-related reproductive complications is presumed to be low; however, further study is needed to determine if maternal heterozygosity for a pathogenic variant in an MEG may contribute to reproductive complications.
• Male sibs who inherit biallelic or heterozygous pathogenic variants in an MEG are not at risk for MEG-MLID-related reproductive problems.
• Offspring with features of one or more imprinting disorders.
• Note: Each affected offspring is heterozygous for a maternally transmitted pathogenic variant in an MEG. In and of itself, the maternally transmitted pathogenic variant is not currently known to lead to clinical manifestations; offspring have clinical manifestations due to abnormal imprinting resulting from the early embryo's inability to properly establish or maintain imprinting.
• Offspring who are clinically healthy.
• Note: Each unaffected offspring is also heterozygous for a maternally transmitted pathogenic variant in an MEG (see
## Related Genetic Counseling Issues
The risk that offspring of a clinical proband will have features of imprinting disorders is presumed to be low, but there is insufficient knowledge about the reproductive outcomes of individuals with MLID to assert that the risk is reduced to that of the general population.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most health care professionals would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
There are limited possibilities for prenatal testing in offspring of a female who has biallelic pathogenic variants in an MEG gene. There is no reliable prenatal test for detection of multilocus methylation changes. For prenatal testing for
Preimplantation diagnostic testing is not possible.
## Chapter Notes
15 May 2025 (ma) Review posted live
27 June 2024 (zt) Original submission
• 15 May 2025 (ma) Review posted live
• 27 June 2024 (zt) Original submission
## Revision History
15 May 2025 (ma) Review posted live
27 June 2024 (zt) Original submission
• 15 May 2025 (ma) Review posted live
• 27 June 2024 (zt) Original submission
## References
## Literature Cited
Inheritance in multilocus imprinting disturbances (MLID) due to pathogenic variants in a maternally expressed gene (MEG). The "molecular proband" is the asymptomatic female (II;2) who has biallelic pathogenic variants in an MEG. The "clinical proband" is heterozygous for a pathogenic variant in an MEG but is affected by an imprinting disorder (III;3 and III;4). In MEG-MLID, the molecular proband is always female. There is not enough knowledge about the reproductive outcomes of clinical probands; they are heterozygous carriers, and in theory genetically they have the same reproductive outcomes as a heterozygous sib who is clinically unaffected by an imprinting disorder. III;2 represents miscarriages and molar pregnancies.
wt = wild type allele; pv = pathogenic variant
|
[] |
15/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mma
|
mma
|
[
"Isolated Methylmalonic Aciduria",
"Isolated Methylmalonic Aciduria",
"Isolated Methylmalonic Acidemia: Partially Deficient or B12-Responsive",
"Methylmalonyl-CoA Epimerase Deficiency",
"Isolated Methylmalonic Acidemia: Infantile/Non-B12-Responsive",
"Cobalamin trafficking protein CblD",
"Corrinoid adenosyltransferase MMAB",
"Methylmalonic aciduria type A protein, mitochondrial",
"Methylmalonyl-CoA epimerase, mitochondrial",
"Methylmalonyl-CoA mutase, mitochondrial",
"MCEE",
"MMAA",
"MMAB",
"MMADHC",
"MMUT",
"Isolated Methylmalonic Acidemia"
] |
Isolated Methylmalonic Acidemia
|
Irini Manoli, Jennifer L Sloan, Charles P Venditti
|
Summary For this Infantile/non-B Partially deficient or B Methylmalonyl-CoA epimerase deficiency, in which findings range from complete absence of symptoms to severe metabolic acidosis. Affected individuals can also develop ataxia, dysarthria, hypotonia, mild spastic paraparesis, and seizures. In those individuals diagnosed by newborn screening and treated from an early age, there appears to be decreased early mortality, less severe symptoms at diagnosis, favorable short-term neurodevelopmental outcome, and lower incidence of movement disorders and irreversible cerebral damage. However, secondary complications may still occur and can include intellectual disability, tubulointerstitial nephritis with progressive impairment of renal function, "metabolic stroke" (bilateral lacunar infarction of the basal ganglia during acute metabolic decompensation), pancreatitis, growth failure, functional immune impairment, bone marrow failure, optic nerve atrophy, arrhythmias and/or cardiomyopathy (dilated or hypertrophic), liver steatosis/fibrosis/cancer, and renal cancer. The diagnosis of isolated MMA is established in a proband by identification of biallelic pathogenic variants in All forms of isolated MMA are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an isolated MMA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the isolated MMA-causing pathogenic variants have been identified in an affected family member, molecular genetic carrier testing and prenatal/preimplantation genetic testing are possible.
|
Isolated Methylmalonic Acidemia/Aciduria: Included Phenotypes
## Diagnosis
For this
Elevated C3 values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see also the
In the US, individual state NBS programs determine cutoffs based on analytic and other considerations, under the guidance of the CDC Newborn Screening Quality Assurance Program (NSQAP) and Association of Public Health Laboratories (APHL) [
Since propionylcarnitine is one of the analytes most frequently responsible for false positive results, ratios including C3/C2, C3/C0, C3/C16, C3/glycine, or C3/methionine are recommended in combination with high blood concentration of C3 as decision criteria for "positive" testing in newborn screening acylcarnitine analysis by MS/MS for methylmalonic acidemia and propionic acidemia [
Additional biomarkers such as C16:1OH (3-hydroxypalmitoleolyl-carnitine) or, more accurately, C17 (heptadecanoylcarnitine) have been suggested to improve the sensitivity of the first-tier newborn screening test [
Amino acid analysis of the dried blood spot will show normal methionine and elevated C3/methionine ratio.
Precision newborn screening and avoidance of false positive results can be further improved with the utilization of the
Prompt evaluation for prevention or treatment of possible hyperammonemia and metabolic ketoacidosis
Daily intramuscular vitamin B
Initiation of a low-protein diet
Carnitine supplementation
Follow-up biochemical testing after an abnormal NBS typically demonstrates:
Elevated plasma methylmalonic acid (MMA) level
Elevated levels of urine MMA and the presence of 3-hydroxypropionate, 2-methylcitrate, and tiglylglycine on urine organic acids
Elevated concentrations of glycine and possibly alanine with normal methionine on plasma amino acids
Elevated plasma concentration of propionylcarnitine (C3) and variable elevations in C4-dicarboxylic or methylmalonic/succinylcarnitine (C4DC) on plasma acylcarnitine profile
Elevated plasma ammonia, metabolic ketoacidosis, pancytopenia, lactic acidosis, hypoglycemia (in some cases)
Normal serum B
Note: (1) Although plasma and/or urine methylmalonic acid concentration can be precisely quantitated (see
If follow-up biochemical testing supports the likelihood of isolated methylmalonic acidemia, additional testing is required to establish the diagnosis (see
A symptomatic individual may present with clinical findings associated with an attenuated MMA phenotype or untreated infantile-onset MMA (see
Supportive – but nonspecific – clinical findings, brain MRI findings, and preliminary laboratory findings can include the following.
In neonates:
Lethargy
Vomiting
Hypotonia
Hypothermia
Respiratory distress
Encephalopathy, coma
Sepsis-like illness
In older infants and children:
Failure to thrive / short stature
Protein aversion
Hypotonia
Intellectual disability
Acute and chronic neurologic symptoms including seizures and abnormal movements (choreoathetosis, dystonia, spasticity)
Acute and chronic renal manifestations (dehydration, renal tubular acidosis, acute kidney injury)
Acutely:
Severe ketoacidosis and lactic acidosis (may first present as a catastrophic/lethal ketoacidosis following an intercurrent illness)
Hyperammonemia
Anemia, neutropenia, and/or thrombocytopenia on complete blood count
In older untreated infants and children: isolated renal tubular acidosis or chronic renal failure
The diagnosis of isolated MMA
Isolated MMA is caused by any ONE of the following:
Complete (
Diminished synthesis of the methylmalonyl-CoA mutase enzyme cofactor 5'-deoxyadenosylcobalamin, associated with
Deficient activity of methylmalonyl-coenzyme A epimerase encoded by
Methylmalonic Acid Concentration in Phenotypes and Enzymatic Subtypes of Methylmalonic Acidemia
100-1,000 µmol/L (if eGFR >50 mL/min/1.73 m
1,000-10,000 µmol/L in those w/advanced renal disease
Cr = creatinine; eGFR = estimated glomerular filtration rate; MCEE = methylmalonyl-coenzyme A epimerase
Biochemical parameters and clinical phenotype are not always concordant, partly because renal function can influence plasma MMA concentration [
Approximate numbers, representing the author's experience with >150 individuals with the B
Normal values have not been exclusively derived from children or neonates. Some laboratories report urine MMA concentrations in mg/g/Cr (normal: <3 mg/g/Cr) and serum concentrations in nmol/L (normal: <271 nmol/L). The molecular weight of MMA is 118 g/mol.
Molecular genetic testing (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Isolated Methylmalonic Acidemia
NA = not applicable
Genes are listed in alphabetic order.
See
Based on
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
For individuals of Hispanic descent, targeted exon 2 analysis for the
Some individuals with isolated MMA remain undiagnosed despite extensive genome and RNA sequencing, suggesting that additional genetic causes of isolated or combined subtypes of MMA may be identified with future research [
In vivo responsiveness to vitamin B
When stable, affected individuals can be given 1.0 mg of hydroxocobalamin (OH-Cbl) (see
A significant (>50%) reduction in plasma or urine mean methylmalonic acid concentration(s) is considered indicative of responsiveness [
In vivo response was reported in all individuals with
Cellular biochemical testing on skin fibroblasts was historically the gold standard for determining the MMA subtype and B
See
• In the US, individual state NBS programs determine cutoffs based on analytic and other considerations, under the guidance of the CDC Newborn Screening Quality Assurance Program (NSQAP) and Association of Public Health Laboratories (APHL) [
• Since propionylcarnitine is one of the analytes most frequently responsible for false positive results, ratios including C3/C2, C3/C0, C3/C16, C3/glycine, or C3/methionine are recommended in combination with high blood concentration of C3 as decision criteria for "positive" testing in newborn screening acylcarnitine analysis by MS/MS for methylmalonic acidemia and propionic acidemia [
• Additional biomarkers such as C16:1OH (3-hydroxypalmitoleolyl-carnitine) or, more accurately, C17 (heptadecanoylcarnitine) have been suggested to improve the sensitivity of the first-tier newborn screening test [
• Amino acid analysis of the dried blood spot will show normal methionine and elevated C3/methionine ratio.
• Precision newborn screening and avoidance of false positive results can be further improved with the utilization of the
• Prompt evaluation for prevention or treatment of possible hyperammonemia and metabolic ketoacidosis
• Daily intramuscular vitamin B
• Initiation of a low-protein diet
• Carnitine supplementation
• Elevated plasma methylmalonic acid (MMA) level
• Elevated levels of urine MMA and the presence of 3-hydroxypropionate, 2-methylcitrate, and tiglylglycine on urine organic acids
• Elevated concentrations of glycine and possibly alanine with normal methionine on plasma amino acids
• Elevated plasma concentration of propionylcarnitine (C3) and variable elevations in C4-dicarboxylic or methylmalonic/succinylcarnitine (C4DC) on plasma acylcarnitine profile
• Elevated plasma ammonia, metabolic ketoacidosis, pancytopenia, lactic acidosis, hypoglycemia (in some cases)
• Normal serum B
• Lethargy
• Vomiting
• Hypotonia
• Hypothermia
• Respiratory distress
• Encephalopathy, coma
• Sepsis-like illness
• Failure to thrive / short stature
• Protein aversion
• Hypotonia
• Intellectual disability
• Acute and chronic neurologic symptoms including seizures and abnormal movements (choreoathetosis, dystonia, spasticity)
• Acute and chronic renal manifestations (dehydration, renal tubular acidosis, acute kidney injury)
• Severe ketoacidosis and lactic acidosis (may first present as a catastrophic/lethal ketoacidosis following an intercurrent illness)
• Hyperammonemia
• Anemia, neutropenia, and/or thrombocytopenia on complete blood count
• Complete (
• Diminished synthesis of the methylmalonyl-CoA mutase enzyme cofactor 5'-deoxyadenosylcobalamin, associated with
• Deficient activity of methylmalonyl-coenzyme A epimerase encoded by
• 100-1,000 µmol/L (if eGFR >50 mL/min/1.73 m
• 1,000-10,000 µmol/L in those w/advanced renal disease
• When stable, affected individuals can be given 1.0 mg of hydroxocobalamin (OH-Cbl) (see
• A significant (>50%) reduction in plasma or urine mean methylmalonic acid concentration(s) is considered indicative of responsiveness [
• In vivo response was reported in all individuals with
## Suggestive Findings
Elevated C3 values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see also the
In the US, individual state NBS programs determine cutoffs based on analytic and other considerations, under the guidance of the CDC Newborn Screening Quality Assurance Program (NSQAP) and Association of Public Health Laboratories (APHL) [
Since propionylcarnitine is one of the analytes most frequently responsible for false positive results, ratios including C3/C2, C3/C0, C3/C16, C3/glycine, or C3/methionine are recommended in combination with high blood concentration of C3 as decision criteria for "positive" testing in newborn screening acylcarnitine analysis by MS/MS for methylmalonic acidemia and propionic acidemia [
Additional biomarkers such as C16:1OH (3-hydroxypalmitoleolyl-carnitine) or, more accurately, C17 (heptadecanoylcarnitine) have been suggested to improve the sensitivity of the first-tier newborn screening test [
Amino acid analysis of the dried blood spot will show normal methionine and elevated C3/methionine ratio.
Precision newborn screening and avoidance of false positive results can be further improved with the utilization of the
Prompt evaluation for prevention or treatment of possible hyperammonemia and metabolic ketoacidosis
Daily intramuscular vitamin B
Initiation of a low-protein diet
Carnitine supplementation
Follow-up biochemical testing after an abnormal NBS typically demonstrates:
Elevated plasma methylmalonic acid (MMA) level
Elevated levels of urine MMA and the presence of 3-hydroxypropionate, 2-methylcitrate, and tiglylglycine on urine organic acids
Elevated concentrations of glycine and possibly alanine with normal methionine on plasma amino acids
Elevated plasma concentration of propionylcarnitine (C3) and variable elevations in C4-dicarboxylic or methylmalonic/succinylcarnitine (C4DC) on plasma acylcarnitine profile
Elevated plasma ammonia, metabolic ketoacidosis, pancytopenia, lactic acidosis, hypoglycemia (in some cases)
Normal serum B
Note: (1) Although plasma and/or urine methylmalonic acid concentration can be precisely quantitated (see
If follow-up biochemical testing supports the likelihood of isolated methylmalonic acidemia, additional testing is required to establish the diagnosis (see
A symptomatic individual may present with clinical findings associated with an attenuated MMA phenotype or untreated infantile-onset MMA (see
Supportive – but nonspecific – clinical findings, brain MRI findings, and preliminary laboratory findings can include the following.
In neonates:
Lethargy
Vomiting
Hypotonia
Hypothermia
Respiratory distress
Encephalopathy, coma
Sepsis-like illness
In older infants and children:
Failure to thrive / short stature
Protein aversion
Hypotonia
Intellectual disability
Acute and chronic neurologic symptoms including seizures and abnormal movements (choreoathetosis, dystonia, spasticity)
Acute and chronic renal manifestations (dehydration, renal tubular acidosis, acute kidney injury)
Acutely:
Severe ketoacidosis and lactic acidosis (may first present as a catastrophic/lethal ketoacidosis following an intercurrent illness)
Hyperammonemia
Anemia, neutropenia, and/or thrombocytopenia on complete blood count
In older untreated infants and children: isolated renal tubular acidosis or chronic renal failure
• In the US, individual state NBS programs determine cutoffs based on analytic and other considerations, under the guidance of the CDC Newborn Screening Quality Assurance Program (NSQAP) and Association of Public Health Laboratories (APHL) [
• Since propionylcarnitine is one of the analytes most frequently responsible for false positive results, ratios including C3/C2, C3/C0, C3/C16, C3/glycine, or C3/methionine are recommended in combination with high blood concentration of C3 as decision criteria for "positive" testing in newborn screening acylcarnitine analysis by MS/MS for methylmalonic acidemia and propionic acidemia [
• Additional biomarkers such as C16:1OH (3-hydroxypalmitoleolyl-carnitine) or, more accurately, C17 (heptadecanoylcarnitine) have been suggested to improve the sensitivity of the first-tier newborn screening test [
• Amino acid analysis of the dried blood spot will show normal methionine and elevated C3/methionine ratio.
• Precision newborn screening and avoidance of false positive results can be further improved with the utilization of the
• Prompt evaluation for prevention or treatment of possible hyperammonemia and metabolic ketoacidosis
• Daily intramuscular vitamin B
• Initiation of a low-protein diet
• Carnitine supplementation
• Elevated plasma methylmalonic acid (MMA) level
• Elevated levels of urine MMA and the presence of 3-hydroxypropionate, 2-methylcitrate, and tiglylglycine on urine organic acids
• Elevated concentrations of glycine and possibly alanine with normal methionine on plasma amino acids
• Elevated plasma concentration of propionylcarnitine (C3) and variable elevations in C4-dicarboxylic or methylmalonic/succinylcarnitine (C4DC) on plasma acylcarnitine profile
• Elevated plasma ammonia, metabolic ketoacidosis, pancytopenia, lactic acidosis, hypoglycemia (in some cases)
• Normal serum B
• Lethargy
• Vomiting
• Hypotonia
• Hypothermia
• Respiratory distress
• Encephalopathy, coma
• Sepsis-like illness
• Failure to thrive / short stature
• Protein aversion
• Hypotonia
• Intellectual disability
• Acute and chronic neurologic symptoms including seizures and abnormal movements (choreoathetosis, dystonia, spasticity)
• Acute and chronic renal manifestations (dehydration, renal tubular acidosis, acute kidney injury)
• Severe ketoacidosis and lactic acidosis (may first present as a catastrophic/lethal ketoacidosis following an intercurrent illness)
• Hyperammonemia
• Anemia, neutropenia, and/or thrombocytopenia on complete blood count
## Scenario 1: Abnormal Newborn Screening (NBS) Result
Elevated C3 values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see also the
In the US, individual state NBS programs determine cutoffs based on analytic and other considerations, under the guidance of the CDC Newborn Screening Quality Assurance Program (NSQAP) and Association of Public Health Laboratories (APHL) [
Since propionylcarnitine is one of the analytes most frequently responsible for false positive results, ratios including C3/C2, C3/C0, C3/C16, C3/glycine, or C3/methionine are recommended in combination with high blood concentration of C3 as decision criteria for "positive" testing in newborn screening acylcarnitine analysis by MS/MS for methylmalonic acidemia and propionic acidemia [
Additional biomarkers such as C16:1OH (3-hydroxypalmitoleolyl-carnitine) or, more accurately, C17 (heptadecanoylcarnitine) have been suggested to improve the sensitivity of the first-tier newborn screening test [
Amino acid analysis of the dried blood spot will show normal methionine and elevated C3/methionine ratio.
Precision newborn screening and avoidance of false positive results can be further improved with the utilization of the
Prompt evaluation for prevention or treatment of possible hyperammonemia and metabolic ketoacidosis
Daily intramuscular vitamin B
Initiation of a low-protein diet
Carnitine supplementation
Follow-up biochemical testing after an abnormal NBS typically demonstrates:
Elevated plasma methylmalonic acid (MMA) level
Elevated levels of urine MMA and the presence of 3-hydroxypropionate, 2-methylcitrate, and tiglylglycine on urine organic acids
Elevated concentrations of glycine and possibly alanine with normal methionine on plasma amino acids
Elevated plasma concentration of propionylcarnitine (C3) and variable elevations in C4-dicarboxylic or methylmalonic/succinylcarnitine (C4DC) on plasma acylcarnitine profile
Elevated plasma ammonia, metabolic ketoacidosis, pancytopenia, lactic acidosis, hypoglycemia (in some cases)
Normal serum B
Note: (1) Although plasma and/or urine methylmalonic acid concentration can be precisely quantitated (see
If follow-up biochemical testing supports the likelihood of isolated methylmalonic acidemia, additional testing is required to establish the diagnosis (see
• In the US, individual state NBS programs determine cutoffs based on analytic and other considerations, under the guidance of the CDC Newborn Screening Quality Assurance Program (NSQAP) and Association of Public Health Laboratories (APHL) [
• Since propionylcarnitine is one of the analytes most frequently responsible for false positive results, ratios including C3/C2, C3/C0, C3/C16, C3/glycine, or C3/methionine are recommended in combination with high blood concentration of C3 as decision criteria for "positive" testing in newborn screening acylcarnitine analysis by MS/MS for methylmalonic acidemia and propionic acidemia [
• Additional biomarkers such as C16:1OH (3-hydroxypalmitoleolyl-carnitine) or, more accurately, C17 (heptadecanoylcarnitine) have been suggested to improve the sensitivity of the first-tier newborn screening test [
• Amino acid analysis of the dried blood spot will show normal methionine and elevated C3/methionine ratio.
• Precision newborn screening and avoidance of false positive results can be further improved with the utilization of the
• Prompt evaluation for prevention or treatment of possible hyperammonemia and metabolic ketoacidosis
• Daily intramuscular vitamin B
• Initiation of a low-protein diet
• Carnitine supplementation
• Elevated plasma methylmalonic acid (MMA) level
• Elevated levels of urine MMA and the presence of 3-hydroxypropionate, 2-methylcitrate, and tiglylglycine on urine organic acids
• Elevated concentrations of glycine and possibly alanine with normal methionine on plasma amino acids
• Elevated plasma concentration of propionylcarnitine (C3) and variable elevations in C4-dicarboxylic or methylmalonic/succinylcarnitine (C4DC) on plasma acylcarnitine profile
• Elevated plasma ammonia, metabolic ketoacidosis, pancytopenia, lactic acidosis, hypoglycemia (in some cases)
• Normal serum B
## Scenario 2: Symptomatic Individual
A symptomatic individual may present with clinical findings associated with an attenuated MMA phenotype or untreated infantile-onset MMA (see
Supportive – but nonspecific – clinical findings, brain MRI findings, and preliminary laboratory findings can include the following.
In neonates:
Lethargy
Vomiting
Hypotonia
Hypothermia
Respiratory distress
Encephalopathy, coma
Sepsis-like illness
In older infants and children:
Failure to thrive / short stature
Protein aversion
Hypotonia
Intellectual disability
Acute and chronic neurologic symptoms including seizures and abnormal movements (choreoathetosis, dystonia, spasticity)
Acute and chronic renal manifestations (dehydration, renal tubular acidosis, acute kidney injury)
Acutely:
Severe ketoacidosis and lactic acidosis (may first present as a catastrophic/lethal ketoacidosis following an intercurrent illness)
Hyperammonemia
Anemia, neutropenia, and/or thrombocytopenia on complete blood count
In older untreated infants and children: isolated renal tubular acidosis or chronic renal failure
• Lethargy
• Vomiting
• Hypotonia
• Hypothermia
• Respiratory distress
• Encephalopathy, coma
• Sepsis-like illness
• Failure to thrive / short stature
• Protein aversion
• Hypotonia
• Intellectual disability
• Acute and chronic neurologic symptoms including seizures and abnormal movements (choreoathetosis, dystonia, spasticity)
• Acute and chronic renal manifestations (dehydration, renal tubular acidosis, acute kidney injury)
• Severe ketoacidosis and lactic acidosis (may first present as a catastrophic/lethal ketoacidosis following an intercurrent illness)
• Hyperammonemia
• Anemia, neutropenia, and/or thrombocytopenia on complete blood count
## Establishing the Diagnosis
The diagnosis of isolated MMA
Isolated MMA is caused by any ONE of the following:
Complete (
Diminished synthesis of the methylmalonyl-CoA mutase enzyme cofactor 5'-deoxyadenosylcobalamin, associated with
Deficient activity of methylmalonyl-coenzyme A epimerase encoded by
Methylmalonic Acid Concentration in Phenotypes and Enzymatic Subtypes of Methylmalonic Acidemia
100-1,000 µmol/L (if eGFR >50 mL/min/1.73 m
1,000-10,000 µmol/L in those w/advanced renal disease
Cr = creatinine; eGFR = estimated glomerular filtration rate; MCEE = methylmalonyl-coenzyme A epimerase
Biochemical parameters and clinical phenotype are not always concordant, partly because renal function can influence plasma MMA concentration [
Approximate numbers, representing the author's experience with >150 individuals with the B
Normal values have not been exclusively derived from children or neonates. Some laboratories report urine MMA concentrations in mg/g/Cr (normal: <3 mg/g/Cr) and serum concentrations in nmol/L (normal: <271 nmol/L). The molecular weight of MMA is 118 g/mol.
Molecular genetic testing (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Isolated Methylmalonic Acidemia
NA = not applicable
Genes are listed in alphabetic order.
See
Based on
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
For individuals of Hispanic descent, targeted exon 2 analysis for the
Some individuals with isolated MMA remain undiagnosed despite extensive genome and RNA sequencing, suggesting that additional genetic causes of isolated or combined subtypes of MMA may be identified with future research [
In vivo responsiveness to vitamin B
When stable, affected individuals can be given 1.0 mg of hydroxocobalamin (OH-Cbl) (see
A significant (>50%) reduction in plasma or urine mean methylmalonic acid concentration(s) is considered indicative of responsiveness [
In vivo response was reported in all individuals with
Cellular biochemical testing on skin fibroblasts was historically the gold standard for determining the MMA subtype and B
See
• Complete (
• Diminished synthesis of the methylmalonyl-CoA mutase enzyme cofactor 5'-deoxyadenosylcobalamin, associated with
• Deficient activity of methylmalonyl-coenzyme A epimerase encoded by
• 100-1,000 µmol/L (if eGFR >50 mL/min/1.73 m
• 1,000-10,000 µmol/L in those w/advanced renal disease
• When stable, affected individuals can be given 1.0 mg of hydroxocobalamin (OH-Cbl) (see
• A significant (>50%) reduction in plasma or urine mean methylmalonic acid concentration(s) is considered indicative of responsiveness [
• In vivo response was reported in all individuals with
## Molecular Genetic Testing Approaches
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Isolated Methylmalonic Acidemia
NA = not applicable
Genes are listed in alphabetic order.
See
Based on
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
For individuals of Hispanic descent, targeted exon 2 analysis for the
Some individuals with isolated MMA remain undiagnosed despite extensive genome and RNA sequencing, suggesting that additional genetic causes of isolated or combined subtypes of MMA may be identified with future research [
## Responsiveness to Vitamin B
In vivo responsiveness to vitamin B
When stable, affected individuals can be given 1.0 mg of hydroxocobalamin (OH-Cbl) (see
A significant (>50%) reduction in plasma or urine mean methylmalonic acid concentration(s) is considered indicative of responsiveness [
In vivo response was reported in all individuals with
• When stable, affected individuals can be given 1.0 mg of hydroxocobalamin (OH-Cbl) (see
• A significant (>50%) reduction in plasma or urine mean methylmalonic acid concentration(s) is considered indicative of responsiveness [
• In vivo response was reported in all individuals with
## Enzymatic Testing
Cellular biochemical testing on skin fibroblasts was historically the gold standard for determining the MMA subtype and B
See
## Clinical Characteristics
The phenotypes of isolated methylmalonic acidemia (MMA) described below that are associated with the enzymatic subtypes
Phenotype Correlations by Gene and Enzymatic Subtype of Isolated Methylmalonic Acidemia
Most common & severe form, typically presenting in infancy
Higher rate of mortality & neurologic & other multisystem complications than in those w/
Renal disease may manifest in childhood in ~43%-60%, w/median age of onset 6-11 yrs.
Onset may occur later, in 1st few mos or yrs of life.
Symptoms often incl feeding problems, failure to thrive, hypotonia, & DD.
Catastrophic decompensation can occur when diagnosis is delayed, incl injury in basal ganglia → movement disorder.
Some persons have isolated renal tubular acidosis or chronic renal failure as primary finding.
Most affected persons have phenotype that resembles
Higher rate of mortality & neurologic & other multisystem complications than in those w/
Chronic renal failure occurs in ~66% & is less frequent than in those w/
Milder disease course
Normal life expectancy
Slower decline in renal function w/≈9%-12% developing chronic renal failure
Better neurocognitive outcomes than in
Only rarely is this subtype responsive to injectable B
May present w/isolated renal tubular acidosis or chronic renal failure
In general, milder features ranging from no symptoms to severe metabolic acidosis.
Not responsive to injectable B
A rare cause of persistent moderate MMA
DD = developmental delay; MCEE = methylmalonyl-coenzyme A epimerase
The most common phenotype, which typically presents during infancy
Sometimes referred to as partial deficiency
Including optic nerve atrophy, basal ganglia injury, and multiorgan failure [
See also
Decreased early mortality, less severe symptoms at diagnosis, favorable short-term neurodevelopmental outcome, and lower incidence of movement disorders and irreversible cerebral damage were recorded in affected individuals identified through expanded NBS, though a number of infants with the
As described prior to newborn screening (NBS) availability, the common phenotypes and associated features of isolated MMA included the following.
The most common phenotype of isolated MMA presents during infancy. Infants are normal at birth but develop lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds.
This can rapidly progress to coma due to hyperammonemic encephalopathy, if untreated.
Laboratory findings typically show a severe, high anion-gap metabolic acidosis, ketosis and ketonuria (highly abnormal in neonates and strongly suggestive of an organic aciduria), hyperammonemia, and hyperglycinemia [
Dialysis may be needed especially if hyperammonemia is significant and persistent.
Thrombocytopenia and neutropenia, suggestive of neonatal sepsis, can be seen.
Affected infants can exhibit feeding problems (typically anorexia and vomiting), failure to thrive, hypotonia, and developmental delay.
Some have protein aversion and/or clinical symptoms of vomiting and lethargy after protein intake.
Until the diagnosis is established and treatment initiated, infants are at risk for a catastrophic decompensation (like that in neonates) [
During such an episode of metabolic decompensation, the child may die despite intensive intervention if prompt treatment specific for MMA (see
Before the availability of NBS, or in cases that are false negative on NBS due to borderline C3 elevations, infants with the
Individuals with partial enzymatic deficiency (
Screening of a large cohort of individuals with undefined MMA identified ten individuals with MCEE deficiency with symptoms including metabolic ketoacidosis, hypoglycemia, seizures, developmental delay, and spasticity. Cardiomyopathy was reported in a single individual, with a similarly affected sib with biochemical but no clinical findings [
Individuals with MCEE deficiency were not responsive to B
A 78-year-old individual with Parkinson disease, dementia, and stroke was found to have
Secondary complications can be observed in any enzymatic subtype but may be dependent on the specific subtype and degree of metabolic control and adherence (see
Therefore, primary and secondary biomarkers are important for monitoring affected individuals and supporting efficacy in therapeutic clinical trials [
The major secondary complications include the following.
In one study about 50% of individuals with
In a natural history study, the mean FSIQ of all individuals with isolated MMA (n=37) was 85.0 ± 20.68, which is in the low-average range (80≤IQ≤89) [
Individuals with
The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
Cystatin-C levels and age-appropriate equations to calculate estimated glomerular filtration rate (GFR) – or preferably, measurement of GFR by iohexol clearance or other methods – should be used for clinical monitoring, due to the fact that creatinine is a late marker of renal dysfunction in individuals with low muscle mass, as is seen in isolated MMA (see
Renal tubular dysfunction presenting as a decrease in urine concentrating ability and acidification, hyporeninemic hypoaldosteronism, tubular acidosis type 4, and hyperkalemia have been reported in a number of affected individuals [
Secondary mitochondrial dysfunction rather than direct nephrotoxicity of methylmalonic acid is hypothesized as the cause for renal disease [
Comorbidities of renal disease including anemia, acidosis, hyperuricemia, secondary hyperparathyroidism, osteopenia/osteoporosis, hypertension, and short stature should be monitored regularly by a multidisciplinary care team (see
The reported incidence in different cohorts is 17%-30% [
Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
Rarely, affected individuals have documented growth hormone (GH) deficiency, for which GH therapy has been used.
GH therapy has also been used for its anabolic effects or as part of the management of chronic kidney disease [
Response to GH therapy may vary; careful monitoring of the diet and metabolic parameters is necessary (see
Additional cardiometabolic risk factors, including obesity, insulin resistance, and hyperlipidemia, need to be monitored regularly to optimize cardiovascular health [
Liver neoplasms have been reported in five individuals, all severely affected (4 with
Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
Periodic screening (typically at least annually or as clinically indicated) including liver transaminases, serum AFP level, and liver ultrasound is recommended in individuals with severe MMA subtypes (see
Overall mortality was about 50% for those with the
More recent reports from the European Registry and Network for Intoxication Type Metabolic Diseases notes a 6% mortality for
Improvements likely reflect changes in diagnosis and NBS, improved treatment guidelines for acute crises/hyperammonemia, optimized nutrition with gastrostomy tube feeding, access to intensive care, hemodialysis and N-carbamylglutamate for the management of hyperammonemia, as well as earlier referral and better morbidity and mortality associated with solid organ transplantation.
Precise genotype-phenotype correlations are difficult to determine since most affected individuals are compound heterozygotes and many pathogenic variants are not recurrent in the population.
Individuals homozygous for this pathogenic variant typically present in the neonatal period and are not responsive to hydroxocobalamin treatment.
Persons with two truncating pathogenic variants usually have the
Most of the pathogenic variants identified in the N-terminal domain have been associated with
The
The
A linker domain spanning residues 482-585 separates the N-terminal, or substrate (methylmalonyl-CoA) binding domain from the C-terminal cobalamin-binding domain. This linker region is less conserved and has a lower frequency of pathogenic variants [
Data in the table have been provided by the authors.
NA = not applicable
Observed in individuals of Mexican/Hispanic descent.
Observed in individuals of African descent
Several studies have estimated the birth prevalence of isolated methylmalonic acidemia. Urine screening for isolated methylmalonic acidemia in Quebec identified "symptomatic methylmalonic aciduria" in approximately 1:80,000 newborns screened [
The aggregate incidence from different newborn screening (NBS) programs in the US is reported as 1:159,614 [
• Most common & severe form, typically presenting in infancy
• Higher rate of mortality & neurologic & other multisystem complications than in those w/
• Renal disease may manifest in childhood in ~43%-60%, w/median age of onset 6-11 yrs.
• Onset may occur later, in 1st few mos or yrs of life.
• Symptoms often incl feeding problems, failure to thrive, hypotonia, & DD.
• Catastrophic decompensation can occur when diagnosis is delayed, incl injury in basal ganglia → movement disorder.
• Some persons have isolated renal tubular acidosis or chronic renal failure as primary finding.
• Most affected persons have phenotype that resembles
• Higher rate of mortality & neurologic & other multisystem complications than in those w/
• Chronic renal failure occurs in ~66% & is less frequent than in those w/
• Milder disease course
• Normal life expectancy
• Slower decline in renal function w/≈9%-12% developing chronic renal failure
• Better neurocognitive outcomes than in
• Only rarely is this subtype responsive to injectable B
• May present w/isolated renal tubular acidosis or chronic renal failure
• In general, milder features ranging from no symptoms to severe metabolic acidosis.
• Not responsive to injectable B
• A rare cause of persistent moderate MMA
• The most common phenotype of isolated MMA presents during infancy. Infants are normal at birth but develop lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds.
• This can rapidly progress to coma due to hyperammonemic encephalopathy, if untreated.
• Laboratory findings typically show a severe, high anion-gap metabolic acidosis, ketosis and ketonuria (highly abnormal in neonates and strongly suggestive of an organic aciduria), hyperammonemia, and hyperglycinemia [
• Dialysis may be needed especially if hyperammonemia is significant and persistent.
• Thrombocytopenia and neutropenia, suggestive of neonatal sepsis, can be seen.
• Affected infants can exhibit feeding problems (typically anorexia and vomiting), failure to thrive, hypotonia, and developmental delay.
• Some have protein aversion and/or clinical symptoms of vomiting and lethargy after protein intake.
• Until the diagnosis is established and treatment initiated, infants are at risk for a catastrophic decompensation (like that in neonates) [
• During such an episode of metabolic decompensation, the child may die despite intensive intervention if prompt treatment specific for MMA (see
• Before the availability of NBS, or in cases that are false negative on NBS due to borderline C3 elevations, infants with the
• Individuals with partial enzymatic deficiency (
• Screening of a large cohort of individuals with undefined MMA identified ten individuals with MCEE deficiency with symptoms including metabolic ketoacidosis, hypoglycemia, seizures, developmental delay, and spasticity. Cardiomyopathy was reported in a single individual, with a similarly affected sib with biochemical but no clinical findings [
• Individuals with MCEE deficiency were not responsive to B
• A 78-year-old individual with Parkinson disease, dementia, and stroke was found to have
• In one study about 50% of individuals with
• In a natural history study, the mean FSIQ of all individuals with isolated MMA (n=37) was 85.0 ± 20.68, which is in the low-average range (80≤IQ≤89) [
• Individuals with
• The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
• Individuals with
• The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
• Individuals with
• The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
• Cystatin-C levels and age-appropriate equations to calculate estimated glomerular filtration rate (GFR) – or preferably, measurement of GFR by iohexol clearance or other methods – should be used for clinical monitoring, due to the fact that creatinine is a late marker of renal dysfunction in individuals with low muscle mass, as is seen in isolated MMA (see
• Renal tubular dysfunction presenting as a decrease in urine concentrating ability and acidification, hyporeninemic hypoaldosteronism, tubular acidosis type 4, and hyperkalemia have been reported in a number of affected individuals [
• Secondary mitochondrial dysfunction rather than direct nephrotoxicity of methylmalonic acid is hypothesized as the cause for renal disease [
• Comorbidities of renal disease including anemia, acidosis, hyperuricemia, secondary hyperparathyroidism, osteopenia/osteoporosis, hypertension, and short stature should be monitored regularly by a multidisciplinary care team (see
•
• The reported incidence in different cohorts is 17%-30% [
• Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
• The reported incidence in different cohorts is 17%-30% [
• Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
•
• After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
• Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
• After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
• Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
• The reported incidence in different cohorts is 17%-30% [
• Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
• After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
• Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
• Rarely, affected individuals have documented growth hormone (GH) deficiency, for which GH therapy has been used.
• GH therapy has also been used for its anabolic effects or as part of the management of chronic kidney disease [
• Response to GH therapy may vary; careful monitoring of the diet and metabolic parameters is necessary (see
• Additional cardiometabolic risk factors, including obesity, insulin resistance, and hyperlipidemia, need to be monitored regularly to optimize cardiovascular health [
• Liver neoplasms have been reported in five individuals, all severely affected (4 with
• Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
• Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
• Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
• Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
• Periodic screening (typically at least annually or as clinically indicated) including liver transaminases, serum AFP level, and liver ultrasound is recommended in individuals with severe MMA subtypes (see
• Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
• Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
• Overall mortality was about 50% for those with the
• More recent reports from the European Registry and Network for Intoxication Type Metabolic Diseases notes a 6% mortality for
• Improvements likely reflect changes in diagnosis and NBS, improved treatment guidelines for acute crises/hyperammonemia, optimized nutrition with gastrostomy tube feeding, access to intensive care, hemodialysis and N-carbamylglutamate for the management of hyperammonemia, as well as earlier referral and better morbidity and mortality associated with solid organ transplantation.
• Individuals homozygous for this pathogenic variant typically present in the neonatal period and are not responsive to hydroxocobalamin treatment.
• Persons with two truncating pathogenic variants usually have the
• Most of the pathogenic variants identified in the N-terminal domain have been associated with
• The
• The
• A linker domain spanning residues 482-585 separates the N-terminal, or substrate (methylmalonyl-CoA) binding domain from the C-terminal cobalamin-binding domain. This linker region is less conserved and has a lower frequency of pathogenic variants [
## Clinical Description
The phenotypes of isolated methylmalonic acidemia (MMA) described below that are associated with the enzymatic subtypes
Phenotype Correlations by Gene and Enzymatic Subtype of Isolated Methylmalonic Acidemia
Most common & severe form, typically presenting in infancy
Higher rate of mortality & neurologic & other multisystem complications than in those w/
Renal disease may manifest in childhood in ~43%-60%, w/median age of onset 6-11 yrs.
Onset may occur later, in 1st few mos or yrs of life.
Symptoms often incl feeding problems, failure to thrive, hypotonia, & DD.
Catastrophic decompensation can occur when diagnosis is delayed, incl injury in basal ganglia → movement disorder.
Some persons have isolated renal tubular acidosis or chronic renal failure as primary finding.
Most affected persons have phenotype that resembles
Higher rate of mortality & neurologic & other multisystem complications than in those w/
Chronic renal failure occurs in ~66% & is less frequent than in those w/
Milder disease course
Normal life expectancy
Slower decline in renal function w/≈9%-12% developing chronic renal failure
Better neurocognitive outcomes than in
Only rarely is this subtype responsive to injectable B
May present w/isolated renal tubular acidosis or chronic renal failure
In general, milder features ranging from no symptoms to severe metabolic acidosis.
Not responsive to injectable B
A rare cause of persistent moderate MMA
DD = developmental delay; MCEE = methylmalonyl-coenzyme A epimerase
The most common phenotype, which typically presents during infancy
Sometimes referred to as partial deficiency
Including optic nerve atrophy, basal ganglia injury, and multiorgan failure [
See also
Decreased early mortality, less severe symptoms at diagnosis, favorable short-term neurodevelopmental outcome, and lower incidence of movement disorders and irreversible cerebral damage were recorded in affected individuals identified through expanded NBS, though a number of infants with the
As described prior to newborn screening (NBS) availability, the common phenotypes and associated features of isolated MMA included the following.
The most common phenotype of isolated MMA presents during infancy. Infants are normal at birth but develop lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds.
This can rapidly progress to coma due to hyperammonemic encephalopathy, if untreated.
Laboratory findings typically show a severe, high anion-gap metabolic acidosis, ketosis and ketonuria (highly abnormal in neonates and strongly suggestive of an organic aciduria), hyperammonemia, and hyperglycinemia [
Dialysis may be needed especially if hyperammonemia is significant and persistent.
Thrombocytopenia and neutropenia, suggestive of neonatal sepsis, can be seen.
Affected infants can exhibit feeding problems (typically anorexia and vomiting), failure to thrive, hypotonia, and developmental delay.
Some have protein aversion and/or clinical symptoms of vomiting and lethargy after protein intake.
Until the diagnosis is established and treatment initiated, infants are at risk for a catastrophic decompensation (like that in neonates) [
During such an episode of metabolic decompensation, the child may die despite intensive intervention if prompt treatment specific for MMA (see
Before the availability of NBS, or in cases that are false negative on NBS due to borderline C3 elevations, infants with the
Individuals with partial enzymatic deficiency (
Screening of a large cohort of individuals with undefined MMA identified ten individuals with MCEE deficiency with symptoms including metabolic ketoacidosis, hypoglycemia, seizures, developmental delay, and spasticity. Cardiomyopathy was reported in a single individual, with a similarly affected sib with biochemical but no clinical findings [
Individuals with MCEE deficiency were not responsive to B
A 78-year-old individual with Parkinson disease, dementia, and stroke was found to have
Secondary complications can be observed in any enzymatic subtype but may be dependent on the specific subtype and degree of metabolic control and adherence (see
Therefore, primary and secondary biomarkers are important for monitoring affected individuals and supporting efficacy in therapeutic clinical trials [
The major secondary complications include the following.
In one study about 50% of individuals with
In a natural history study, the mean FSIQ of all individuals with isolated MMA (n=37) was 85.0 ± 20.68, which is in the low-average range (80≤IQ≤89) [
Individuals with
The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
Cystatin-C levels and age-appropriate equations to calculate estimated glomerular filtration rate (GFR) – or preferably, measurement of GFR by iohexol clearance or other methods – should be used for clinical monitoring, due to the fact that creatinine is a late marker of renal dysfunction in individuals with low muscle mass, as is seen in isolated MMA (see
Renal tubular dysfunction presenting as a decrease in urine concentrating ability and acidification, hyporeninemic hypoaldosteronism, tubular acidosis type 4, and hyperkalemia have been reported in a number of affected individuals [
Secondary mitochondrial dysfunction rather than direct nephrotoxicity of methylmalonic acid is hypothesized as the cause for renal disease [
Comorbidities of renal disease including anemia, acidosis, hyperuricemia, secondary hyperparathyroidism, osteopenia/osteoporosis, hypertension, and short stature should be monitored regularly by a multidisciplinary care team (see
The reported incidence in different cohorts is 17%-30% [
Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
Rarely, affected individuals have documented growth hormone (GH) deficiency, for which GH therapy has been used.
GH therapy has also been used for its anabolic effects or as part of the management of chronic kidney disease [
Response to GH therapy may vary; careful monitoring of the diet and metabolic parameters is necessary (see
Additional cardiometabolic risk factors, including obesity, insulin resistance, and hyperlipidemia, need to be monitored regularly to optimize cardiovascular health [
Liver neoplasms have been reported in five individuals, all severely affected (4 with
Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
Periodic screening (typically at least annually or as clinically indicated) including liver transaminases, serum AFP level, and liver ultrasound is recommended in individuals with severe MMA subtypes (see
Overall mortality was about 50% for those with the
More recent reports from the European Registry and Network for Intoxication Type Metabolic Diseases notes a 6% mortality for
Improvements likely reflect changes in diagnosis and NBS, improved treatment guidelines for acute crises/hyperammonemia, optimized nutrition with gastrostomy tube feeding, access to intensive care, hemodialysis and N-carbamylglutamate for the management of hyperammonemia, as well as earlier referral and better morbidity and mortality associated with solid organ transplantation.
• Most common & severe form, typically presenting in infancy
• Higher rate of mortality & neurologic & other multisystem complications than in those w/
• Renal disease may manifest in childhood in ~43%-60%, w/median age of onset 6-11 yrs.
• Onset may occur later, in 1st few mos or yrs of life.
• Symptoms often incl feeding problems, failure to thrive, hypotonia, & DD.
• Catastrophic decompensation can occur when diagnosis is delayed, incl injury in basal ganglia → movement disorder.
• Some persons have isolated renal tubular acidosis or chronic renal failure as primary finding.
• Most affected persons have phenotype that resembles
• Higher rate of mortality & neurologic & other multisystem complications than in those w/
• Chronic renal failure occurs in ~66% & is less frequent than in those w/
• Milder disease course
• Normal life expectancy
• Slower decline in renal function w/≈9%-12% developing chronic renal failure
• Better neurocognitive outcomes than in
• Only rarely is this subtype responsive to injectable B
• May present w/isolated renal tubular acidosis or chronic renal failure
• In general, milder features ranging from no symptoms to severe metabolic acidosis.
• Not responsive to injectable B
• A rare cause of persistent moderate MMA
• The most common phenotype of isolated MMA presents during infancy. Infants are normal at birth but develop lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds.
• This can rapidly progress to coma due to hyperammonemic encephalopathy, if untreated.
• Laboratory findings typically show a severe, high anion-gap metabolic acidosis, ketosis and ketonuria (highly abnormal in neonates and strongly suggestive of an organic aciduria), hyperammonemia, and hyperglycinemia [
• Dialysis may be needed especially if hyperammonemia is significant and persistent.
• Thrombocytopenia and neutropenia, suggestive of neonatal sepsis, can be seen.
• Affected infants can exhibit feeding problems (typically anorexia and vomiting), failure to thrive, hypotonia, and developmental delay.
• Some have protein aversion and/or clinical symptoms of vomiting and lethargy after protein intake.
• Until the diagnosis is established and treatment initiated, infants are at risk for a catastrophic decompensation (like that in neonates) [
• During such an episode of metabolic decompensation, the child may die despite intensive intervention if prompt treatment specific for MMA (see
• Before the availability of NBS, or in cases that are false negative on NBS due to borderline C3 elevations, infants with the
• Individuals with partial enzymatic deficiency (
• Screening of a large cohort of individuals with undefined MMA identified ten individuals with MCEE deficiency with symptoms including metabolic ketoacidosis, hypoglycemia, seizures, developmental delay, and spasticity. Cardiomyopathy was reported in a single individual, with a similarly affected sib with biochemical but no clinical findings [
• Individuals with MCEE deficiency were not responsive to B
• A 78-year-old individual with Parkinson disease, dementia, and stroke was found to have
• In one study about 50% of individuals with
• In a natural history study, the mean FSIQ of all individuals with isolated MMA (n=37) was 85.0 ± 20.68, which is in the low-average range (80≤IQ≤89) [
• Individuals with
• The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
• Individuals with
• The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
• Individuals with
• The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
• Cystatin-C levels and age-appropriate equations to calculate estimated glomerular filtration rate (GFR) – or preferably, measurement of GFR by iohexol clearance or other methods – should be used for clinical monitoring, due to the fact that creatinine is a late marker of renal dysfunction in individuals with low muscle mass, as is seen in isolated MMA (see
• Renal tubular dysfunction presenting as a decrease in urine concentrating ability and acidification, hyporeninemic hypoaldosteronism, tubular acidosis type 4, and hyperkalemia have been reported in a number of affected individuals [
• Secondary mitochondrial dysfunction rather than direct nephrotoxicity of methylmalonic acid is hypothesized as the cause for renal disease [
• Comorbidities of renal disease including anemia, acidosis, hyperuricemia, secondary hyperparathyroidism, osteopenia/osteoporosis, hypertension, and short stature should be monitored regularly by a multidisciplinary care team (see
•
• The reported incidence in different cohorts is 17%-30% [
• Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
• The reported incidence in different cohorts is 17%-30% [
• Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
•
• After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
• Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
• After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
• Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
• The reported incidence in different cohorts is 17%-30% [
• Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
• After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
• Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
• Rarely, affected individuals have documented growth hormone (GH) deficiency, for which GH therapy has been used.
• GH therapy has also been used for its anabolic effects or as part of the management of chronic kidney disease [
• Response to GH therapy may vary; careful monitoring of the diet and metabolic parameters is necessary (see
• Additional cardiometabolic risk factors, including obesity, insulin resistance, and hyperlipidemia, need to be monitored regularly to optimize cardiovascular health [
• Liver neoplasms have been reported in five individuals, all severely affected (4 with
• Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
• Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
• Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
• Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
• Periodic screening (typically at least annually or as clinically indicated) including liver transaminases, serum AFP level, and liver ultrasound is recommended in individuals with severe MMA subtypes (see
• Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
• Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
• Overall mortality was about 50% for those with the
• More recent reports from the European Registry and Network for Intoxication Type Metabolic Diseases notes a 6% mortality for
• Improvements likely reflect changes in diagnosis and NBS, improved treatment guidelines for acute crises/hyperammonemia, optimized nutrition with gastrostomy tube feeding, access to intensive care, hemodialysis and N-carbamylglutamate for the management of hyperammonemia, as well as earlier referral and better morbidity and mortality associated with solid organ transplantation.
## Effect of Newborn Screening
Decreased early mortality, less severe symptoms at diagnosis, favorable short-term neurodevelopmental outcome, and lower incidence of movement disorders and irreversible cerebral damage were recorded in affected individuals identified through expanded NBS, though a number of infants with the
## Common Phenotypes and Associated Features
As described prior to newborn screening (NBS) availability, the common phenotypes and associated features of isolated MMA included the following.
The most common phenotype of isolated MMA presents during infancy. Infants are normal at birth but develop lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds.
This can rapidly progress to coma due to hyperammonemic encephalopathy, if untreated.
Laboratory findings typically show a severe, high anion-gap metabolic acidosis, ketosis and ketonuria (highly abnormal in neonates and strongly suggestive of an organic aciduria), hyperammonemia, and hyperglycinemia [
Dialysis may be needed especially if hyperammonemia is significant and persistent.
Thrombocytopenia and neutropenia, suggestive of neonatal sepsis, can be seen.
Affected infants can exhibit feeding problems (typically anorexia and vomiting), failure to thrive, hypotonia, and developmental delay.
Some have protein aversion and/or clinical symptoms of vomiting and lethargy after protein intake.
Until the diagnosis is established and treatment initiated, infants are at risk for a catastrophic decompensation (like that in neonates) [
During such an episode of metabolic decompensation, the child may die despite intensive intervention if prompt treatment specific for MMA (see
Before the availability of NBS, or in cases that are false negative on NBS due to borderline C3 elevations, infants with the
Individuals with partial enzymatic deficiency (
Screening of a large cohort of individuals with undefined MMA identified ten individuals with MCEE deficiency with symptoms including metabolic ketoacidosis, hypoglycemia, seizures, developmental delay, and spasticity. Cardiomyopathy was reported in a single individual, with a similarly affected sib with biochemical but no clinical findings [
Individuals with MCEE deficiency were not responsive to B
A 78-year-old individual with Parkinson disease, dementia, and stroke was found to have
• The most common phenotype of isolated MMA presents during infancy. Infants are normal at birth but develop lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds.
• This can rapidly progress to coma due to hyperammonemic encephalopathy, if untreated.
• Laboratory findings typically show a severe, high anion-gap metabolic acidosis, ketosis and ketonuria (highly abnormal in neonates and strongly suggestive of an organic aciduria), hyperammonemia, and hyperglycinemia [
• Dialysis may be needed especially if hyperammonemia is significant and persistent.
• Thrombocytopenia and neutropenia, suggestive of neonatal sepsis, can be seen.
• Affected infants can exhibit feeding problems (typically anorexia and vomiting), failure to thrive, hypotonia, and developmental delay.
• Some have protein aversion and/or clinical symptoms of vomiting and lethargy after protein intake.
• Until the diagnosis is established and treatment initiated, infants are at risk for a catastrophic decompensation (like that in neonates) [
• During such an episode of metabolic decompensation, the child may die despite intensive intervention if prompt treatment specific for MMA (see
• Before the availability of NBS, or in cases that are false negative on NBS due to borderline C3 elevations, infants with the
• Individuals with partial enzymatic deficiency (
• Screening of a large cohort of individuals with undefined MMA identified ten individuals with MCEE deficiency with symptoms including metabolic ketoacidosis, hypoglycemia, seizures, developmental delay, and spasticity. Cardiomyopathy was reported in a single individual, with a similarly affected sib with biochemical but no clinical findings [
• Individuals with MCEE deficiency were not responsive to B
• A 78-year-old individual with Parkinson disease, dementia, and stroke was found to have
## Secondary Complications
Secondary complications can be observed in any enzymatic subtype but may be dependent on the specific subtype and degree of metabolic control and adherence (see
Therefore, primary and secondary biomarkers are important for monitoring affected individuals and supporting efficacy in therapeutic clinical trials [
The major secondary complications include the following.
In one study about 50% of individuals with
In a natural history study, the mean FSIQ of all individuals with isolated MMA (n=37) was 85.0 ± 20.68, which is in the low-average range (80≤IQ≤89) [
Individuals with
The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
Cystatin-C levels and age-appropriate equations to calculate estimated glomerular filtration rate (GFR) – or preferably, measurement of GFR by iohexol clearance or other methods – should be used for clinical monitoring, due to the fact that creatinine is a late marker of renal dysfunction in individuals with low muscle mass, as is seen in isolated MMA (see
Renal tubular dysfunction presenting as a decrease in urine concentrating ability and acidification, hyporeninemic hypoaldosteronism, tubular acidosis type 4, and hyperkalemia have been reported in a number of affected individuals [
Secondary mitochondrial dysfunction rather than direct nephrotoxicity of methylmalonic acid is hypothesized as the cause for renal disease [
Comorbidities of renal disease including anemia, acidosis, hyperuricemia, secondary hyperparathyroidism, osteopenia/osteoporosis, hypertension, and short stature should be monitored regularly by a multidisciplinary care team (see
The reported incidence in different cohorts is 17%-30% [
Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
Rarely, affected individuals have documented growth hormone (GH) deficiency, for which GH therapy has been used.
GH therapy has also been used for its anabolic effects or as part of the management of chronic kidney disease [
Response to GH therapy may vary; careful monitoring of the diet and metabolic parameters is necessary (see
Additional cardiometabolic risk factors, including obesity, insulin resistance, and hyperlipidemia, need to be monitored regularly to optimize cardiovascular health [
Liver neoplasms have been reported in five individuals, all severely affected (4 with
Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
Periodic screening (typically at least annually or as clinically indicated) including liver transaminases, serum AFP level, and liver ultrasound is recommended in individuals with severe MMA subtypes (see
Overall mortality was about 50% for those with the
More recent reports from the European Registry and Network for Intoxication Type Metabolic Diseases notes a 6% mortality for
Improvements likely reflect changes in diagnosis and NBS, improved treatment guidelines for acute crises/hyperammonemia, optimized nutrition with gastrostomy tube feeding, access to intensive care, hemodialysis and N-carbamylglutamate for the management of hyperammonemia, as well as earlier referral and better morbidity and mortality associated with solid organ transplantation.
• In one study about 50% of individuals with
• In a natural history study, the mean FSIQ of all individuals with isolated MMA (n=37) was 85.0 ± 20.68, which is in the low-average range (80≤IQ≤89) [
• Individuals with
• The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
• Individuals with
• The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
• Individuals with
• The age of disease onset, the presence of severe hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairments.
• Cystatin-C levels and age-appropriate equations to calculate estimated glomerular filtration rate (GFR) – or preferably, measurement of GFR by iohexol clearance or other methods – should be used for clinical monitoring, due to the fact that creatinine is a late marker of renal dysfunction in individuals with low muscle mass, as is seen in isolated MMA (see
• Renal tubular dysfunction presenting as a decrease in urine concentrating ability and acidification, hyporeninemic hypoaldosteronism, tubular acidosis type 4, and hyperkalemia have been reported in a number of affected individuals [
• Secondary mitochondrial dysfunction rather than direct nephrotoxicity of methylmalonic acid is hypothesized as the cause for renal disease [
• Comorbidities of renal disease including anemia, acidosis, hyperuricemia, secondary hyperparathyroidism, osteopenia/osteoporosis, hypertension, and short stature should be monitored regularly by a multidisciplinary care team (see
•
• The reported incidence in different cohorts is 17%-30% [
• Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
• The reported incidence in different cohorts is 17%-30% [
• Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
•
• After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
• Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
• After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
• Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
• The reported incidence in different cohorts is 17%-30% [
• Delayed myelination, incomplete opercularization, subcortical white matter changes, cortical atrophy, and brain stem and cerebellar changes have also been described [
• After transplant, individuals can still develop acute lesions of the basal ganglia without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the central nervous system compartment can lead to injury despite other systemic benefits of the transplantation. It is therefore important to continue dietary restrictions and metabolic care [
• Neurotoxicity from anti-rejection medications, especially calcineurin inhibitors (e.g., tacrolimus), has been observed in individuals with MMA who have undergone solid organ transplantation. These include tremors, seizures, and posterior reversible encephalopathy syndrome [
• Rarely, affected individuals have documented growth hormone (GH) deficiency, for which GH therapy has been used.
• GH therapy has also been used for its anabolic effects or as part of the management of chronic kidney disease [
• Response to GH therapy may vary; careful monitoring of the diet and metabolic parameters is necessary (see
• Additional cardiometabolic risk factors, including obesity, insulin resistance, and hyperlipidemia, need to be monitored regularly to optimize cardiovascular health [
• Liver neoplasms have been reported in five individuals, all severely affected (4 with
• Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
• Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
• Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
• Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
• Periodic screening (typically at least annually or as clinically indicated) including liver transaminases, serum AFP level, and liver ultrasound is recommended in individuals with severe MMA subtypes (see
• Three children had hepatoblastoma (diagnosed at 4 months, 19 months, and 11 years of age).
• Two adults had hepatocellular carcinoma (diagnosed at age 22 years and 31 years).
• Overall mortality was about 50% for those with the
• More recent reports from the European Registry and Network for Intoxication Type Metabolic Diseases notes a 6% mortality for
• Improvements likely reflect changes in diagnosis and NBS, improved treatment guidelines for acute crises/hyperammonemia, optimized nutrition with gastrostomy tube feeding, access to intensive care, hemodialysis and N-carbamylglutamate for the management of hyperammonemia, as well as earlier referral and better morbidity and mortality associated with solid organ transplantation.
## Genotype-Phenotype Correlations
Precise genotype-phenotype correlations are difficult to determine since most affected individuals are compound heterozygotes and many pathogenic variants are not recurrent in the population.
Individuals homozygous for this pathogenic variant typically present in the neonatal period and are not responsive to hydroxocobalamin treatment.
Persons with two truncating pathogenic variants usually have the
Most of the pathogenic variants identified in the N-terminal domain have been associated with
The
The
A linker domain spanning residues 482-585 separates the N-terminal, or substrate (methylmalonyl-CoA) binding domain from the C-terminal cobalamin-binding domain. This linker region is less conserved and has a lower frequency of pathogenic variants [
Data in the table have been provided by the authors.
NA = not applicable
Observed in individuals of Mexican/Hispanic descent.
Observed in individuals of African descent
• Individuals homozygous for this pathogenic variant typically present in the neonatal period and are not responsive to hydroxocobalamin treatment.
• Persons with two truncating pathogenic variants usually have the
• Most of the pathogenic variants identified in the N-terminal domain have been associated with
• The
• The
• A linker domain spanning residues 482-585 separates the N-terminal, or substrate (methylmalonyl-CoA) binding domain from the C-terminal cobalamin-binding domain. This linker region is less conserved and has a lower frequency of pathogenic variants [
## Prevalence
Several studies have estimated the birth prevalence of isolated methylmalonic acidemia. Urine screening for isolated methylmalonic acidemia in Quebec identified "symptomatic methylmalonic aciduria" in approximately 1:80,000 newborns screened [
The aggregate incidence from different newborn screening (NBS) programs in the US is reported as 1:159,614 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Other genetic causes of elevated methylmalonic acidemia/aciduria are listed in
It is important to note that individuals with
With the exception of
Genetic Disorders with Methylmalonic Acidemia/Aciduria in the Differential Diagnosis of Isolated Methylmalonic Acidemia
cbl = cobalamin; DD = developmental delay; FTT = failure to thrive; ID = intellectual disability; IUGR = intrauterine growth restriction; MA = malonic acid; MMA = methylmalonic acid; mtDNA = mitochondrial DNA; NBS = newborn screening
Polymorphisms in
These older reports were published before the identification of
"Atypical" MMA has also been reported in an individual with mitochondrial depletion syndrome/complex IV deficiency and combined propionic and methylmalonic acidemia [
Despite extensive genome and RNA sequencing, the genetic cause of isolated MMA and low propionate incorporation remains unknown in many individuals [
Maternal B
It is important to screen pregnant mothers by testing maternal serum B
## Management
Consensus guidelines on the diagnosis, management, and follow-up for individuals with methylmalonic acidemia were published in 2014 [
When isolated MMA is suspected during the diagnostic evaluation due to elevated propionylcarnitine (C3) on a newborn blood spot, metabolic treatment should be initiated immediately, while the suspected diagnosis is being confirmed.
Once confirmed, development and evaluation of treatment plans, training and education of affected individuals and their families, and careful monitoring of dietary treatment (to avoid malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.
To establish the extent of disease and needs in an individual diagnosed with isolated MMA, the evaluations summarized
Recommended Evaluations Following Initial Diagnosis of Isolated Methylmalonic Acidemia
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
Review diet/food records w/metabolic dietitian.
Provide patient/family w/sick-day diet instructions & emergency treatment letter detailing mgmt plan & specialist contact information (see
Generally, 1.0-mg injections (preferably of OHCbl) daily for 3-5 days
Obtain >1 baseline & follow-up measures over 10 days to assess for a ↓ in serum & urine methylmalonic acid (>50% ↓ is considered a positive B
Serum vitamin B
Serum chemistry panel incl renal function, liver enzymes
CBC w/differential, iron status, folate
Arterial or venous blood gas
Plasma ammonium & lactic acid concentration
Urinalysis & urine ketone measurement
Quantitative plasma amino acids
Urine organic acids
Serum methylmalonic acid & (if available) methylcitrate levels
Measurement of free & total carnitine levels
Pancreatic enzymes (amylase, lipase)
Serum albumin, total protein, & prealbumin to assess for nutritional status
Blood pressure measurement
EKG
Echocardiogram
Consult w/cardiologist
Assess for evidence of growth failure, need for gastrostomy tube to meet caloric needs, growth hormone treatment.
Prevent & treat osteopenia due to low-protein diet, renal osteodystrophy, delayed puberty.
To assess for signs & symptoms of mvmt disorder, seizures, neuropathy
Brain imaging (MRI, MRS) in case of abnormal neurologic exam findings
CBC = complete blood count; OHCbl = hydroxocobalamin (as opposed to cyanocobalamin); MOI = mode of inheritance
After a new diagnosis of isolated methylmalonic acidemia in a child, the closest hospital and local pediatrician should also be informed. The family needs to have an updated emergency treatment letter and plan.
Na
By gas chromatography and mass spectrometry (GC-MS)
Hearing loss may occur in those who have experienced episodes of metabolic decompensation. The risk of hearing loss likely increases with age and can be seen along with optic nerve atrophy.
Medical/biochemical geneticist, certified genetic counselor, certified advanced genetic nurse
Guidelines developed by professionals across 12 European countries and the US based on rigorous literature evaluation and expert group meetings outline the current management recommendations and areas for further research. See
Routine Daily Treatment in Individuals with Isolated Methylmalonic Acidemia
Safe levels of natural protein per age group should be the aim (see 2007
The individual protein amount prescribed depends on growth parameters, metabolic stability, & stage of renal failure.
A propiogenic amino acid-deficient formula
Use medical foods in moderation, w/relative intake of natural protein to propiogenic amino-acid-deficient formula not exceeding a ratio of 1:1
Natural protein must be carefully titrated to allow for normal growth.
As infants grow, total protein load is slowly ↓, based on growth, plasma amino acid concentrations, & plasma & urine methylmalonic acid concentrations.
Adjustment of dietary whole (complete)-protein intake (based on lab findings) is required lifelong (see
Isolated valine & isoleucine deficiencies may be caused in part by overuse of propiogenic amino-acid deficient formula; individual amino acid supplementation should be avoided (see
A ratio of complete protein to medical formula of 60%/40% to 70%/30% of total protein prescription is usually not assoc w/deficiency of valine or isoleucine [Authors, personal observation].
Attn to protein:energy ratio is important; when available, accurate assessment of resting energy expenditure can guide dietary & caloric prescriptions & avoid overfeeding.
Plasma amino acids should be drawn ~4 hrs after food intake.
Continue protein restriction & dietary monitoring after liver transplantation to avoid extrahepatic disease complications.
Oral dosage of 50-100 mg/kg/day, up to ~300 mg/kg/day, of L-carnitine divided into 3-4 doses is common.
Dose is adjusted on an individual basis to maintain plasma free carnitine concentration w/in normal age-appropriate reference range.
Rotating antibiotic regimens may be considered in some persons.
Responsiveness to antibiotic should be determined by a ↓ in serum methylmalonic acid concentration compared to patient's baseline value, or a ↓ in whole-body output of methylmalonic acid on antibiotic therapy by a timed urine collection compared to patient's baseline value.
Chronic cyclic antibiotic therapy is not innocuous; it introduces the risk of repopulation w/resistant flora & has been assoc w/peripheral neuropathy.
Propiogenic amino acid precursors include isoleucine, valine, methionine and threonine
These dietary guidelines
For example, Propimex
An iatrogenic essential amino acid deficiency can be induced by the relatively high leucine intake through the MMA formulas that can negatively affect long-term growth and possibly other outcomes, especially if propiogenic amino-acid deficient formula is prescribed in excess of complete protein sources [
For example, Pro-Phree
In patients with low protein tolerance, severe restriction of propiogenic amino acid precursors (isoleucine, valine, methionine, and threonine) can produce a nutritional deficiency state.
Carnitine may replace the free carnitine pool and enhance the conjugation and excretion of propionylcarnitine. The contribution of propionylcarnitine excretion to the total propionate load is, however, small. The relief of intracellular CoA accretion may be the mechanism by which carnitine supplementation benefits some individuals.
This could pose a serious infectious threat and could be especially dangerous to individuals with isolated methylmalonic acidemia, since most deaths are related to metabolic decompensation, often precipitated by infection [
Treatment of Secondary Complications in Individuals with Isolated Methylmalonic Acidemia
Supportive developmental therapies (may incl PT, OT, speech & cognitive therapies)
Coordination of individualized educational plan in school
See
Avoid nephrotoxic medications (see
IVF = intravenous fluids; OT = occupational therapy; PT = physical therapy; TPN = total parenteral nutrition
Documented growth hormone deficiency is a rare cause of growth failure [
Emergency Outpatient Treatment in Individuals with Isolated Methylmalonic Acidemia
Carbohydrate supplementation orally or via tube feed
Reduce natural protein intake
Increase carnitine supplementation
Trial of outpatient treatment at home for up to 12 hours
Initiation of sick-day dietary plan
Reassessment (~every 2 hours) for clinical changes
Limit ibuprofen/NSAID use for renoprotection.
Avoid excessive acetaminophen use for risk of liver toxicity.
Fever <38.5°C (101°F); enteral or gastrostomy tube feeding is tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability)
Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide nutritional arrangements in the outpatient setting, with some centers recommending frequent provision of carbohydrate-rich, protein-free beverages every two hours, with frequent reassessment.
Some centers advocate additional steps such as reducing natural protein intake to zero or to 50% of the normal prescribed regimen for short periods (<24 hours) in the outpatient setting during intercurrent illness. Protein restriction more than 24-48 hours could lead to catabolism and should be avoided.
Temporarily increasing L-carnitine doses (e.g., to 200 mg/kg/day in infants) may be considered.
Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features should be discussed with the designated center of expertise for inherited metabolic diseases.
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma), often occurring in the setting of intercurrent illness and/or inadequate caloric intake, should be managed symptomatically and with generous caloric support in a hospital setting, with aggressive treatment and supportive care. Immediate consultation with a metabolic/biochemical geneticist is essential. Individuals with MMA can deteriorate rapidly and consultations with neurology, nephrology, and ICU teams are often required during crises (see
Acute Inpatient Treatment in Individuals with Methylmalonic Acidemia
Administration of high-energy IV fluids (D10/0.45 or 0.9 saline) at 1.5x maintenance rate to achieve age-appropriate glucose infusion rate (GIR), &, if needed insulin
Lipid emulsion is often necessary to provide sufficient calories at a dose of 1- 2 g/kg/day.
Address electrolytes & pH imbalances w/bicarbonate bolus, expect need for potassium replacement, as needed.
↓ or omit total protein for ≤24-48 hours.
L-carnitine IV supplementation at 50-100 mg/kg/day either BID or QID
Blood glucose, electrolyte concentrations (particularly sodium, potassium & bicarbonate concentrations), blood gases (w/monitoring of the anion gap), complete blood count & differential, serum lactate, urine ketones & urine output should be followed serially.
Central or peripheral TPN, which typically contains glucose & amino acids, & in some instances lipids, may be required. Thiamine may be added, esp in the presence of lactic acidosis.
Lipid infusions must be used w/caution due to risk of pancreatitis.
Dietary protein should be reintroduced enterally as soon as is feasible given the clinical scenario & may need to be further augmented w/TPN.
Nasograstric or orogastric feeding should be strongly considered so that enteral feedings can be reintroduced w/o delay.
N-carbamylglutamate (NCG, Carbaglu
Administer IV sodium benzoate
Hemodialysis or hemofiltration in consultation w/nephrologist may be required in the event of treatment failure (uncontrollable acidosis &/or hyperammonemia).
A STAT plasma ammonia level should be obtained in the ED or on admission.
NCG activates the first step in the urea cycle (CPS1 enzyme) & is effective in lowering ammonia concentration during acute crises in patients w/MMA. Chronic or periodic use has been attempted in cases w/frequent decompensations, but has not obtained regulatory approval.
Use of phenylacetate may accentuate low glutamine levels by generating phenylacetylglutamine & deplete 2-ketoglutarate in the TCA cycle.
Initiate the treatment listed above for ↑ catabolism.
Neurologic consultation
Brain MRI
BID = twice a day; ED = emergency department; PT = physical therapy; QID = four times a day; TPN = total parenteral nutrition
Inpatient emergency treatment should: (1) take place at the closest medical facility, (2) be started without delay, and (3) be supervised by physicians and specialist dieticians at the responsible metabolic center, who should be contacted without delay.
Intravenous glucose solutions should preferably consist of D
Use of insulin if hyperglycemia emerges; intravenous insulin given at a starting dose of 0.01-0.02 IU/kg/hour in the event of persistent hyperglycemia (>150-180 mg/dL in plasma, or glucosuria)
Consult published guidelines,
Total protein can be gradually reintroduced depending on the patient's acid-base balance and remaining laboratory values, including ammonia, lactic acid, and plasma amino acids, among others.
The dose of N-carbamylglutamate (NCG) is 100 mg/kg bolus, followed by 25-62 mg/kg every 6 hours PO (orally). NCG is an N-acetylglutamate analog that allosterically activates CPS1 (carbamyl phosphate synthetase 1), the first step of the urea cycle [
The dose of sodium benzoate is 250 mg/kg as a bolus given over 90-120 min, followed by 250 mg/kg/day for maintenance, administered in 10% dextrose IV (intravenously). The same dose regimen is used for sodium phenylbutyrate (PBA). The maximum dose of sodium benzoate or sodium PBA is 5.5 g/m
May include both bone marrow hypoplasia and/or dysplasia
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with isolated methylmalonic acidemia together with pediatric or adult metabolic experts, dietitians, psychologists, and social workers.
As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized and there is limited availability of clinics for adults with IEMs, continuous supervision by a center with expertise in metabolic diseases with sufficient resources is essential.
See also
Large case series of affected individuals undergoing elective liver or combined liver/kidney transplantation (as opposed to isolated kidney transplantation) have detailed the indications, peri-operative complications, surgical and anesthesia approaches, anti-rejection regimens, and long-term outcomes in people with MMA undergoing these procedures. Inclusion of enzymatic and genotype information in case series of transplanted individuals allows for better comparisons of the outcomes and genotype-phenotype associations that could inform decisions about the indication and timing of transplantation in individual cases.
Liver transplantation is increasingly offered to younger affected individuals with significant metabolic instability, often in infancy, as a measure to prevent neurologic damage from recurrent metabolic crises associated with hyperammonemia. Referral to centers with experience in managing people with organic acidemias and continued monitoring and dietary therapy are essential for all MMA transplant recipients.
Prevention of Primary Manifestations in Individuals with Isolated Methylmalonic Acidemia
The underlying biochemical parameters & frequency of metabolic decompensation improve significantly in persons undergoing liver transplantation despite persistent metabolic abnormalities.
Liver transplantation is not curative. Patients remain at risk for long-term complications incl renal disease, basal ganglia injury & neurologic complications, & optic nerve atrophy.
Neurotoxicity due to calcineurin inhibitors has been described in transplanted patients.
More mildly affected persons w/
Elective kidney transplantation, before the onset of renal disease, cannot stabilize persons w/
Most of the metabolic conversion of propionate occurs in the liver, so liver transplantation has the potential to provide enough enzymatic activity to avert severe metabolic crises for the most significantly affected individuals (MMA
More than 100 individuals with MMA have undergone living-donor [
Liver transplantation is associated with complications related to surgery (hepatic artery thrombosis, bile duct stenosis, perforation), graft rejection, and lifelong immunosuppressive therapy [
Neurotoxicity from calcineurin inhibitors, including posterior reversible encephalopathy syndrome (PRES), has been reported [
A smaller number (~20) of individuals with MMA (mostly with milder
A regimen of coenzyme Q
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see also
Prevention of Secondary Manifestations in Individuals with Isolated Methylmalonic Acidemia
Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
Treatment protocols & provision of emergency letters or cards to incl guidance for care in the event of illness while on holiday/vacation
MediAlert
Adequate supplies of specialized dietary products (protein-free or propiogenic amino acid deficient formulas); medication required for maintenance & emergency treatment (vitamin B
Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers/pediatricians, & to teachers & school staff.
Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for MMA & containing contact info for the primary treating metabolic center.
For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates.
Notify designated metabolic center in advance of the procedure to discuss perioperative management w/surgeons & anesthesiologists.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
Essential information including written treatment protocols should be in place in anticipation of possible future need for inpatient emergency treatment.
Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5°C; (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur.
Special considerations regarding choices of anesthetic agents in this patient population may apply [
Perioperative/perianesthetic management precautions may include visitations at specialist anesthetic clinics for affected persons deemed to be at high risk for perioperative complications.
During the first year of life, infants may need to be evaluated as frequently as every week and continued at intervals determined by the frequency of metabolic crises/admissions, growth patterns, and dietary needs. Attention to transition periods (e.g., after the first two years, in adolescence) with other stressors in the family are necessary for modification of dietary prescription.
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the following are recommended. See
Recommended Surveillance for Individuals with Isolated Methylmalonic Acidemia
Plasma amino acids
Plasma & urine MMA levels
Serum acylcarnitine profile & free & total carnitine levels
Blood chemistries
CBC
Measurement of creatinine, cystatin-C, & (if available) GFR (e.g., iohexol plasma decay)
Renal imaging
Bone mineral density (DXA)
Early referral to nephrologist is critical for consideration of renoprotective measures.
Monitoring of renal comorbidities by multidisciplinary team
Liver ultrasound
Measurement of liver transaminases & alpha-fetoprotein
CBC = complete blood count; GFR = glomerular filtration rate; PT = physical therapy
Frequent monitoring of plasma amino acids is necessary to avoid deficiencies of essential amino acids (particularly isoleucine, valine, and methionine) as a result of excessive protein restriction and the development of acrodermatitis-enteropathica-like cutaneous lesions in methylmalonic aciduria, as in other organic acidurias (
Including Na+, K+, CI–, glucose, urea, creatinine, bicarbonate, AST, ALT, alkaline phosphatase, bilirubin (T/U), triglycerides, and cholesterol
Comorbidities of renal disease may include anemia, acidosis, hyperuricemia, secondary hyperparathyroidism, osteopenia/osteoporosis, hypertension, and short stature. In addition to cystatin-C, biochemical markers of bone health (Ca, P, alkaline phosphatase, parathyroid hormone, 1.25 dihydroxy-vit D (D3), and uric acid should be assessed periodically.
Combined equations based on creatinine and cystatin-C and measured GFR by iohexol clearance or other methods are expected to reflect more accurately the kidney function in people with MMA [
To allow for early referral to nephrologist and appropriate timing of renal transplantation when needed [
Nephrotoxic medication should be avoided (see
DXA scan is typically done in older individuals, starting in adolescence, unless there is evidence for renal disease earlier.
Particularly in individuals with severe MMA subtypes
Enrollment in early intervention programs for physical, occupational, and speech therapy is recommended.
To assess for optic nerve thinning/pallor
Hearing loss can occur in isolated MMA and may be a result of episodes of metabolic decompensation.
The following should be avoided:
Fasting. During acute illness, intake of adequate calories is necessary to arrest/prevent decompensation.
Stress
Increased dietary protein
Supplementation with the individual propiogenic amino acids valine and isoleucine, as they directly increase the toxic metabolite load in patients with disordered propionate oxidation [
Nephrotoxic medications or agents (e.g. ibuprofen)
Agents that prolong QTc in the EKG
Evaluation of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of isolated methylmalonic acidemia.
For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, measure serum methylmalonic acid, urine organic acids, plasma acylcarnitine profile, plasma amino acids, and serum B
Prenatal diagnosis of at-risk sibs may allow for prompt treatment of affected newborns at the time of delivery or prenatal administration of vitamin B
See
In pregnancies of affected women with MMA, complications observed included acute decompensation or hyperammonemia, deterioration of renal function, and obstetric complications including preeclampsia, preterm delivery, and cæsarean section [
Despite high maternal MMA levels, fetal growth and development have been reported to be normal, suggesting negligible teratogenic effects to the fetus from exposure to high methylmalonic acid levels in utero, though long-term follow up with age-appropriate neurocognitive testing is limited [
Pregnancies in transplant recipients are rare and further studies on the health of the offspring are needed [
See
Increased understanding of the underlying pathophysiology and the generation of disease-specific animal or cellular models has allowed the development of several novel therapies for isolated MMA [
Liver-targeted genomic therapies including systemic canonic recombinant adeno-associated virus (rAAV) gene therapy [
Studies using primary hepatocytes from individuals with methylmalonic and propionic acidemia have found that administration of the small molecule 2,2-dimethylbutanoic acid (HST5040) leads to a dose dependent reduction in levels of methylmalonyl-CoA and other serum metabolites. This small molecule is being tested in clinical trials [
Investigational therapies intended to increase CoA levels by allosterically modulating pantothenate kinases, key enzymes in the CoA biosynthesis pathway, have been shown to increase free CoA and alleviate mitochondrial dysfunction in mouse models of propionic academia (PA) [
Carefully designed clinical studies are required to evaluate the efficacy of antioxidant regimens in people with MMA.
Review the following for more information on current clinical trials on isolated MMA:
Search
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
• Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
• Review diet/food records w/metabolic dietitian.
• Provide patient/family w/sick-day diet instructions & emergency treatment letter detailing mgmt plan & specialist contact information (see
• Generally, 1.0-mg injections (preferably of OHCbl) daily for 3-5 days
• Obtain >1 baseline & follow-up measures over 10 days to assess for a ↓ in serum & urine methylmalonic acid (>50% ↓ is considered a positive B
• Serum vitamin B
• Serum chemistry panel incl renal function, liver enzymes
• CBC w/differential, iron status, folate
• Arterial or venous blood gas
• Plasma ammonium & lactic acid concentration
• Urinalysis & urine ketone measurement
• Quantitative plasma amino acids
• Urine organic acids
• Serum methylmalonic acid & (if available) methylcitrate levels
• Measurement of free & total carnitine levels
• Pancreatic enzymes (amylase, lipase)
• Serum albumin, total protein, & prealbumin to assess for nutritional status
• Blood pressure measurement
• EKG
• Echocardiogram
• Consult w/cardiologist
• Assess for evidence of growth failure, need for gastrostomy tube to meet caloric needs, growth hormone treatment.
• Prevent & treat osteopenia due to low-protein diet, renal osteodystrophy, delayed puberty.
• To assess for signs & symptoms of mvmt disorder, seizures, neuropathy
• Brain imaging (MRI, MRS) in case of abnormal neurologic exam findings
• Safe levels of natural protein per age group should be the aim (see 2007
• The individual protein amount prescribed depends on growth parameters, metabolic stability, & stage of renal failure.
• A propiogenic amino acid-deficient formula
• Use medical foods in moderation, w/relative intake of natural protein to propiogenic amino-acid-deficient formula not exceeding a ratio of 1:1
• Natural protein must be carefully titrated to allow for normal growth.
• As infants grow, total protein load is slowly ↓, based on growth, plasma amino acid concentrations, & plasma & urine methylmalonic acid concentrations.
• Adjustment of dietary whole (complete)-protein intake (based on lab findings) is required lifelong (see
• Isolated valine & isoleucine deficiencies may be caused in part by overuse of propiogenic amino-acid deficient formula; individual amino acid supplementation should be avoided (see
• A ratio of complete protein to medical formula of 60%/40% to 70%/30% of total protein prescription is usually not assoc w/deficiency of valine or isoleucine [Authors, personal observation].
• Attn to protein:energy ratio is important; when available, accurate assessment of resting energy expenditure can guide dietary & caloric prescriptions & avoid overfeeding.
• Plasma amino acids should be drawn ~4 hrs after food intake.
• Continue protein restriction & dietary monitoring after liver transplantation to avoid extrahepatic disease complications.
• Oral dosage of 50-100 mg/kg/day, up to ~300 mg/kg/day, of L-carnitine divided into 3-4 doses is common.
• Dose is adjusted on an individual basis to maintain plasma free carnitine concentration w/in normal age-appropriate reference range.
• Rotating antibiotic regimens may be considered in some persons.
• Responsiveness to antibiotic should be determined by a ↓ in serum methylmalonic acid concentration compared to patient's baseline value, or a ↓ in whole-body output of methylmalonic acid on antibiotic therapy by a timed urine collection compared to patient's baseline value.
• Chronic cyclic antibiotic therapy is not innocuous; it introduces the risk of repopulation w/resistant flora & has been assoc w/peripheral neuropathy.
• Supportive developmental therapies (may incl PT, OT, speech & cognitive therapies)
• Coordination of individualized educational plan in school
• See
• Avoid nephrotoxic medications (see
• Carbohydrate supplementation orally or via tube feed
• Reduce natural protein intake
• Increase carnitine supplementation
• Trial of outpatient treatment at home for up to 12 hours
• Initiation of sick-day dietary plan
• Reassessment (~every 2 hours) for clinical changes
• Limit ibuprofen/NSAID use for renoprotection.
• Avoid excessive acetaminophen use for risk of liver toxicity.
• Administration of high-energy IV fluids (D10/0.45 or 0.9 saline) at 1.5x maintenance rate to achieve age-appropriate glucose infusion rate (GIR), &, if needed insulin
• Lipid emulsion is often necessary to provide sufficient calories at a dose of 1- 2 g/kg/day.
• Address electrolytes & pH imbalances w/bicarbonate bolus, expect need for potassium replacement, as needed.
• ↓ or omit total protein for ≤24-48 hours.
• L-carnitine IV supplementation at 50-100 mg/kg/day either BID or QID
• Blood glucose, electrolyte concentrations (particularly sodium, potassium & bicarbonate concentrations), blood gases (w/monitoring of the anion gap), complete blood count & differential, serum lactate, urine ketones & urine output should be followed serially.
• Central or peripheral TPN, which typically contains glucose & amino acids, & in some instances lipids, may be required. Thiamine may be added, esp in the presence of lactic acidosis.
• Lipid infusions must be used w/caution due to risk of pancreatitis.
• Dietary protein should be reintroduced enterally as soon as is feasible given the clinical scenario & may need to be further augmented w/TPN.
• Nasograstric or orogastric feeding should be strongly considered so that enteral feedings can be reintroduced w/o delay.
• N-carbamylglutamate (NCG, Carbaglu
• Administer IV sodium benzoate
• Hemodialysis or hemofiltration in consultation w/nephrologist may be required in the event of treatment failure (uncontrollable acidosis &/or hyperammonemia).
• A STAT plasma ammonia level should be obtained in the ED or on admission.
• NCG activates the first step in the urea cycle (CPS1 enzyme) & is effective in lowering ammonia concentration during acute crises in patients w/MMA. Chronic or periodic use has been attempted in cases w/frequent decompensations, but has not obtained regulatory approval.
• Use of phenylacetate may accentuate low glutamine levels by generating phenylacetylglutamine & deplete 2-ketoglutarate in the TCA cycle.
• Initiate the treatment listed above for ↑ catabolism.
• Neurologic consultation
• Brain MRI
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with isolated methylmalonic acidemia together with pediatric or adult metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized and there is limited availability of clinics for adults with IEMs, continuous supervision by a center with expertise in metabolic diseases with sufficient resources is essential.
• The underlying biochemical parameters & frequency of metabolic decompensation improve significantly in persons undergoing liver transplantation despite persistent metabolic abnormalities.
• Liver transplantation is not curative. Patients remain at risk for long-term complications incl renal disease, basal ganglia injury & neurologic complications, & optic nerve atrophy.
• Neurotoxicity due to calcineurin inhibitors has been described in transplanted patients.
• More mildly affected persons w/
• Elective kidney transplantation, before the onset of renal disease, cannot stabilize persons w/
• Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
• Treatment protocols & provision of emergency letters or cards to incl guidance for care in the event of illness while on holiday/vacation
• MediAlert
• Adequate supplies of specialized dietary products (protein-free or propiogenic amino acid deficient formulas); medication required for maintenance & emergency treatment (vitamin B
• Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers/pediatricians, & to teachers & school staff.
• Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for MMA & containing contact info for the primary treating metabolic center.
• For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates.
• Notify designated metabolic center in advance of the procedure to discuss perioperative management w/surgeons & anesthesiologists.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
• Plasma amino acids
• Plasma & urine MMA levels
• Serum acylcarnitine profile & free & total carnitine levels
• Blood chemistries
• CBC
• Measurement of creatinine, cystatin-C, & (if available) GFR (e.g., iohexol plasma decay)
• Renal imaging
• Bone mineral density (DXA)
• Early referral to nephrologist is critical for consideration of renoprotective measures.
• Monitoring of renal comorbidities by multidisciplinary team
• Liver ultrasound
• Measurement of liver transaminases & alpha-fetoprotein
• Fasting. During acute illness, intake of adequate calories is necessary to arrest/prevent decompensation.
• Stress
• Increased dietary protein
• Supplementation with the individual propiogenic amino acids valine and isoleucine, as they directly increase the toxic metabolite load in patients with disordered propionate oxidation [
• Nephrotoxic medications or agents (e.g. ibuprofen)
• Agents that prolong QTc in the EKG
• In pregnancies of affected women with MMA, complications observed included acute decompensation or hyperammonemia, deterioration of renal function, and obstetric complications including preeclampsia, preterm delivery, and cæsarean section [
• Despite high maternal MMA levels, fetal growth and development have been reported to be normal, suggesting negligible teratogenic effects to the fetus from exposure to high methylmalonic acid levels in utero, though long-term follow up with age-appropriate neurocognitive testing is limited [
• Pregnancies in transplant recipients are rare and further studies on the health of the offspring are needed [
• Liver-targeted genomic therapies including systemic canonic recombinant adeno-associated virus (rAAV) gene therapy [
• Studies using primary hepatocytes from individuals with methylmalonic and propionic acidemia have found that administration of the small molecule 2,2-dimethylbutanoic acid (HST5040) leads to a dose dependent reduction in levels of methylmalonyl-CoA and other serum metabolites. This small molecule is being tested in clinical trials [
• Investigational therapies intended to increase CoA levels by allosterically modulating pantothenate kinases, key enzymes in the CoA biosynthesis pathway, have been shown to increase free CoA and alleviate mitochondrial dysfunction in mouse models of propionic academia (PA) [
• Carefully designed clinical studies are required to evaluate the efficacy of antioxidant regimens in people with MMA.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with isolated MMA, the evaluations summarized
Recommended Evaluations Following Initial Diagnosis of Isolated Methylmalonic Acidemia
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
Review diet/food records w/metabolic dietitian.
Provide patient/family w/sick-day diet instructions & emergency treatment letter detailing mgmt plan & specialist contact information (see
Generally, 1.0-mg injections (preferably of OHCbl) daily for 3-5 days
Obtain >1 baseline & follow-up measures over 10 days to assess for a ↓ in serum & urine methylmalonic acid (>50% ↓ is considered a positive B
Serum vitamin B
Serum chemistry panel incl renal function, liver enzymes
CBC w/differential, iron status, folate
Arterial or venous blood gas
Plasma ammonium & lactic acid concentration
Urinalysis & urine ketone measurement
Quantitative plasma amino acids
Urine organic acids
Serum methylmalonic acid & (if available) methylcitrate levels
Measurement of free & total carnitine levels
Pancreatic enzymes (amylase, lipase)
Serum albumin, total protein, & prealbumin to assess for nutritional status
Blood pressure measurement
EKG
Echocardiogram
Consult w/cardiologist
Assess for evidence of growth failure, need for gastrostomy tube to meet caloric needs, growth hormone treatment.
Prevent & treat osteopenia due to low-protein diet, renal osteodystrophy, delayed puberty.
To assess for signs & symptoms of mvmt disorder, seizures, neuropathy
Brain imaging (MRI, MRS) in case of abnormal neurologic exam findings
CBC = complete blood count; OHCbl = hydroxocobalamin (as opposed to cyanocobalamin); MOI = mode of inheritance
After a new diagnosis of isolated methylmalonic acidemia in a child, the closest hospital and local pediatrician should also be informed. The family needs to have an updated emergency treatment letter and plan.
Na
By gas chromatography and mass spectrometry (GC-MS)
Hearing loss may occur in those who have experienced episodes of metabolic decompensation. The risk of hearing loss likely increases with age and can be seen along with optic nerve atrophy.
Medical/biochemical geneticist, certified genetic counselor, certified advanced genetic nurse
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
• Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
• Review diet/food records w/metabolic dietitian.
• Provide patient/family w/sick-day diet instructions & emergency treatment letter detailing mgmt plan & specialist contact information (see
• Generally, 1.0-mg injections (preferably of OHCbl) daily for 3-5 days
• Obtain >1 baseline & follow-up measures over 10 days to assess for a ↓ in serum & urine methylmalonic acid (>50% ↓ is considered a positive B
• Serum vitamin B
• Serum chemistry panel incl renal function, liver enzymes
• CBC w/differential, iron status, folate
• Arterial or venous blood gas
• Plasma ammonium & lactic acid concentration
• Urinalysis & urine ketone measurement
• Quantitative plasma amino acids
• Urine organic acids
• Serum methylmalonic acid & (if available) methylcitrate levels
• Measurement of free & total carnitine levels
• Pancreatic enzymes (amylase, lipase)
• Serum albumin, total protein, & prealbumin to assess for nutritional status
• Blood pressure measurement
• EKG
• Echocardiogram
• Consult w/cardiologist
• Assess for evidence of growth failure, need for gastrostomy tube to meet caloric needs, growth hormone treatment.
• Prevent & treat osteopenia due to low-protein diet, renal osteodystrophy, delayed puberty.
• To assess for signs & symptoms of mvmt disorder, seizures, neuropathy
• Brain imaging (MRI, MRS) in case of abnormal neurologic exam findings
## Treatment of Manifestations
Guidelines developed by professionals across 12 European countries and the US based on rigorous literature evaluation and expert group meetings outline the current management recommendations and areas for further research. See
Routine Daily Treatment in Individuals with Isolated Methylmalonic Acidemia
Safe levels of natural protein per age group should be the aim (see 2007
The individual protein amount prescribed depends on growth parameters, metabolic stability, & stage of renal failure.
A propiogenic amino acid-deficient formula
Use medical foods in moderation, w/relative intake of natural protein to propiogenic amino-acid-deficient formula not exceeding a ratio of 1:1
Natural protein must be carefully titrated to allow for normal growth.
As infants grow, total protein load is slowly ↓, based on growth, plasma amino acid concentrations, & plasma & urine methylmalonic acid concentrations.
Adjustment of dietary whole (complete)-protein intake (based on lab findings) is required lifelong (see
Isolated valine & isoleucine deficiencies may be caused in part by overuse of propiogenic amino-acid deficient formula; individual amino acid supplementation should be avoided (see
A ratio of complete protein to medical formula of 60%/40% to 70%/30% of total protein prescription is usually not assoc w/deficiency of valine or isoleucine [Authors, personal observation].
Attn to protein:energy ratio is important; when available, accurate assessment of resting energy expenditure can guide dietary & caloric prescriptions & avoid overfeeding.
Plasma amino acids should be drawn ~4 hrs after food intake.
Continue protein restriction & dietary monitoring after liver transplantation to avoid extrahepatic disease complications.
Oral dosage of 50-100 mg/kg/day, up to ~300 mg/kg/day, of L-carnitine divided into 3-4 doses is common.
Dose is adjusted on an individual basis to maintain plasma free carnitine concentration w/in normal age-appropriate reference range.
Rotating antibiotic regimens may be considered in some persons.
Responsiveness to antibiotic should be determined by a ↓ in serum methylmalonic acid concentration compared to patient's baseline value, or a ↓ in whole-body output of methylmalonic acid on antibiotic therapy by a timed urine collection compared to patient's baseline value.
Chronic cyclic antibiotic therapy is not innocuous; it introduces the risk of repopulation w/resistant flora & has been assoc w/peripheral neuropathy.
Propiogenic amino acid precursors include isoleucine, valine, methionine and threonine
These dietary guidelines
For example, Propimex
An iatrogenic essential amino acid deficiency can be induced by the relatively high leucine intake through the MMA formulas that can negatively affect long-term growth and possibly other outcomes, especially if propiogenic amino-acid deficient formula is prescribed in excess of complete protein sources [
For example, Pro-Phree
In patients with low protein tolerance, severe restriction of propiogenic amino acid precursors (isoleucine, valine, methionine, and threonine) can produce a nutritional deficiency state.
Carnitine may replace the free carnitine pool and enhance the conjugation and excretion of propionylcarnitine. The contribution of propionylcarnitine excretion to the total propionate load is, however, small. The relief of intracellular CoA accretion may be the mechanism by which carnitine supplementation benefits some individuals.
This could pose a serious infectious threat and could be especially dangerous to individuals with isolated methylmalonic acidemia, since most deaths are related to metabolic decompensation, often precipitated by infection [
Treatment of Secondary Complications in Individuals with Isolated Methylmalonic Acidemia
Supportive developmental therapies (may incl PT, OT, speech & cognitive therapies)
Coordination of individualized educational plan in school
See
Avoid nephrotoxic medications (see
IVF = intravenous fluids; OT = occupational therapy; PT = physical therapy; TPN = total parenteral nutrition
Documented growth hormone deficiency is a rare cause of growth failure [
Emergency Outpatient Treatment in Individuals with Isolated Methylmalonic Acidemia
Carbohydrate supplementation orally or via tube feed
Reduce natural protein intake
Increase carnitine supplementation
Trial of outpatient treatment at home for up to 12 hours
Initiation of sick-day dietary plan
Reassessment (~every 2 hours) for clinical changes
Limit ibuprofen/NSAID use for renoprotection.
Avoid excessive acetaminophen use for risk of liver toxicity.
Fever <38.5°C (101°F); enteral or gastrostomy tube feeding is tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability)
Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide nutritional arrangements in the outpatient setting, with some centers recommending frequent provision of carbohydrate-rich, protein-free beverages every two hours, with frequent reassessment.
Some centers advocate additional steps such as reducing natural protein intake to zero or to 50% of the normal prescribed regimen for short periods (<24 hours) in the outpatient setting during intercurrent illness. Protein restriction more than 24-48 hours could lead to catabolism and should be avoided.
Temporarily increasing L-carnitine doses (e.g., to 200 mg/kg/day in infants) may be considered.
Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features should be discussed with the designated center of expertise for inherited metabolic diseases.
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma), often occurring in the setting of intercurrent illness and/or inadequate caloric intake, should be managed symptomatically and with generous caloric support in a hospital setting, with aggressive treatment and supportive care. Immediate consultation with a metabolic/biochemical geneticist is essential. Individuals with MMA can deteriorate rapidly and consultations with neurology, nephrology, and ICU teams are often required during crises (see
Acute Inpatient Treatment in Individuals with Methylmalonic Acidemia
Administration of high-energy IV fluids (D10/0.45 or 0.9 saline) at 1.5x maintenance rate to achieve age-appropriate glucose infusion rate (GIR), &, if needed insulin
Lipid emulsion is often necessary to provide sufficient calories at a dose of 1- 2 g/kg/day.
Address electrolytes & pH imbalances w/bicarbonate bolus, expect need for potassium replacement, as needed.
↓ or omit total protein for ≤24-48 hours.
L-carnitine IV supplementation at 50-100 mg/kg/day either BID or QID
Blood glucose, electrolyte concentrations (particularly sodium, potassium & bicarbonate concentrations), blood gases (w/monitoring of the anion gap), complete blood count & differential, serum lactate, urine ketones & urine output should be followed serially.
Central or peripheral TPN, which typically contains glucose & amino acids, & in some instances lipids, may be required. Thiamine may be added, esp in the presence of lactic acidosis.
Lipid infusions must be used w/caution due to risk of pancreatitis.
Dietary protein should be reintroduced enterally as soon as is feasible given the clinical scenario & may need to be further augmented w/TPN.
Nasograstric or orogastric feeding should be strongly considered so that enteral feedings can be reintroduced w/o delay.
N-carbamylglutamate (NCG, Carbaglu
Administer IV sodium benzoate
Hemodialysis or hemofiltration in consultation w/nephrologist may be required in the event of treatment failure (uncontrollable acidosis &/or hyperammonemia).
A STAT plasma ammonia level should be obtained in the ED or on admission.
NCG activates the first step in the urea cycle (CPS1 enzyme) & is effective in lowering ammonia concentration during acute crises in patients w/MMA. Chronic or periodic use has been attempted in cases w/frequent decompensations, but has not obtained regulatory approval.
Use of phenylacetate may accentuate low glutamine levels by generating phenylacetylglutamine & deplete 2-ketoglutarate in the TCA cycle.
Initiate the treatment listed above for ↑ catabolism.
Neurologic consultation
Brain MRI
BID = twice a day; ED = emergency department; PT = physical therapy; QID = four times a day; TPN = total parenteral nutrition
Inpatient emergency treatment should: (1) take place at the closest medical facility, (2) be started without delay, and (3) be supervised by physicians and specialist dieticians at the responsible metabolic center, who should be contacted without delay.
Intravenous glucose solutions should preferably consist of D
Use of insulin if hyperglycemia emerges; intravenous insulin given at a starting dose of 0.01-0.02 IU/kg/hour in the event of persistent hyperglycemia (>150-180 mg/dL in plasma, or glucosuria)
Consult published guidelines,
Total protein can be gradually reintroduced depending on the patient's acid-base balance and remaining laboratory values, including ammonia, lactic acid, and plasma amino acids, among others.
The dose of N-carbamylglutamate (NCG) is 100 mg/kg bolus, followed by 25-62 mg/kg every 6 hours PO (orally). NCG is an N-acetylglutamate analog that allosterically activates CPS1 (carbamyl phosphate synthetase 1), the first step of the urea cycle [
The dose of sodium benzoate is 250 mg/kg as a bolus given over 90-120 min, followed by 250 mg/kg/day for maintenance, administered in 10% dextrose IV (intravenously). The same dose regimen is used for sodium phenylbutyrate (PBA). The maximum dose of sodium benzoate or sodium PBA is 5.5 g/m
May include both bone marrow hypoplasia and/or dysplasia
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with isolated methylmalonic acidemia together with pediatric or adult metabolic experts, dietitians, psychologists, and social workers.
As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized and there is limited availability of clinics for adults with IEMs, continuous supervision by a center with expertise in metabolic diseases with sufficient resources is essential.
• Safe levels of natural protein per age group should be the aim (see 2007
• The individual protein amount prescribed depends on growth parameters, metabolic stability, & stage of renal failure.
• A propiogenic amino acid-deficient formula
• Use medical foods in moderation, w/relative intake of natural protein to propiogenic amino-acid-deficient formula not exceeding a ratio of 1:1
• Natural protein must be carefully titrated to allow for normal growth.
• As infants grow, total protein load is slowly ↓, based on growth, plasma amino acid concentrations, & plasma & urine methylmalonic acid concentrations.
• Adjustment of dietary whole (complete)-protein intake (based on lab findings) is required lifelong (see
• Isolated valine & isoleucine deficiencies may be caused in part by overuse of propiogenic amino-acid deficient formula; individual amino acid supplementation should be avoided (see
• A ratio of complete protein to medical formula of 60%/40% to 70%/30% of total protein prescription is usually not assoc w/deficiency of valine or isoleucine [Authors, personal observation].
• Attn to protein:energy ratio is important; when available, accurate assessment of resting energy expenditure can guide dietary & caloric prescriptions & avoid overfeeding.
• Plasma amino acids should be drawn ~4 hrs after food intake.
• Continue protein restriction & dietary monitoring after liver transplantation to avoid extrahepatic disease complications.
• Oral dosage of 50-100 mg/kg/day, up to ~300 mg/kg/day, of L-carnitine divided into 3-4 doses is common.
• Dose is adjusted on an individual basis to maintain plasma free carnitine concentration w/in normal age-appropriate reference range.
• Rotating antibiotic regimens may be considered in some persons.
• Responsiveness to antibiotic should be determined by a ↓ in serum methylmalonic acid concentration compared to patient's baseline value, or a ↓ in whole-body output of methylmalonic acid on antibiotic therapy by a timed urine collection compared to patient's baseline value.
• Chronic cyclic antibiotic therapy is not innocuous; it introduces the risk of repopulation w/resistant flora & has been assoc w/peripheral neuropathy.
• Supportive developmental therapies (may incl PT, OT, speech & cognitive therapies)
• Coordination of individualized educational plan in school
• See
• Avoid nephrotoxic medications (see
• Carbohydrate supplementation orally or via tube feed
• Reduce natural protein intake
• Increase carnitine supplementation
• Trial of outpatient treatment at home for up to 12 hours
• Initiation of sick-day dietary plan
• Reassessment (~every 2 hours) for clinical changes
• Limit ibuprofen/NSAID use for renoprotection.
• Avoid excessive acetaminophen use for risk of liver toxicity.
• Administration of high-energy IV fluids (D10/0.45 or 0.9 saline) at 1.5x maintenance rate to achieve age-appropriate glucose infusion rate (GIR), &, if needed insulin
• Lipid emulsion is often necessary to provide sufficient calories at a dose of 1- 2 g/kg/day.
• Address electrolytes & pH imbalances w/bicarbonate bolus, expect need for potassium replacement, as needed.
• ↓ or omit total protein for ≤24-48 hours.
• L-carnitine IV supplementation at 50-100 mg/kg/day either BID or QID
• Blood glucose, electrolyte concentrations (particularly sodium, potassium & bicarbonate concentrations), blood gases (w/monitoring of the anion gap), complete blood count & differential, serum lactate, urine ketones & urine output should be followed serially.
• Central or peripheral TPN, which typically contains glucose & amino acids, & in some instances lipids, may be required. Thiamine may be added, esp in the presence of lactic acidosis.
• Lipid infusions must be used w/caution due to risk of pancreatitis.
• Dietary protein should be reintroduced enterally as soon as is feasible given the clinical scenario & may need to be further augmented w/TPN.
• Nasograstric or orogastric feeding should be strongly considered so that enteral feedings can be reintroduced w/o delay.
• N-carbamylglutamate (NCG, Carbaglu
• Administer IV sodium benzoate
• Hemodialysis or hemofiltration in consultation w/nephrologist may be required in the event of treatment failure (uncontrollable acidosis &/or hyperammonemia).
• A STAT plasma ammonia level should be obtained in the ED or on admission.
• NCG activates the first step in the urea cycle (CPS1 enzyme) & is effective in lowering ammonia concentration during acute crises in patients w/MMA. Chronic or periodic use has been attempted in cases w/frequent decompensations, but has not obtained regulatory approval.
• Use of phenylacetate may accentuate low glutamine levels by generating phenylacetylglutamine & deplete 2-ketoglutarate in the TCA cycle.
• Initiate the treatment listed above for ↑ catabolism.
• Neurologic consultation
• Brain MRI
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with isolated methylmalonic acidemia together with pediatric or adult metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized and there is limited availability of clinics for adults with IEMs, continuous supervision by a center with expertise in metabolic diseases with sufficient resources is essential.
## Prevention of Primary Manifestations
See also
Large case series of affected individuals undergoing elective liver or combined liver/kidney transplantation (as opposed to isolated kidney transplantation) have detailed the indications, peri-operative complications, surgical and anesthesia approaches, anti-rejection regimens, and long-term outcomes in people with MMA undergoing these procedures. Inclusion of enzymatic and genotype information in case series of transplanted individuals allows for better comparisons of the outcomes and genotype-phenotype associations that could inform decisions about the indication and timing of transplantation in individual cases.
Liver transplantation is increasingly offered to younger affected individuals with significant metabolic instability, often in infancy, as a measure to prevent neurologic damage from recurrent metabolic crises associated with hyperammonemia. Referral to centers with experience in managing people with organic acidemias and continued monitoring and dietary therapy are essential for all MMA transplant recipients.
Prevention of Primary Manifestations in Individuals with Isolated Methylmalonic Acidemia
The underlying biochemical parameters & frequency of metabolic decompensation improve significantly in persons undergoing liver transplantation despite persistent metabolic abnormalities.
Liver transplantation is not curative. Patients remain at risk for long-term complications incl renal disease, basal ganglia injury & neurologic complications, & optic nerve atrophy.
Neurotoxicity due to calcineurin inhibitors has been described in transplanted patients.
More mildly affected persons w/
Elective kidney transplantation, before the onset of renal disease, cannot stabilize persons w/
Most of the metabolic conversion of propionate occurs in the liver, so liver transplantation has the potential to provide enough enzymatic activity to avert severe metabolic crises for the most significantly affected individuals (MMA
More than 100 individuals with MMA have undergone living-donor [
Liver transplantation is associated with complications related to surgery (hepatic artery thrombosis, bile duct stenosis, perforation), graft rejection, and lifelong immunosuppressive therapy [
Neurotoxicity from calcineurin inhibitors, including posterior reversible encephalopathy syndrome (PRES), has been reported [
A smaller number (~20) of individuals with MMA (mostly with milder
A regimen of coenzyme Q
• The underlying biochemical parameters & frequency of metabolic decompensation improve significantly in persons undergoing liver transplantation despite persistent metabolic abnormalities.
• Liver transplantation is not curative. Patients remain at risk for long-term complications incl renal disease, basal ganglia injury & neurologic complications, & optic nerve atrophy.
• Neurotoxicity due to calcineurin inhibitors has been described in transplanted patients.
• More mildly affected persons w/
• Elective kidney transplantation, before the onset of renal disease, cannot stabilize persons w/
## Prevention of Secondary Complications
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see also
Prevention of Secondary Manifestations in Individuals with Isolated Methylmalonic Acidemia
Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
Treatment protocols & provision of emergency letters or cards to incl guidance for care in the event of illness while on holiday/vacation
MediAlert
Adequate supplies of specialized dietary products (protein-free or propiogenic amino acid deficient formulas); medication required for maintenance & emergency treatment (vitamin B
Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers/pediatricians, & to teachers & school staff.
Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for MMA & containing contact info for the primary treating metabolic center.
For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates.
Notify designated metabolic center in advance of the procedure to discuss perioperative management w/surgeons & anesthesiologists.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
Essential information including written treatment protocols should be in place in anticipation of possible future need for inpatient emergency treatment.
Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5°C; (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur.
Special considerations regarding choices of anesthetic agents in this patient population may apply [
Perioperative/perianesthetic management precautions may include visitations at specialist anesthetic clinics for affected persons deemed to be at high risk for perioperative complications.
• Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
• Treatment protocols & provision of emergency letters or cards to incl guidance for care in the event of illness while on holiday/vacation
• MediAlert
• Adequate supplies of specialized dietary products (protein-free or propiogenic amino acid deficient formulas); medication required for maintenance & emergency treatment (vitamin B
• Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers/pediatricians, & to teachers & school staff.
• Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for MMA & containing contact info for the primary treating metabolic center.
• For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates.
• Notify designated metabolic center in advance of the procedure to discuss perioperative management w/surgeons & anesthesiologists.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
## Surveillance
During the first year of life, infants may need to be evaluated as frequently as every week and continued at intervals determined by the frequency of metabolic crises/admissions, growth patterns, and dietary needs. Attention to transition periods (e.g., after the first two years, in adolescence) with other stressors in the family are necessary for modification of dietary prescription.
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the following are recommended. See
Recommended Surveillance for Individuals with Isolated Methylmalonic Acidemia
Plasma amino acids
Plasma & urine MMA levels
Serum acylcarnitine profile & free & total carnitine levels
Blood chemistries
CBC
Measurement of creatinine, cystatin-C, & (if available) GFR (e.g., iohexol plasma decay)
Renal imaging
Bone mineral density (DXA)
Early referral to nephrologist is critical for consideration of renoprotective measures.
Monitoring of renal comorbidities by multidisciplinary team
Liver ultrasound
Measurement of liver transaminases & alpha-fetoprotein
CBC = complete blood count; GFR = glomerular filtration rate; PT = physical therapy
Frequent monitoring of plasma amino acids is necessary to avoid deficiencies of essential amino acids (particularly isoleucine, valine, and methionine) as a result of excessive protein restriction and the development of acrodermatitis-enteropathica-like cutaneous lesions in methylmalonic aciduria, as in other organic acidurias (
Including Na+, K+, CI–, glucose, urea, creatinine, bicarbonate, AST, ALT, alkaline phosphatase, bilirubin (T/U), triglycerides, and cholesterol
Comorbidities of renal disease may include anemia, acidosis, hyperuricemia, secondary hyperparathyroidism, osteopenia/osteoporosis, hypertension, and short stature. In addition to cystatin-C, biochemical markers of bone health (Ca, P, alkaline phosphatase, parathyroid hormone, 1.25 dihydroxy-vit D (D3), and uric acid should be assessed periodically.
Combined equations based on creatinine and cystatin-C and measured GFR by iohexol clearance or other methods are expected to reflect more accurately the kidney function in people with MMA [
To allow for early referral to nephrologist and appropriate timing of renal transplantation when needed [
Nephrotoxic medication should be avoided (see
DXA scan is typically done in older individuals, starting in adolescence, unless there is evidence for renal disease earlier.
Particularly in individuals with severe MMA subtypes
Enrollment in early intervention programs for physical, occupational, and speech therapy is recommended.
To assess for optic nerve thinning/pallor
Hearing loss can occur in isolated MMA and may be a result of episodes of metabolic decompensation.
• Plasma amino acids
• Plasma & urine MMA levels
• Serum acylcarnitine profile & free & total carnitine levels
• Blood chemistries
• CBC
• Measurement of creatinine, cystatin-C, & (if available) GFR (e.g., iohexol plasma decay)
• Renal imaging
• Bone mineral density (DXA)
• Early referral to nephrologist is critical for consideration of renoprotective measures.
• Monitoring of renal comorbidities by multidisciplinary team
• Liver ultrasound
• Measurement of liver transaminases & alpha-fetoprotein
## Agents/Circumstances to Avoid
The following should be avoided:
Fasting. During acute illness, intake of adequate calories is necessary to arrest/prevent decompensation.
Stress
Increased dietary protein
Supplementation with the individual propiogenic amino acids valine and isoleucine, as they directly increase the toxic metabolite load in patients with disordered propionate oxidation [
Nephrotoxic medications or agents (e.g. ibuprofen)
Agents that prolong QTc in the EKG
• Fasting. During acute illness, intake of adequate calories is necessary to arrest/prevent decompensation.
• Stress
• Increased dietary protein
• Supplementation with the individual propiogenic amino acids valine and isoleucine, as they directly increase the toxic metabolite load in patients with disordered propionate oxidation [
• Nephrotoxic medications or agents (e.g. ibuprofen)
• Agents that prolong QTc in the EKG
## Evaluation of Relatives at Risk
Evaluation of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of isolated methylmalonic acidemia.
For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, measure serum methylmalonic acid, urine organic acids, plasma acylcarnitine profile, plasma amino acids, and serum B
Prenatal diagnosis of at-risk sibs may allow for prompt treatment of affected newborns at the time of delivery or prenatal administration of vitamin B
See
## Pregnancy Management
In pregnancies of affected women with MMA, complications observed included acute decompensation or hyperammonemia, deterioration of renal function, and obstetric complications including preeclampsia, preterm delivery, and cæsarean section [
Despite high maternal MMA levels, fetal growth and development have been reported to be normal, suggesting negligible teratogenic effects to the fetus from exposure to high methylmalonic acid levels in utero, though long-term follow up with age-appropriate neurocognitive testing is limited [
Pregnancies in transplant recipients are rare and further studies on the health of the offspring are needed [
See
• In pregnancies of affected women with MMA, complications observed included acute decompensation or hyperammonemia, deterioration of renal function, and obstetric complications including preeclampsia, preterm delivery, and cæsarean section [
• Despite high maternal MMA levels, fetal growth and development have been reported to be normal, suggesting negligible teratogenic effects to the fetus from exposure to high methylmalonic acid levels in utero, though long-term follow up with age-appropriate neurocognitive testing is limited [
• Pregnancies in transplant recipients are rare and further studies on the health of the offspring are needed [
## Therapies Under Investigation
Increased understanding of the underlying pathophysiology and the generation of disease-specific animal or cellular models has allowed the development of several novel therapies for isolated MMA [
Liver-targeted genomic therapies including systemic canonic recombinant adeno-associated virus (rAAV) gene therapy [
Studies using primary hepatocytes from individuals with methylmalonic and propionic acidemia have found that administration of the small molecule 2,2-dimethylbutanoic acid (HST5040) leads to a dose dependent reduction in levels of methylmalonyl-CoA and other serum metabolites. This small molecule is being tested in clinical trials [
Investigational therapies intended to increase CoA levels by allosterically modulating pantothenate kinases, key enzymes in the CoA biosynthesis pathway, have been shown to increase free CoA and alleviate mitochondrial dysfunction in mouse models of propionic academia (PA) [
Carefully designed clinical studies are required to evaluate the efficacy of antioxidant regimens in people with MMA.
Review the following for more information on current clinical trials on isolated MMA:
Search
• Liver-targeted genomic therapies including systemic canonic recombinant adeno-associated virus (rAAV) gene therapy [
• Studies using primary hepatocytes from individuals with methylmalonic and propionic acidemia have found that administration of the small molecule 2,2-dimethylbutanoic acid (HST5040) leads to a dose dependent reduction in levels of methylmalonyl-CoA and other serum metabolites. This small molecule is being tested in clinical trials [
• Investigational therapies intended to increase CoA levels by allosterically modulating pantothenate kinases, key enzymes in the CoA biosynthesis pathway, have been shown to increase free CoA and alleviate mitochondrial dysfunction in mouse models of propionic academia (PA) [
• Carefully designed clinical studies are required to evaluate the efficacy of antioxidant regimens in people with MMA.
## Genetic Counseling
All forms of isolated methylmalonic acidemia (MMA) – including complete or partial deficiency of the enzyme methylmalonyl-CoA mutase; defect in transport or synthesis of the methylmalonyl-CoA mutase cofactor, 5'deoxyadenosyl-cobalamin; and deficiency of the enzyme methylmalonyl-CoA epimerase – are inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an isolated MMA-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy has been reported (
Heterozygotes (carriers) of a pathogenic variant in an isolated MMA-related gene (i.e.,
If both parents are known to be heterozygous for an isolated MMA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
Heterozygotes (carriers) of a pathogenic variant in an isolated MMA-causing gene (i.e.,
Carrier testing for at-risk relatives requires prior identification of the isolated MMA-causing pathogenic variants in the family.
Methods other than molecular genetic testing are not reliable for carrier testing.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an isolated MMA-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy has been reported (
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy has been reported (
• Heterozygotes (carriers) of a pathogenic variant in an isolated MMA-related gene (i.e.,
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy has been reported (
• If both parents are known to be heterozygous for an isolated MMA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) of a pathogenic variant in an isolated MMA-causing gene (i.e.,
• Carrier testing for at-risk relatives requires prior identification of the isolated MMA-causing pathogenic variants in the family.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
All forms of isolated methylmalonic acidemia (MMA) – including complete or partial deficiency of the enzyme methylmalonyl-CoA mutase; defect in transport or synthesis of the methylmalonyl-CoA mutase cofactor, 5'deoxyadenosyl-cobalamin; and deficiency of the enzyme methylmalonyl-CoA epimerase – are inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an isolated MMA-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy has been reported (
Heterozygotes (carriers) of a pathogenic variant in an isolated MMA-related gene (i.e.,
If both parents are known to be heterozygous for an isolated MMA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
Heterozygotes (carriers) of a pathogenic variant in an isolated MMA-causing gene (i.e.,
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an isolated MMA-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy has been reported (
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy has been reported (
• Heterozygotes (carriers) of a pathogenic variant in an isolated MMA-related gene (i.e.,
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy has been reported (
• If both parents are known to be heterozygous for an isolated MMA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) of a pathogenic variant in an isolated MMA-causing gene (i.e.,
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the isolated MMA-causing pathogenic variants in the family.
Methods other than molecular genetic testing are not reliable for carrier testing.
• Carrier testing for at-risk relatives requires prior identification of the isolated MMA-causing pathogenic variants in the family.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
## Resources
TEMPLE (Tools Enabling Metabolic Parents LEarning)
United Kingdom
Health Resources & Services Administration
•
• TEMPLE (Tools Enabling Metabolic Parents LEarning)
• United Kingdom
•
•
•
•
• Health Resources & Services Administration
•
•
•
•
•
## Molecular Genetics
Isolated Methylmalonic Acidemia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Isolated Methylmalonic Acidemia (
Isolated MMA results from the failure to isomerize (convert) methylmalonyl-CoA into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid (
Aberrant post-translational modifications (methylmalonylation) have inhibitory effects on critical enzymes in the urea cycle and glycine cleavage pathways, causing the secondary disease manifestations such as hyperammonemia and hyperglycinemia in MMA [
Plasma fibroblast growth factor 21 (FGF21) has been characterized as a marker of hepatic mitochondrial dysfunction in MMA murine models and was shown to correlate with disease severity and long-term complications in different patient cohorts [
Isolated Methylmalonic Acidemia: Gene-Specific Laboratory Considerations
NGS = next generation sequencing; WES = whole-exome sequencing
Genes from
Isolated Methylmalonic Acidemia: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes from
See also
## Molecular Pathogenesis
Isolated MMA results from the failure to isomerize (convert) methylmalonyl-CoA into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid (
Aberrant post-translational modifications (methylmalonylation) have inhibitory effects on critical enzymes in the urea cycle and glycine cleavage pathways, causing the secondary disease manifestations such as hyperammonemia and hyperglycinemia in MMA [
Plasma fibroblast growth factor 21 (FGF21) has been characterized as a marker of hepatic mitochondrial dysfunction in MMA murine models and was shown to correlate with disease severity and long-term complications in different patient cohorts [
Isolated Methylmalonic Acidemia: Gene-Specific Laboratory Considerations
NGS = next generation sequencing; WES = whole-exome sequencing
Genes from
Isolated Methylmalonic Acidemia: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes from
See also
## Chapter Notes
Dr Manoli is a pediatrician and clinical and biochemical geneticist. She is a clinician associate investigator and senior staff clinician in the Organic Acid Research Section of the National Human Genome Research Institute, and an attending physician at the National Institutes of Health Clinical Center.
Dr Sloan is a genetic counselor, molecular geneticist, and cytogeneticist. She is a staff scientist in the Organic Acid Research Section of the National Human Genome Research Institute.
Dr Venditti is a pediatrician and clinical and biochemical geneticist. He is a senior investigator and the director of the Organic Acid Research Section at the National Human Genome Research Institute and an attending physician at the National Institutes of Health Clinical Center.
Websites:
The authors are supported by the Intramural Research Program of the National Human Genome Research Institute, Bethesda, MD. They have a longitudinal natural history protocol on methylmalonic acidemias and cobalamin disorders at the NIH (Study URL:
The authors wish to acknowledge the non-profit organizations "Angels for Alyssa," "A Cure for Clark," and the Organic Acidemia Association (OAA), all founded by families and friends of patients with MMA, for their ongoing dedication and support of MMA research.
8 September 2022 (ma) Comprehensive update posted live
1 December 2016 (cpv) Revision: Molecular Genetics:
7 January 2016 (me) Comprehensive update posted live
28 September 2010 (me) Comprehensive update posted live
18 January 2007 (cd) Revision: testing for mutations in
16 August 2005 (me) Review posted live
11 May 2004 (cpv) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 8 September 2022 (ma) Comprehensive update posted live
• 1 December 2016 (cpv) Revision: Molecular Genetics:
• 7 January 2016 (me) Comprehensive update posted live
• 28 September 2010 (me) Comprehensive update posted live
• 18 January 2007 (cd) Revision: testing for mutations in
• 16 August 2005 (me) Review posted live
• 11 May 2004 (cpv) Original submission
## Author Notes
Dr Manoli is a pediatrician and clinical and biochemical geneticist. She is a clinician associate investigator and senior staff clinician in the Organic Acid Research Section of the National Human Genome Research Institute, and an attending physician at the National Institutes of Health Clinical Center.
Dr Sloan is a genetic counselor, molecular geneticist, and cytogeneticist. She is a staff scientist in the Organic Acid Research Section of the National Human Genome Research Institute.
Dr Venditti is a pediatrician and clinical and biochemical geneticist. He is a senior investigator and the director of the Organic Acid Research Section at the National Human Genome Research Institute and an attending physician at the National Institutes of Health Clinical Center.
Websites:
## Acknowledgments
The authors are supported by the Intramural Research Program of the National Human Genome Research Institute, Bethesda, MD. They have a longitudinal natural history protocol on methylmalonic acidemias and cobalamin disorders at the NIH (Study URL:
The authors wish to acknowledge the non-profit organizations "Angels for Alyssa," "A Cure for Clark," and the Organic Acidemia Association (OAA), all founded by families and friends of patients with MMA, for their ongoing dedication and support of MMA research.
## Revision History
8 September 2022 (ma) Comprehensive update posted live
1 December 2016 (cpv) Revision: Molecular Genetics:
7 January 2016 (me) Comprehensive update posted live
28 September 2010 (me) Comprehensive update posted live
18 January 2007 (cd) Revision: testing for mutations in
16 August 2005 (me) Review posted live
11 May 2004 (cpv) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 8 September 2022 (ma) Comprehensive update posted live
• 1 December 2016 (cpv) Revision: Molecular Genetics:
• 7 January 2016 (me) Comprehensive update posted live
• 28 September 2010 (me) Comprehensive update posted live
• 18 January 2007 (cd) Revision: testing for mutations in
• 16 August 2005 (me) Review posted live
• 11 May 2004 (cpv) Original submission
## References
## Literature Cited
Major pathway of the conversion of propionyl-CoA into succinyl-CoA. The biotin-dependent enzyme propionyl-CoA carboxylase converts propionyl-CoA into D-methylmalonyl-CoA, which is then racemized into L-methylmalonyl-CoA and isomerized into succinyl-CoA, a Krebs cycle intermediate. The L-methylmalonyl-CoA mutase reaction requires 5'-deoxyadenosylcobalamin, an activated form of vitamin B
The color-coded boxes around the cobalamin-processing enzymes indicate their role in causing: (1) methylmalonyl-CoA mutase or isolated AdoCbl deficiency and associated increase in serum methylmalonic acid [sMMA] (blue); (2) isolated MeCbl deficiency and hyperhomocysteinemia (green); (3) both cofactor deficiencies causing elevations in MMA and homocysteine (purple). Note: The light blue striped boxes indicate the enzymes (and the genes encoding them) that are deficient in different disorders in which methylmalonic acidemia occurs: epimerase deficiency (
MMA = methylmalonic acid; Cbl = cobalamin; Cbl
The genes (and the enzymatic subtypes) associated with isolated methylmalonic acidemia included in this
Isolated methylmalonic acidemia caused by mutation of
An algorithm of conditions to be considered in the differential diagnosis of elevated serum or urine methylmalonic acid detected either during the follow up of an increased propionylcarnitine (C3) on newborn screening or following a positive urine organic acid screen in a symptomatic individual. The algorithm includes disorders that can present after the newborn period.
AC = acylcarnitine profile; CBC = complete blood count; Cbl = cobalamin; MMA = methylmalonic acid; Mut = mutase; OA = organic acids; PA = propionic acid; TC-II = transcobalamin II
Footnotes:
1. Succinate ligase deficiency (caused by biallelic pathogenic variants in
2. CMAMMA presents with
3. Methylmalonyl-semialdehyde-dehydrogenase deficiency (MMASDH) and other ill-defined syndromes should be considered (see
4. B
5. In rare instances metabolites can be normal in affected individuals.
|
[] |
16/8/2005
|
8/9/2022
|
1/12/2016
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mmd
|
mmd
|
[
"Minicore Disease",
"Minicore Myopathy",
"Multicore Disease",
"Multicore Myopathy",
"Multiminicore Myopathy",
"Minicore Disease",
"Minicore Myopathy",
"Multicore Disease",
"Multicore Myopathy",
"Multiminicore Myopathy",
"Ryanodine receptor 1",
"Selenoprotein N",
"RYR1",
"SELENON",
"Multiminicore Disease"
] |
Multiminicore Disease – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Alan H Beggs, Pankaj B Agrawal
|
Summary Multiminicore disease (MmD) is broadly classified into four groups: Classic form (75% of individuals) Moderate form, with hand involvement (<10%) Antenatal form, with arthrogryposis multiplex congenita (<10%) Ophthalmoplegic form (<10%) Onset of the classic form is usually congenital or early in childhood with neonatal hypotonia, delayed motor development, axial muscle weakness, scoliosis, and significant respiratory involvement (often with secondary cardiac impairment). Spinal rigidity of varying severity is present. The diagnosis of MmD is based on the presence of multiple "minicores" visible on muscle biopsy using oxidative stains, clinical findings of static or slowly progressive weakness, and absence of findings diagnostic of other neuromuscular disorders. Pathogenic variants in MmD is most often inherited in an autosomal recessive manner. The occurrence of MMD in two generations in a few families has been reported, suggestive of autosomal dominant inheritance. Assuming autosomal recessive inheritance, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
|
## Diagnosis
Multiminicore disease (MmD) has a wide clinical spectrum with four distinct phenotypes (see
The diagnosis of MmD is based on the presence of multiple "minicores," small zones of sarcomeric disorganization and/or diminished oxidative activity that correlate with lack of mitochondria in muscle fibers. Unlike the cores typical of central core disease, minicores affect both type I and type II fibers and are short in length, spanning only a few sarcomeres in the fiber longitudinal axis.
Note: Because minicores are not specific to MmD, the diagnosis of MmD is based on the presence of minicores in a large proportion of muscle fibers associated with static or slowly progressive weakness and absence of findings diagnostic of other disorders.
Anti-alpha-actinin and anti-actin antibodies do not reveal any abnormalities [
Studies may suggest a myopathic process but have a limited role in making the diagnosis.
Molecular Genetic Testing Used in Multiminicore Disease
See
See
Autosomal recessive
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No deletions or duplications involving
Exons sequenced may vary by laboratory.
Clinical evaluation includes the following:
Personal medical history and physical examination, with particular attention to features of congenital myopathy or muscular dystrophy (e.g., weakness, hypotonia, failure to thrive, scoliosis)
Family history, with particular attention to features of congenital myopathy or muscular dystrophy
Genetic diagnosis requires molecular genetic testing of
Because the majority of individuals with MmD have a pathogenic variant in
If no
Although no deletions or duplications of either
• Personal medical history and physical examination, with particular attention to features of congenital myopathy or muscular dystrophy (e.g., weakness, hypotonia, failure to thrive, scoliosis)
• Family history, with particular attention to features of congenital myopathy or muscular dystrophy
• Because the majority of individuals with MmD have a pathogenic variant in
• If no
• Although no deletions or duplications of either
## Clinical Diagnosis
Multiminicore disease (MmD) has a wide clinical spectrum with four distinct phenotypes (see
## Testing
The diagnosis of MmD is based on the presence of multiple "minicores," small zones of sarcomeric disorganization and/or diminished oxidative activity that correlate with lack of mitochondria in muscle fibers. Unlike the cores typical of central core disease, minicores affect both type I and type II fibers and are short in length, spanning only a few sarcomeres in the fiber longitudinal axis.
Note: Because minicores are not specific to MmD, the diagnosis of MmD is based on the presence of minicores in a large proportion of muscle fibers associated with static or slowly progressive weakness and absence of findings diagnostic of other disorders.
Anti-alpha-actinin and anti-actin antibodies do not reveal any abnormalities [
Studies may suggest a myopathic process but have a limited role in making the diagnosis.
Molecular Genetic Testing Used in Multiminicore Disease
See
See
Autosomal recessive
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No deletions or duplications involving
Exons sequenced may vary by laboratory.
## Muscle Biopsy
The diagnosis of MmD is based on the presence of multiple "minicores," small zones of sarcomeric disorganization and/or diminished oxidative activity that correlate with lack of mitochondria in muscle fibers. Unlike the cores typical of central core disease, minicores affect both type I and type II fibers and are short in length, spanning only a few sarcomeres in the fiber longitudinal axis.
Note: Because minicores are not specific to MmD, the diagnosis of MmD is based on the presence of minicores in a large proportion of muscle fibers associated with static or slowly progressive weakness and absence of findings diagnostic of other disorders.
Anti-alpha-actinin and anti-actin antibodies do not reveal any abnormalities [
## Biochemical and Electrophysiologic Studies
Studies may suggest a myopathic process but have a limited role in making the diagnosis.
## Molecular Genetic Testing
Molecular Genetic Testing Used in Multiminicore Disease
See
See
Autosomal recessive
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No deletions or duplications involving
Exons sequenced may vary by laboratory.
## Testing Strategy
Clinical evaluation includes the following:
Personal medical history and physical examination, with particular attention to features of congenital myopathy or muscular dystrophy (e.g., weakness, hypotonia, failure to thrive, scoliosis)
Family history, with particular attention to features of congenital myopathy or muscular dystrophy
Genetic diagnosis requires molecular genetic testing of
Because the majority of individuals with MmD have a pathogenic variant in
If no
Although no deletions or duplications of either
• Personal medical history and physical examination, with particular attention to features of congenital myopathy or muscular dystrophy (e.g., weakness, hypotonia, failure to thrive, scoliosis)
• Family history, with particular attention to features of congenital myopathy or muscular dystrophy
• Because the majority of individuals with MmD have a pathogenic variant in
• If no
• Although no deletions or duplications of either
## Clinical Characteristics
Multiminicore disease (MmD) is characterized by axial and proximal muscle weakness. It is usually slowly progressive; however, fatal cases have been described. High-arched palate and chest deformities are common.
MmD is broadly classified into four forms [
Classic form
Moderate form, with hand involvement
Antenatal form, with arthrogryposis multiplex congenita
Ophthalmoplegic form
In all forms, males and females are equally affected.
Onset is usually congenital or occurs in early childhood with neonatal hypotonia and delayed motor development including head lag, a common and early sign.
Axial muscle weakness leads to development of scoliosis and major respiratory involvement in approximately two thirds of individuals. Scoliosis develops at a mean age of 8.5 years and is generally cervicodorsal and progressive [
Rigid spine muscular dystrophy (RSMD), characterized by limited flexion of dorsolumbar and cervical spine (caused by contractures of spinal extensor muscles) is now considered a form of classic MmD. The majority of individuals with these findings have
Strength of trunk and neck flexors is usually scored 1 to 2 out of 5, pelvic and shoulder girdle muscles 3 to 4, and distal muscles normal or only moderately weak (3+ to 5). Individuals are usually ambulatory, as limb muscle strength is relatively preserved.
Facial muscle strength ranges from normal to severe weakness; extraocular muscles are spared.
Individuals may walk well into adulthood despite severe scoliosis and need for ventilatory support. In a few severe cases the disease may progress slowly through adolescence and adulthood, eventually leading to loss of ambulation.
Death often occurs as a result of respiratory infection in a setting of severe respiratory insufficiency.
Late onset of the disease is usually associated with better prognosis.
Rigid spine muscular dystrophy or rigid spine syndrome are now considered the same entity as severe classic MmD.
MmD is thought to be rare. Actual prevalence figures are unknown. The disease occurs in diverse ethnic and racial groups.
• Classic form
• Moderate form, with hand involvement
• Antenatal form, with arthrogryposis multiplex congenita
• Ophthalmoplegic form
•
• Onset is usually congenital or occurs in early childhood with neonatal hypotonia and delayed motor development including head lag, a common and early sign.
• Axial muscle weakness leads to development of scoliosis and major respiratory involvement in approximately two thirds of individuals. Scoliosis develops at a mean age of 8.5 years and is generally cervicodorsal and progressive [
• Rigid spine muscular dystrophy (RSMD), characterized by limited flexion of dorsolumbar and cervical spine (caused by contractures of spinal extensor muscles) is now considered a form of classic MmD. The majority of individuals with these findings have
• Strength of trunk and neck flexors is usually scored 1 to 2 out of 5, pelvic and shoulder girdle muscles 3 to 4, and distal muscles normal or only moderately weak (3+ to 5). Individuals are usually ambulatory, as limb muscle strength is relatively preserved.
• Facial muscle strength ranges from normal to severe weakness; extraocular muscles are spared.
• Onset is usually congenital or occurs in early childhood with neonatal hypotonia and delayed motor development including head lag, a common and early sign.
• Axial muscle weakness leads to development of scoliosis and major respiratory involvement in approximately two thirds of individuals. Scoliosis develops at a mean age of 8.5 years and is generally cervicodorsal and progressive [
• Rigid spine muscular dystrophy (RSMD), characterized by limited flexion of dorsolumbar and cervical spine (caused by contractures of spinal extensor muscles) is now considered a form of classic MmD. The majority of individuals with these findings have
• Strength of trunk and neck flexors is usually scored 1 to 2 out of 5, pelvic and shoulder girdle muscles 3 to 4, and distal muscles normal or only moderately weak (3+ to 5). Individuals are usually ambulatory, as limb muscle strength is relatively preserved.
• Facial muscle strength ranges from normal to severe weakness; extraocular muscles are spared.
• Individuals may walk well into adulthood despite severe scoliosis and need for ventilatory support. In a few severe cases the disease may progress slowly through adolescence and adulthood, eventually leading to loss of ambulation.
• Death often occurs as a result of respiratory infection in a setting of severe respiratory insufficiency.
• Late onset of the disease is usually associated with better prognosis.
• Onset is usually congenital or occurs in early childhood with neonatal hypotonia and delayed motor development including head lag, a common and early sign.
• Axial muscle weakness leads to development of scoliosis and major respiratory involvement in approximately two thirds of individuals. Scoliosis develops at a mean age of 8.5 years and is generally cervicodorsal and progressive [
• Rigid spine muscular dystrophy (RSMD), characterized by limited flexion of dorsolumbar and cervical spine (caused by contractures of spinal extensor muscles) is now considered a form of classic MmD. The majority of individuals with these findings have
• Strength of trunk and neck flexors is usually scored 1 to 2 out of 5, pelvic and shoulder girdle muscles 3 to 4, and distal muscles normal or only moderately weak (3+ to 5). Individuals are usually ambulatory, as limb muscle strength is relatively preserved.
• Facial muscle strength ranges from normal to severe weakness; extraocular muscles are spared.
## Clinical Description
Multiminicore disease (MmD) is characterized by axial and proximal muscle weakness. It is usually slowly progressive; however, fatal cases have been described. High-arched palate and chest deformities are common.
MmD is broadly classified into four forms [
Classic form
Moderate form, with hand involvement
Antenatal form, with arthrogryposis multiplex congenita
Ophthalmoplegic form
In all forms, males and females are equally affected.
Onset is usually congenital or occurs in early childhood with neonatal hypotonia and delayed motor development including head lag, a common and early sign.
Axial muscle weakness leads to development of scoliosis and major respiratory involvement in approximately two thirds of individuals. Scoliosis develops at a mean age of 8.5 years and is generally cervicodorsal and progressive [
Rigid spine muscular dystrophy (RSMD), characterized by limited flexion of dorsolumbar and cervical spine (caused by contractures of spinal extensor muscles) is now considered a form of classic MmD. The majority of individuals with these findings have
Strength of trunk and neck flexors is usually scored 1 to 2 out of 5, pelvic and shoulder girdle muscles 3 to 4, and distal muscles normal or only moderately weak (3+ to 5). Individuals are usually ambulatory, as limb muscle strength is relatively preserved.
Facial muscle strength ranges from normal to severe weakness; extraocular muscles are spared.
Individuals may walk well into adulthood despite severe scoliosis and need for ventilatory support. In a few severe cases the disease may progress slowly through adolescence and adulthood, eventually leading to loss of ambulation.
Death often occurs as a result of respiratory infection in a setting of severe respiratory insufficiency.
Late onset of the disease is usually associated with better prognosis.
• Classic form
• Moderate form, with hand involvement
• Antenatal form, with arthrogryposis multiplex congenita
• Ophthalmoplegic form
•
• Onset is usually congenital or occurs in early childhood with neonatal hypotonia and delayed motor development including head lag, a common and early sign.
• Axial muscle weakness leads to development of scoliosis and major respiratory involvement in approximately two thirds of individuals. Scoliosis develops at a mean age of 8.5 years and is generally cervicodorsal and progressive [
• Rigid spine muscular dystrophy (RSMD), characterized by limited flexion of dorsolumbar and cervical spine (caused by contractures of spinal extensor muscles) is now considered a form of classic MmD. The majority of individuals with these findings have
• Strength of trunk and neck flexors is usually scored 1 to 2 out of 5, pelvic and shoulder girdle muscles 3 to 4, and distal muscles normal or only moderately weak (3+ to 5). Individuals are usually ambulatory, as limb muscle strength is relatively preserved.
• Facial muscle strength ranges from normal to severe weakness; extraocular muscles are spared.
• Onset is usually congenital or occurs in early childhood with neonatal hypotonia and delayed motor development including head lag, a common and early sign.
• Axial muscle weakness leads to development of scoliosis and major respiratory involvement in approximately two thirds of individuals. Scoliosis develops at a mean age of 8.5 years and is generally cervicodorsal and progressive [
• Rigid spine muscular dystrophy (RSMD), characterized by limited flexion of dorsolumbar and cervical spine (caused by contractures of spinal extensor muscles) is now considered a form of classic MmD. The majority of individuals with these findings have
• Strength of trunk and neck flexors is usually scored 1 to 2 out of 5, pelvic and shoulder girdle muscles 3 to 4, and distal muscles normal or only moderately weak (3+ to 5). Individuals are usually ambulatory, as limb muscle strength is relatively preserved.
• Facial muscle strength ranges from normal to severe weakness; extraocular muscles are spared.
• Individuals may walk well into adulthood despite severe scoliosis and need for ventilatory support. In a few severe cases the disease may progress slowly through adolescence and adulthood, eventually leading to loss of ambulation.
• Death often occurs as a result of respiratory infection in a setting of severe respiratory insufficiency.
• Late onset of the disease is usually associated with better prognosis.
• Onset is usually congenital or occurs in early childhood with neonatal hypotonia and delayed motor development including head lag, a common and early sign.
• Axial muscle weakness leads to development of scoliosis and major respiratory involvement in approximately two thirds of individuals. Scoliosis develops at a mean age of 8.5 years and is generally cervicodorsal and progressive [
• Rigid spine muscular dystrophy (RSMD), characterized by limited flexion of dorsolumbar and cervical spine (caused by contractures of spinal extensor muscles) is now considered a form of classic MmD. The majority of individuals with these findings have
• Strength of trunk and neck flexors is usually scored 1 to 2 out of 5, pelvic and shoulder girdle muscles 3 to 4, and distal muscles normal or only moderately weak (3+ to 5). Individuals are usually ambulatory, as limb muscle strength is relatively preserved.
• Facial muscle strength ranges from normal to severe weakness; extraocular muscles are spared.
## Genotype-Phenotype Correlations
## Nomenclature
Rigid spine muscular dystrophy or rigid spine syndrome are now considered the same entity as severe classic MmD.
## Prevalence
MmD is thought to be rare. Actual prevalence figures are unknown. The disease occurs in diverse ethnic and racial groups.
## Genetically Related (Allelic) Disorders
In a recent study [
Two sibs with CFTD homozygous for a
Three women in one family who were homozygous for the c.943G>A pathogenic variant had similar clinical findings. Only one had a muscle biopsy; it revealed type 1 fibers to be 10.5% smaller than type 2 fibers (for the diagnosis of CFTD, the type 1 fibers should be >12% smaller), consistent with nonspecific myopathy. No histopathologic features of MmD, RSMD, or desmin-related myopathy were found.
It is important to remember that a few cases of CFTD and
One family in whom muscle fibers showed coexistence of minicores, central cores, and a few rod-like structures had a homozygous
Another family homozygous for an
Ten individuals in whom muscle biopsy revealed significant overlap between central cores and minicores were identified to carry compound heterozygous
A missense
• Two sibs with CFTD homozygous for a
• Three women in one family who were homozygous for the c.943G>A pathogenic variant had similar clinical findings. Only one had a muscle biopsy; it revealed type 1 fibers to be 10.5% smaller than type 2 fibers (for the diagnosis of CFTD, the type 1 fibers should be >12% smaller), consistent with nonspecific myopathy. No histopathologic features of MmD, RSMD, or desmin-related myopathy were found.
• One family in whom muscle fibers showed coexistence of minicores, central cores, and a few rod-like structures had a homozygous
• Another family homozygous for an
• Ten individuals in whom muscle biopsy revealed significant overlap between central cores and minicores were identified to carry compound heterozygous
In a recent study [
Two sibs with CFTD homozygous for a
Three women in one family who were homozygous for the c.943G>A pathogenic variant had similar clinical findings. Only one had a muscle biopsy; it revealed type 1 fibers to be 10.5% smaller than type 2 fibers (for the diagnosis of CFTD, the type 1 fibers should be >12% smaller), consistent with nonspecific myopathy. No histopathologic features of MmD, RSMD, or desmin-related myopathy were found.
It is important to remember that a few cases of CFTD and
• Two sibs with CFTD homozygous for a
• Three women in one family who were homozygous for the c.943G>A pathogenic variant had similar clinical findings. Only one had a muscle biopsy; it revealed type 1 fibers to be 10.5% smaller than type 2 fibers (for the diagnosis of CFTD, the type 1 fibers should be >12% smaller), consistent with nonspecific myopathy. No histopathologic features of MmD, RSMD, or desmin-related myopathy were found.
##
One family in whom muscle fibers showed coexistence of minicores, central cores, and a few rod-like structures had a homozygous
Another family homozygous for an
Ten individuals in whom muscle biopsy revealed significant overlap between central cores and minicores were identified to carry compound heterozygous
A missense
• One family in whom muscle fibers showed coexistence of minicores, central cores, and a few rod-like structures had a homozygous
• Another family homozygous for an
• Ten individuals in whom muscle biopsy revealed significant overlap between central cores and minicores were identified to carry compound heterozygous
## Differential Diagnosis
All forms of congenital myopathy have a number of common clinical features: generalized proximal weakness, hypotonia, hyporeflexia, poor muscle bulk, and features secondary to myopathy (e.g., elongated facies, high arched palate, pectus carinatum, scoliosis, foot deformities). Presence of severe rapidly progressive scoliosis favors a diagnosis of classic multiminicore disease (MmD); however, marked clinical overlap exists among MmD and congenital myopathies as well as other neuromuscular disorders including congenital muscular dystrophy. Therefore, the diagnosis of MmD rests on the presence of typical structural changes on muscle biopsy.
Minicore lesions can coexist with central cores, rods or centrally located nuclei, and variable fibrosis. The differential diagnosis in those cases can include central core disease, nemaline myopathy,
Dominant pathogenic variants in
## Management
To establish the extent of disease and needs in an individual diagnosed with multiminicore disease (MmD), the following evaluations are recommended:
Comprehensive respiratory evaluation including assessment of breathing rate, signs of respiratory distress, ability to maintain oxygen saturations, pulmonary function studies, and sleep studies to rule out nocturnal hypoxia
Assessment of feeding abilities including suck, swallow, gastroesophageal reflux, and maintenance of airway while feeding; evaluation of growth parameters to identify failure to thrive and determine need for interventions including gavage feeds and gastrostomy tube insertion
Spinal x-rays to evaluate for presence of scoliosis; physical examination for joint contractures
Cardiac evaluation for cardiomyopathy/cardiac involvement secondary to respiratory complications
Physical and occupational therapy evaluation to develop interventions based on the distribution and extent of weakness
Speech evaluation, especially if dysarthria or hypernasal speech is present
Orthodontic evaluation for palatal anomalies
Consultation with a clinical geneticist and/or genetic counselor
Treatment is aimed at prevention of disease manifestations, early diagnosis by regular screening, and aggressive management of complications that may develop. Effective treatment requires a multidisciplinary approach that can improve both quality of life and survival for the affected individual.
Ongoing careful assessment of the potential need for part-time or permanent respiratory support is absolutely critical, as affected individuals may rapidly enter respiratory crisis or may unknowingly suffer from potentially fatal nocturnal hypoventilation.
Feeding support with tube/gavage feeds is needed if oral intake is poor. Failure to thrive may need to be overcome with high-caloric density formulas/feeds. Gastroesophageal reflux (if present) is treated in the usual manner.
Physical and occupational therapy may help to improve/maintain gross motor and fine motor functions.
Speech therapy should be provided for individuals with dysarthria/hypernasal speech.
Annual influenza and other respiratory infection-related immunizations are advised.
Aggressive treatment of lower respiratory infections is critical.
Monitoring for potential complications that can influence the prognosis of MmD includes the following:
Frequent and regular monitoring of the spine particularly during childhood and adolescence when scoliosis can rapidly progress during the adolescent growth spurt
Careful monitoring of respiratory function from an early stage because of the risk for insidious nocturnal hypoxia and sudden respiratory failure. Monitoring of respiratory function should include the following:
Close attention to nocturnal hypoventilation symptoms including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance
Lung function tests (FEV1 and FVC)
Sleep studies
Assessment of the need for intermittent or permanent ventilation. Nocturnal ventilation, when indicated, may significantly improve the prognosis.
Assessment of cardiac status because of the risk of cardiac impairment secondary to respiratory involvement
Growth should be assessed regularly.
Regular neuromuscular evaluation to assess disease progress is indicated.
See
In women with MmD, there is risk for malignant hyperthermia during delivery if inhalational anesthetic agents are used. A woman who has a fetus affected by MmD may develop polyhydramnios during pregnancy and may report a history of poor fetal movements. Abnormal presentation of an affected fetus may complicate delivery.
Search
• Comprehensive respiratory evaluation including assessment of breathing rate, signs of respiratory distress, ability to maintain oxygen saturations, pulmonary function studies, and sleep studies to rule out nocturnal hypoxia
• Assessment of feeding abilities including suck, swallow, gastroesophageal reflux, and maintenance of airway while feeding; evaluation of growth parameters to identify failure to thrive and determine need for interventions including gavage feeds and gastrostomy tube insertion
• Spinal x-rays to evaluate for presence of scoliosis; physical examination for joint contractures
• Cardiac evaluation for cardiomyopathy/cardiac involvement secondary to respiratory complications
• Physical and occupational therapy evaluation to develop interventions based on the distribution and extent of weakness
• Speech evaluation, especially if dysarthria or hypernasal speech is present
• Orthodontic evaluation for palatal anomalies
• Consultation with a clinical geneticist and/or genetic counselor
• Frequent and regular monitoring of the spine particularly during childhood and adolescence when scoliosis can rapidly progress during the adolescent growth spurt
• Careful monitoring of respiratory function from an early stage because of the risk for insidious nocturnal hypoxia and sudden respiratory failure. Monitoring of respiratory function should include the following:
• Close attention to nocturnal hypoventilation symptoms including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance
• Lung function tests (FEV1 and FVC)
• Sleep studies
• Assessment of the need for intermittent or permanent ventilation. Nocturnal ventilation, when indicated, may significantly improve the prognosis.
• Close attention to nocturnal hypoventilation symptoms including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance
• Lung function tests (FEV1 and FVC)
• Sleep studies
• Assessment of the need for intermittent or permanent ventilation. Nocturnal ventilation, when indicated, may significantly improve the prognosis.
• Assessment of cardiac status because of the risk of cardiac impairment secondary to respiratory involvement
• Close attention to nocturnal hypoventilation symptoms including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance
• Lung function tests (FEV1 and FVC)
• Sleep studies
• Assessment of the need for intermittent or permanent ventilation. Nocturnal ventilation, when indicated, may significantly improve the prognosis.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with multiminicore disease (MmD), the following evaluations are recommended:
Comprehensive respiratory evaluation including assessment of breathing rate, signs of respiratory distress, ability to maintain oxygen saturations, pulmonary function studies, and sleep studies to rule out nocturnal hypoxia
Assessment of feeding abilities including suck, swallow, gastroesophageal reflux, and maintenance of airway while feeding; evaluation of growth parameters to identify failure to thrive and determine need for interventions including gavage feeds and gastrostomy tube insertion
Spinal x-rays to evaluate for presence of scoliosis; physical examination for joint contractures
Cardiac evaluation for cardiomyopathy/cardiac involvement secondary to respiratory complications
Physical and occupational therapy evaluation to develop interventions based on the distribution and extent of weakness
Speech evaluation, especially if dysarthria or hypernasal speech is present
Orthodontic evaluation for palatal anomalies
Consultation with a clinical geneticist and/or genetic counselor
• Comprehensive respiratory evaluation including assessment of breathing rate, signs of respiratory distress, ability to maintain oxygen saturations, pulmonary function studies, and sleep studies to rule out nocturnal hypoxia
• Assessment of feeding abilities including suck, swallow, gastroesophageal reflux, and maintenance of airway while feeding; evaluation of growth parameters to identify failure to thrive and determine need for interventions including gavage feeds and gastrostomy tube insertion
• Spinal x-rays to evaluate for presence of scoliosis; physical examination for joint contractures
• Cardiac evaluation for cardiomyopathy/cardiac involvement secondary to respiratory complications
• Physical and occupational therapy evaluation to develop interventions based on the distribution and extent of weakness
• Speech evaluation, especially if dysarthria or hypernasal speech is present
• Orthodontic evaluation for palatal anomalies
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Treatment is aimed at prevention of disease manifestations, early diagnosis by regular screening, and aggressive management of complications that may develop. Effective treatment requires a multidisciplinary approach that can improve both quality of life and survival for the affected individual.
Ongoing careful assessment of the potential need for part-time or permanent respiratory support is absolutely critical, as affected individuals may rapidly enter respiratory crisis or may unknowingly suffer from potentially fatal nocturnal hypoventilation.
Feeding support with tube/gavage feeds is needed if oral intake is poor. Failure to thrive may need to be overcome with high-caloric density formulas/feeds. Gastroesophageal reflux (if present) is treated in the usual manner.
Physical and occupational therapy may help to improve/maintain gross motor and fine motor functions.
Speech therapy should be provided for individuals with dysarthria/hypernasal speech.
## Prevention of Secondary Complications
Annual influenza and other respiratory infection-related immunizations are advised.
Aggressive treatment of lower respiratory infections is critical.
## Surveillance
Monitoring for potential complications that can influence the prognosis of MmD includes the following:
Frequent and regular monitoring of the spine particularly during childhood and adolescence when scoliosis can rapidly progress during the adolescent growth spurt
Careful monitoring of respiratory function from an early stage because of the risk for insidious nocturnal hypoxia and sudden respiratory failure. Monitoring of respiratory function should include the following:
Close attention to nocturnal hypoventilation symptoms including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance
Lung function tests (FEV1 and FVC)
Sleep studies
Assessment of the need for intermittent or permanent ventilation. Nocturnal ventilation, when indicated, may significantly improve the prognosis.
Assessment of cardiac status because of the risk of cardiac impairment secondary to respiratory involvement
Growth should be assessed regularly.
Regular neuromuscular evaluation to assess disease progress is indicated.
• Frequent and regular monitoring of the spine particularly during childhood and adolescence when scoliosis can rapidly progress during the adolescent growth spurt
• Careful monitoring of respiratory function from an early stage because of the risk for insidious nocturnal hypoxia and sudden respiratory failure. Monitoring of respiratory function should include the following:
• Close attention to nocturnal hypoventilation symptoms including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance
• Lung function tests (FEV1 and FVC)
• Sleep studies
• Assessment of the need for intermittent or permanent ventilation. Nocturnal ventilation, when indicated, may significantly improve the prognosis.
• Close attention to nocturnal hypoventilation symptoms including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance
• Lung function tests (FEV1 and FVC)
• Sleep studies
• Assessment of the need for intermittent or permanent ventilation. Nocturnal ventilation, when indicated, may significantly improve the prognosis.
• Assessment of cardiac status because of the risk of cardiac impairment secondary to respiratory involvement
• Close attention to nocturnal hypoventilation symptoms including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance
• Lung function tests (FEV1 and FVC)
• Sleep studies
• Assessment of the need for intermittent or permanent ventilation. Nocturnal ventilation, when indicated, may significantly improve the prognosis.
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
See
## Pregnancy Management
In women with MmD, there is risk for malignant hyperthermia during delivery if inhalational anesthetic agents are used. A woman who has a fetus affected by MmD may develop polyhydramnios during pregnancy and may report a history of poor fetal movements. Abnormal presentation of an affected fetus may complicate delivery.
## Therapies Under Investigation
Search
## Genetic Counseling
Multiminicore disease (MmD) is most often inherited in an autosomal recessive manner [
Note: Monoallelic expression of just the mutated allele in skeletal muscle has been seen in some persons heterozygous at the genomic DNA level for recessive
The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
Carriers (heterozygotes) are asymptomatic.
Carrier testing for at-risk family members is possible once the pathogenic variants in the family have been identified.
Note: Pseudodominant inheritance is more likely to occur in autosomal recessive disorders with a high carrier frequency (e.g., in populations/families with high rates of consanguinity).
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
• The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
• Carriers (heterozygotes) are asymptomatic.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Multiminicore disease (MmD) is most often inherited in an autosomal recessive manner [
Note: Monoallelic expression of just the mutated allele in skeletal muscle has been seen in some persons heterozygous at the genomic DNA level for recessive
## Risk to Family Members
The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
Carriers (heterozygotes) are asymptomatic.
• The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
• Carriers (heterozygotes) are asymptomatic.
## Carrier (Heterozygote) Detection
Carrier testing for at-risk family members is possible once the pathogenic variants in the family have been identified.
## Related Genetic Counseling Issues
Note: Pseudodominant inheritance is more likely to occur in autosomal recessive disorders with a high carrier frequency (e.g., in populations/families with high rates of consanguinity).
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Diagnosis
Once the
## Resources
P.O. Box 13312
Pittsburgh PA 15243
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
19401 South Vermont Avenue
Suite J100
Torrance CA 90502
•
• P.O. Box 13312
• Pittsburgh PA 15243
•
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
•
•
• 19401 South Vermont Avenue
• Suite J100
• Torrance CA 90502
•
## Molecular Genetics
Multiminicore Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Multiminicore Disease (
Up to two thirds of pathogenic variants cause premature termination of translation; the remaining pathogenic variants are missense changes. Variants appear to be distributed throughout the gene.
Selenoprotein N has an EF hand Ca
Up to two thirds of pathogenic variants cause premature termination of translation; the remaining pathogenic variants are missense changes. Variants appear to be distributed throughout the gene.
Selenoprotein N has an EF hand Ca
##
## References
## Literature Cited
## Chapter Notes
Web page:
The authors gratefully acknowledge generous support by the Lee and Penny Anderson Family Foundation and the Muscular Dystrophy Association (USA) for ongoing research on multiminicore disease.
18 April 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
24 January 2013 (me) Comprehensive update posted live
10 April 2008 (me) Comprehensive update posted live
10 January 2006 (cd) Revision:
26 July 2005 (me) Comprehensive update posted live
25 March 2003 (me) Review posted live
6 December 2002 (ab) Original submission
• 18 April 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 24 January 2013 (me) Comprehensive update posted live
• 10 April 2008 (me) Comprehensive update posted live
• 10 January 2006 (cd) Revision:
• 26 July 2005 (me) Comprehensive update posted live
• 25 March 2003 (me) Review posted live
• 6 December 2002 (ab) Original submission
## Author Notes
Web page:
## Acknowledgments
The authors gratefully acknowledge generous support by the Lee and Penny Anderson Family Foundation and the Muscular Dystrophy Association (USA) for ongoing research on multiminicore disease.
## Revision History
18 April 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
24 January 2013 (me) Comprehensive update posted live
10 April 2008 (me) Comprehensive update posted live
10 January 2006 (cd) Revision:
26 July 2005 (me) Comprehensive update posted live
25 March 2003 (me) Review posted live
6 December 2002 (ab) Original submission
• 18 April 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 24 January 2013 (me) Comprehensive update posted live
• 10 April 2008 (me) Comprehensive update posted live
• 10 January 2006 (cd) Revision:
• 26 July 2005 (me) Comprehensive update posted live
• 25 March 2003 (me) Review posted live
• 6 December 2002 (ab) Original submission
|
[
"PB Agrawal, RS Greenleaf, KK Tomczak, VL Lehtokari, C Wallgren-Pettersson, W Wallefeld, NG Laing, BT Darras, SK Maciver, PR Dormitzer, AH Beggs. Nemaline myopathy with minicores caused by mutation of the CFL2 gene encoding the skeletal muscle actin-binding protein, cofilin-2.. Am J Hum Genet. 2007;80:162-7",
"CG Bönnemann, TG Thompson, PF van der Ven, HH Goebel, I Warlo, B Vollmers, J Reimann, J Herms, M Gautel, F Takada, AH Beggs, DO Fürst, LM Kunkel, F Hanefeld, R Schröder. Filamin C accumulation is a strong but nonspecific immunohistochemical marker of core formation in muscle.. J Neurol Sci. 2003;206:71-8",
"NF Clarke, W Kidson, S Quijano-Roy, B Estournet, A Ferreiro, P Guicheney, JI Manson, AJ Kornberg, LK Shield, KN North. SEPN1: associated with congenital fiber-type disproportion and insulin resistance.. Ann Neurol. 2006;59:546-52",
"NF Clarke, LB Waddell, ST Cooper, M Perry, RL Smith, AJ Kornberg, F Muntoni, S Lillis, V Straub, K Bushby, M Guglieri, MD King, MA Farrell, I Marty, J Lunardi, N Monnier, KN North. Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion.. Hum Mutat. 2010;31:E1544-50",
"T Cullup, PJ Lamont, S Cirak, MS Damian, W Wallefeld, R Gooding, SV Tan, J Sheehan, F Muntoni, S Abbs, CA Sewry, V Dubowitz, NG Laing, H Jungbluth. Mutations in MYH7 cause Multi-minicore Disease (MmD) with variable cardiac involvement.. Neuromuscul Disord. 2012;22:1096-104",
"S Ducreux, F Zorzato, A Ferreiro, H Jungbluth, F Muntoni, N Monnier, CR Müller, S Treves. Functional properties of ryanodine receptors carrying three amino acid substitutions identified in patients affected by multi-minicore disease and central core disease, expressed in immortalized lymphocytes.. Biochem J. 2006;395:259-66",
"AF Dulhunty, NA Beard, P Pouliquin, T Kimura. Novel regulators of RyR Ca2+ release channels: insight into molecular changes in genetically-linked myopathies.. J Muscle Res Cell Motil. 2006;27:351-65",
"A Ferreiro, C Ceuterick-de Groote, JJ Marks, N Goemans, G Schreiber, F Hanefeld, M Fardeau, JJ Martin, HH Goebel, P Richard, P Guicheney, CG Bönnemann. Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene.. Ann Neurol. 2004;55:676-86",
"A Ferreiro, B Estournet, D Chateau, NB Romero, C Laroche, S Odent, A Toutain, A Cabello, D Fontan, HG dos Santos, CA Haenggeli, E Bertini, JA Urtizberea, P Guicheney, M Fardeau. Multi-minicore disease--searching for boundaries: phenotype analysis of 38 cases.. Ann Neurol. 2000;48:745-57",
"A Ferreiro, M. Fardeau. 80th ENMC International Workshop on Multi-Minicore Disease: 1st International MmD Workshop. 12-13th May, 2000, Soestduinen, The Netherlands.. Neuromuscul Disord. 2002;12:60-8",
"A Ferreiro, N Monnier, NB Romero, JP Leroy, C Bönnemann, CA Haenggeli, V Straub, WD Voss, Y Nivoche, H Jungbluth, A Lemainque, T Voit, J Lunardi, M Fardeau, P Guicheney. A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene.. Ann Neurol. 2002a;51:750-9",
"A Ferreiro, S Quijano-Roy, C Pichereau, B Moghadaszadeh, N Goemans, C Bönnemann, H Jungbluth, V Straub, M Villanova, JP Leroy, NB Romero, JJ Martin, F Muntoni, T Voit, B Estournet, P Richard, M Fardeau, P Guicheney. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies.. Am J Hum Genet. 2002b;71:739-49",
"D Fischer, J Matten, J Reimann, C Bönnemann, R Schröder. Expression, localization and functional divergence of alphaB-crystallin and heat shock protein 27 in core myopathies and neurogenic atrophy.. Acta Neuropathol. 2002;104:297-304",
"IM Gommans, M Davis, K Saar, M Lammens, F Mastaglia, P Lamont, G van Duijnhoven, HJ ter Laak, A Reis, OJ Vogels, N Laing, BG van Engelen, H Kremer. A locus on chromosome 15q for a dominantly inherited nemaline myopathy with core-like lesions.. Brain. 2003;126:1545-51",
"S Guis, D Figarella-Branger, N Monnier, D Bendahan, G Kozak-Ribbens, JP Mattei, J Lunardi, PJ Cozzone, JF Pellissier. Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization.. Arch Neurol. 2004;61:106-13",
"H Jungbluth, CR Müller, B Halliger-Keller, M Brockington, SC Brown, L Feng, A Chattopadhyay, E Mercuri, AY Manzur, A Ferreiro, NG Laing, MR Davis, HP Roper, V Dubowitz, G Bydder, CA Sewry, F Muntoni. Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores.. Neurology. 2002;59:284-7",
"H Jungbluth, C Sewry, SC Brown, AY Manzur, E Mercuri, K Bushby, P Rowe, MA Johnson, I Hughes, A Kelsey, V Dubowitz, F Muntoni. Minicore myopathy in children: a clinical and histopathological study of 19 cases.. Neuromuscul Disord. 2000;10:264-73",
"H Jungbluth, CA Sewry, SC Brown, KJ Nowak, NG Laing, C Wallgren-Pettersson, K Pelin, AY Manzur, E Mercuri, V Dubowitz, F Muntoni. Mild phenotype of nemaline myopathy with sleep hypoventilation due to a mutation in the skeletal muscle alpha-actin (ACTA1) gene.. Neuromuscul Disord. 2001;11:35-40",
"H Jungbluth, H Zhou, L Hartley, B Halliger-Keller, S Messina, C Longman, M Brockington, SA Robb, V Straub, T Voit, M Swash, A Ferreiro, G Bydder, CA Sewry, C Müller, F Muntoni. Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene.. Neurology. 2005;65:1930-5",
"AM Kaindl, F Rüschendorf, S Krause, HH Goebel, K Koehler, C Becker, D Pongratz, J Müller-Höcker, P Nürnberg, G Stoltenburg-Didinger, H Lochmüller, A Huebner. Missense mutations of ACTA1 cause dominant congenital myopathy with cores.. J Med Genet. 2004;41:842-8",
"B Moghadaszadeh, N Petit, C Jaillard, M Brockington, S Quijano Roy, L Merlini, N Romero, B Estournet, I Desguerre, D Chaigne, F Muntoni, H Topaloglu, P. Guicheney. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome.. Nat Genet. 2001;29:17-8",
"N Monnier, A Ferreiro, I Marty, A Labarre-Vila, P Mezin, J. Lunardi. A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia.. Hum Mol Genet. 2003;12:1171-8",
"N Monnier, I Marty, J Faure, C Castiglioni, C Desnuelle, S Sacconi, B Estournet, A Ferreiro, N Romero, A Laquerriere, L Lazaro, JJ Martin, E Morava, A Rossi, A Van der Kooi, M de Visser, C Verschuuren, J Lunardi. Null mutations causing depletion of the type 1 ryanodine receptor (RYR1) are commonly associated with recessive structural congenital myopathies with cores.. Hum Mutat. 2008;29:670-8",
"N Monnier, NB Romero, J Lerale, P Landrieu, Y Nivoche, M Fardeau, J Lunardi. Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor.. Hum Mol Genet. 2001;10:2581-92",
"A Nadaj-Pakleza, A Fidziańska, B Ryniewicz, A Kostera-Pruszczyk, A Ferreiro, H Kwieciński, A. Kamińska. Multi-minicore myopathy: a clinical and histopathological study of 17 cases.. Folia Neuropathol. 2007;45:56-65",
"Y Okamoto, H Takashima, I Higuchi, W Matsuyama, M Suehara, Y Nishihira, A Hashiguchi, R Hirano, AR Ng, M Nakagawa, S Izumo, M Osame, K Arimura. Molecular mechanism of rigid spine with muscular dystrophy type 1 caused by novel mutations of selenoprotein N gene.. Neurogenetics. 2006;7:175-83",
"PC Scacheri, EP Hoffman, JD Fratkin, C Semino-Mora, A Senchak, MR Davis, NG Laing, V Vedanarayanan, SH Subramony. A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy.. Neurology. 2000;55:1689-96",
"H Tajsharghi, N Darin, M Tulinius, A Oldfors. Early onset myopathy with a novel mutation in the Selenoprotein N gene (SEPN1).. Neuromuscul Disord. 2005;15:299-302",
"N Tilgen, F Zorzato, B Halliger-Keller, F Muntoni, C Sewry, LM Palmucci, C Schneider, E Hauser, F Lehmann-Horn, CR Müller, S Treves. Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis.. Hum Mol Genet. 2001;10:2879-87",
"JM Wilmshurst, S Lillis, H Zhou, K Pillay, H Henderson, W Kress, CR Müller, A Ndondo, V Cloke, T Cullup, E Bertini, C Boennemann, V Straub, R Quinlivan, JJ Dowling, S Al-Sarraj, S Treves, S Abbs, AY Manzur, CA Sewry, F Muntoni, H Jungbluth. RYR1 mutations are a common cause of congenital myopathies with central nuclei.. Ann Neurol. 2010;68:717-26",
"S Wu, MC Ibarra, MC Malicdan, K Murayama, Y Ichihara, H Kikuchi, I Nonaka, S Noguchi, YK Hayashi, I Nishino. Central core disease is due to RYR1 mutations in more than 90% of patients.. Brain. 2006;129:1470-80",
"H Zhou, M Brockington, H Jungbluth, D Monk, P Stanier, CA Sewry, GE Moore, F Muntoni. Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies.. Am J Hum Genet. 2006;79:859-68",
"H Zhou, H Jungbluth, CA Sewry, L Feng, E Bertini, K Bushby, V Straub, H Roper, MR Rose, M Brockington, M Kinali, A Manzur, S Robb, R Appleton, S Messina, A D'Amico, R Quinlivan, M Swash, CR Müller, S Brown, S Treves, F Muntoni. Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies.. Brain. 2007;130:2024-36",
"F Zorzato, H Jungbluth, H Zhou, F Muntoni, S Treves. Functional effects of mutations identified in patients with multiminicore disease.. IUBMB Life. 2007;59:14-20"
] |
25/3/2003
|
24/1/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mmihs-ov
|
mmihs-ov
|
[
"Berdon Syndrome",
"MMHS",
"Berdon Syndrome",
"Actin, gamma-enteric smooth muscle",
"Leiomodin-1",
"Myosin light chain kinase, smooth muscle",
"Myosin regulatory light polypeptide 9",
"Myosin-11",
"Phosducin-like protein 3",
"Plasma membrane calcium-transporting ATPase 4",
"ACTG2",
"ATP2B4",
"LMOD1",
"MYH11",
"MYL9",
"MYLK",
"PDCL3",
"Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome",
"Overview"
] |
Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome Overview
|
Lusine Ambartsumyan
|
Summary The purpose of this overview is to: Describe the Review the Provide an Review Inform
|
## Clinical Characteristics of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by megacystis (bladder distention in the absence of mechanical obstruction), microcolon, and intestinal hypoperistalsis (dysmotility). This rare disorder is associated with significant morbidity and mortality.
MMIHS may be suspected prenatally secondary to findings of fetal megacystis on prenatal ultrasound. Affected infants present shortly after birth with symptoms of bowel and bladder obstruction. The most common presenting symptom is abdominal distention that is secondary to a massively dilated bladder in the absence of mechanical obstruction with or without dilated bowel loops. Other manifestations include bilious emesis, failure to pass meconium, and inability to spontaneously void requiring catheterization [
Infants and children with MMIHS have myopathic dysfunction of bladder and associated urologic comorbidities that include urinary retention, febrile urinary tract infections, vesicoureteral reflux (VUR), and hydronephrosis with resultant risk of kidney failure [
Intestinal dysfunction ultimately leads to nutritional compromise and intestinal failure resulting in dependence on total parenteral nutrition (TPN). Subsequently individuals may develop complications from TPN including central line infections, liver dysfunction, and liver failure. Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN as a result of liver failure or inability to maintain central venous access [
The prognosis for individuals with MMIHS, in light of its variable genetic causes, has not been well elucidated. Data on individuals prior to molecular diagnosis suggest a poor and often fatal prognosis especially within the first year of life. Sepsis followed by multiorgan failure and malnutrition have been reported as the most frequent causes of death [
Specialized centers with multidisciplinary care, intestinal rehabilitation, TPN management, and multivisceral transplantation have been credited for improving survival rates from 12.6% (1976-2004) to 55.6% (2004-2011) [
In a recent single-center long-term follow up of children with and without intestinal transplant, survival at five, ten, and 20 years was 100%, 100%, and 86%, respectively [
In a systematic review, prenatal diagnosis of MMIHS was suspected in 26% of individuals using prenatal ultrasound findings [
Grossly dilated bladder with or without hydroureteronephrosis in the setting of normal or increased amniotic fluid volume may be found on the second trimester prenatal ultrasound [
Gastrointestinal abnormalities on prenatal ultrasound are less common (24%) and include gastric distention (visible in the second trimester) and dilated bowel loops (visible in the third trimester) [
Dilated esophagus and microcolon have been reported using fetal MRI [
Abdominal distention
Absent or decreased bowel sounds
Bilious emesis
Failure to pass meconium
Inability to void requiring catheterization
Abdominal radiograph shows gastric distention and dilatation of small bowel loops with paucity of distal gas [
Fluoroscopic upper-gastrointestinal series reveals dilated stomach and small intestine with associated malrotation [
Contrast enema demonstrates a small-caliber colon (microcolon) and may show an associated malrotation [
Urologic findings on kidney/bladder ultrasound and cystography include a dilated bladder with large capacity, hydroureteronephrosis, and VUR. [
Differential Diagnosis of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
VACTERL = (
Isolated (without additional features of MMIHS)
• Abdominal distention
• Absent or decreased bowel sounds
• Bilious emesis
• Failure to pass meconium
• Inability to void requiring catheterization
• Abdominal radiograph shows gastric distention and dilatation of small bowel loops with paucity of distal gas [
• Fluoroscopic upper-gastrointestinal series reveals dilated stomach and small intestine with associated malrotation [
• Contrast enema demonstrates a small-caliber colon (microcolon) and may show an associated malrotation [
• Urologic findings on kidney/bladder ultrasound and cystography include a dilated bladder with large capacity, hydroureteronephrosis, and VUR. [
## Establishing the Clinical Diagnosis of MMIHS
In a systematic review, prenatal diagnosis of MMIHS was suspected in 26% of individuals using prenatal ultrasound findings [
Grossly dilated bladder with or without hydroureteronephrosis in the setting of normal or increased amniotic fluid volume may be found on the second trimester prenatal ultrasound [
Gastrointestinal abnormalities on prenatal ultrasound are less common (24%) and include gastric distention (visible in the second trimester) and dilated bowel loops (visible in the third trimester) [
Dilated esophagus and microcolon have been reported using fetal MRI [
Abdominal distention
Absent or decreased bowel sounds
Bilious emesis
Failure to pass meconium
Inability to void requiring catheterization
Abdominal radiograph shows gastric distention and dilatation of small bowel loops with paucity of distal gas [
Fluoroscopic upper-gastrointestinal series reveals dilated stomach and small intestine with associated malrotation [
Contrast enema demonstrates a small-caliber colon (microcolon) and may show an associated malrotation [
Urologic findings on kidney/bladder ultrasound and cystography include a dilated bladder with large capacity, hydroureteronephrosis, and VUR. [
• Abdominal distention
• Absent or decreased bowel sounds
• Bilious emesis
• Failure to pass meconium
• Inability to void requiring catheterization
• Abdominal radiograph shows gastric distention and dilatation of small bowel loops with paucity of distal gas [
• Fluoroscopic upper-gastrointestinal series reveals dilated stomach and small intestine with associated malrotation [
• Contrast enema demonstrates a small-caliber colon (microcolon) and may show an associated malrotation [
• Urologic findings on kidney/bladder ultrasound and cystography include a dilated bladder with large capacity, hydroureteronephrosis, and VUR. [
## Prenatal Imaging Features of MMIHS
In a systematic review, prenatal diagnosis of MMIHS was suspected in 26% of individuals using prenatal ultrasound findings [
Grossly dilated bladder with or without hydroureteronephrosis in the setting of normal or increased amniotic fluid volume may be found on the second trimester prenatal ultrasound [
Gastrointestinal abnormalities on prenatal ultrasound are less common (24%) and include gastric distention (visible in the second trimester) and dilated bowel loops (visible in the third trimester) [
Dilated esophagus and microcolon have been reported using fetal MRI [
## Postnatal Clinical and Imaging Features of MMIHS
Abdominal distention
Absent or decreased bowel sounds
Bilious emesis
Failure to pass meconium
Inability to void requiring catheterization
Abdominal radiograph shows gastric distention and dilatation of small bowel loops with paucity of distal gas [
Fluoroscopic upper-gastrointestinal series reveals dilated stomach and small intestine with associated malrotation [
Contrast enema demonstrates a small-caliber colon (microcolon) and may show an associated malrotation [
Urologic findings on kidney/bladder ultrasound and cystography include a dilated bladder with large capacity, hydroureteronephrosis, and VUR. [
• Abdominal distention
• Absent or decreased bowel sounds
• Bilious emesis
• Failure to pass meconium
• Inability to void requiring catheterization
• Abdominal radiograph shows gastric distention and dilatation of small bowel loops with paucity of distal gas [
• Fluoroscopic upper-gastrointestinal series reveals dilated stomach and small intestine with associated malrotation [
• Contrast enema demonstrates a small-caliber colon (microcolon) and may show an associated malrotation [
• Urologic findings on kidney/bladder ultrasound and cystography include a dilated bladder with large capacity, hydroureteronephrosis, and VUR. [
## Differential Diagnosis of MMIHS
Differential Diagnosis of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
VACTERL = (
Isolated (without additional features of MMIHS)
## Genetic Causes of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: Genes and Distinguishing Clinical Features
Overlapping features of MMIHS & prune belly sequence (1 person)
Overlapping features of MMIHS & MSMDS (1 person)
Mydriasis
No vascular smooth muscle dysfunction
AD = autosomal dominant; AR = autosomal recessive; del/dups = deletions/duplications; MMIHS = megacystis-microcolon-intestinal hypoperistalsis syndrome; MOI = mode of inheritance; MSMDS = multisystemic smooth muscle dysfunction syndrome; NA = not applicable
Genes are listed alphabetically.
Vascular smooth muscle dysfunction including aortic aneurysms or dissection has not been reported.
One reported individual resulted in fetal death, and one was terminated during pregnancy.
A heterozygous variant in
• Overlapping features of MMIHS & prune belly sequence (1 person)
• Overlapping features of MMIHS & MSMDS (1 person)
• Mydriasis
• No vascular smooth muscle dysfunction
## Evaluation Strategy to Identify the Genetic Cause of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
Establishing a specific genetic cause of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS):
Can aid in discussions of prognosis (which are beyond the scope of this
Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
Fetal megacystis on prenatal ultrasound in the setting of normal or increased amniotic fluid specifically in the second or third trimester of pregnancy
Clinical symptoms of bowel and bladder obstruction shortly after birth characterized by abdominal distention, abnormal bowel sounds, bilious emesis, failure to pass meconium, and inability to void spontaneously requiring catheterization [
Manifestations of MMIHS, bowel/bladder dysfunction, chronic intestinal pseudo-obstruction (CIPO), and multisystemic smooth muscle dysfunction syndrome (MSMDS), as well as familial forms of myopathy, neuropathy, mitochondrial diseases, and other conditions that affect the enteric nervous system or smooth muscle
Parental consanguinity
Recurrent fetal loss
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Can aid in discussions of prognosis (which are beyond the scope of this
• Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
• Fetal megacystis on prenatal ultrasound in the setting of normal or increased amniotic fluid specifically in the second or third trimester of pregnancy
• Clinical symptoms of bowel and bladder obstruction shortly after birth characterized by abdominal distention, abnormal bowel sounds, bilious emesis, failure to pass meconium, and inability to void spontaneously requiring catheterization [
• Manifestations of MMIHS, bowel/bladder dysfunction, chronic intestinal pseudo-obstruction (CIPO), and multisystemic smooth muscle dysfunction syndrome (MSMDS), as well as familial forms of myopathy, neuropathy, mitochondrial diseases, and other conditions that affect the enteric nervous system or smooth muscle
• Parental consanguinity
• Recurrent fetal loss
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
To establish the extent of disease and needs in an individual diagnosed with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Urodynamic studies to evaluate the degree of bladder dysfunction (e.g., enlarged bladder capacity for age, detrusor acontractility with failure to empty) [
Voiding cystourethrogram to evaluate for outlet obstruction, vesicoureteral reflux (VUR), and bladder capacity [
Kidney and bladder ultrasound to evaluate for hydronephrosis and renal parenchyma
Laboratory evaluation of kidney function (blood urea nitrogen, creatinine, glomerular filtration rate) and electrolytes (potassium, phosphorus, calcium)
Bowel imaging: abdominal radiograph, contrast enema, and fluoroscopic upper gastrointestinal series. Computed tomography examination of the abdomen may be indicated to evaluate for a mechanical obstruction.
Laboratory monitoring of liver enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase), cholestasis (total and direct bilirubin), and liver function (prothrombin time, partial thromboplastin time, international normalized ratio, albumin)
Laboratory evaluation of macronutrient (carbohydrates, fat, protein) and micronutrient (vitamins, minerals) deficiencies in the setting of intestinal dysfunction and progressive malabsorption
Nutrition evaluation and close monitoring of growth parameters
Surgical interventions such as enterostomies (e.g., gastrostomy, jejunostomy) for nutrition administration and proximal bowel decompression [
Bowel diversion (e.g., ileostomy, colostomy) for distal bowel decompression [
Total parenteral nutrition (TPN) when appropriate for malnutrition as a result of intestinal failure from intestinal dysmotility
Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN because of complications (e.g., liver dysfunction and cholestasis, lack of adequate central venous access, recurrent central line-associated bloodstream infections) [
Referral to cardiologist and monitoring for pulmonary hypertension, aortic dilatation, and patent ductus arteriosus
Referral to neurologist for evaluation for abnormal cerebral vasculature [
The prognosis for individuals with MMIHS in light of its variable genetic causes has not been well elucidated. Data on individuals prior to molecular diagnosis suggests a poor and often fatal prognosis within the first year of life.
The evaluation and management are primarily supportive. Specialized centers offer multidisciplinary medical and surgical models of care including comprehensive TPN management and multivisceral transplantation.
Goals of bladder management include bladder decompression and subsequent monitoring and prevention of kidney failure.
Goals of bowel management include providing means of nutrition in the setting of intestinal dysmotility via enteral or parenteral means while monitoring for nutritional failure and TPN-associated complications (line infections, liver disease).
Treatment/medications to be avoided or limited include those that diminish bowel and bladder motility.
Search
• Urodynamic studies to evaluate the degree of bladder dysfunction (e.g., enlarged bladder capacity for age, detrusor acontractility with failure to empty) [
• Voiding cystourethrogram to evaluate for outlet obstruction, vesicoureteral reflux (VUR), and bladder capacity [
• Kidney and bladder ultrasound to evaluate for hydronephrosis and renal parenchyma
• Laboratory evaluation of kidney function (blood urea nitrogen, creatinine, glomerular filtration rate) and electrolytes (potassium, phosphorus, calcium)
• Bowel imaging: abdominal radiograph, contrast enema, and fluoroscopic upper gastrointestinal series. Computed tomography examination of the abdomen may be indicated to evaluate for a mechanical obstruction.
• Laboratory monitoring of liver enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase), cholestasis (total and direct bilirubin), and liver function (prothrombin time, partial thromboplastin time, international normalized ratio, albumin)
• Laboratory evaluation of macronutrient (carbohydrates, fat, protein) and micronutrient (vitamins, minerals) deficiencies in the setting of intestinal dysfunction and progressive malabsorption
• Nutrition evaluation and close monitoring of growth parameters
• Surgical interventions such as enterostomies (e.g., gastrostomy, jejunostomy) for nutrition administration and proximal bowel decompression [
• Bowel diversion (e.g., ileostomy, colostomy) for distal bowel decompression [
• Total parenteral nutrition (TPN) when appropriate for malnutrition as a result of intestinal failure from intestinal dysmotility
• Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN because of complications (e.g., liver dysfunction and cholestasis, lack of adequate central venous access, recurrent central line-associated bloodstream infections) [
• Referral to cardiologist and monitoring for pulmonary hypertension, aortic dilatation, and patent ductus arteriosus
• Referral to neurologist for evaluation for abnormal cerebral vasculature [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Urodynamic studies to evaluate the degree of bladder dysfunction (e.g., enlarged bladder capacity for age, detrusor acontractility with failure to empty) [
Voiding cystourethrogram to evaluate for outlet obstruction, vesicoureteral reflux (VUR), and bladder capacity [
Kidney and bladder ultrasound to evaluate for hydronephrosis and renal parenchyma
Laboratory evaluation of kidney function (blood urea nitrogen, creatinine, glomerular filtration rate) and electrolytes (potassium, phosphorus, calcium)
Bowel imaging: abdominal radiograph, contrast enema, and fluoroscopic upper gastrointestinal series. Computed tomography examination of the abdomen may be indicated to evaluate for a mechanical obstruction.
Laboratory monitoring of liver enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase), cholestasis (total and direct bilirubin), and liver function (prothrombin time, partial thromboplastin time, international normalized ratio, albumin)
Laboratory evaluation of macronutrient (carbohydrates, fat, protein) and micronutrient (vitamins, minerals) deficiencies in the setting of intestinal dysfunction and progressive malabsorption
Nutrition evaluation and close monitoring of growth parameters
• Urodynamic studies to evaluate the degree of bladder dysfunction (e.g., enlarged bladder capacity for age, detrusor acontractility with failure to empty) [
• Voiding cystourethrogram to evaluate for outlet obstruction, vesicoureteral reflux (VUR), and bladder capacity [
• Kidney and bladder ultrasound to evaluate for hydronephrosis and renal parenchyma
• Laboratory evaluation of kidney function (blood urea nitrogen, creatinine, glomerular filtration rate) and electrolytes (potassium, phosphorus, calcium)
• Bowel imaging: abdominal radiograph, contrast enema, and fluoroscopic upper gastrointestinal series. Computed tomography examination of the abdomen may be indicated to evaluate for a mechanical obstruction.
• Laboratory monitoring of liver enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase), cholestasis (total and direct bilirubin), and liver function (prothrombin time, partial thromboplastin time, international normalized ratio, albumin)
• Laboratory evaluation of macronutrient (carbohydrates, fat, protein) and micronutrient (vitamins, minerals) deficiencies in the setting of intestinal dysfunction and progressive malabsorption
• Nutrition evaluation and close monitoring of growth parameters
## Treatment of Manifestations
Surgical interventions such as enterostomies (e.g., gastrostomy, jejunostomy) for nutrition administration and proximal bowel decompression [
Bowel diversion (e.g., ileostomy, colostomy) for distal bowel decompression [
Total parenteral nutrition (TPN) when appropriate for malnutrition as a result of intestinal failure from intestinal dysmotility
Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN because of complications (e.g., liver dysfunction and cholestasis, lack of adequate central venous access, recurrent central line-associated bloodstream infections) [
Referral to cardiologist and monitoring for pulmonary hypertension, aortic dilatation, and patent ductus arteriosus
Referral to neurologist for evaluation for abnormal cerebral vasculature [
• Surgical interventions such as enterostomies (e.g., gastrostomy, jejunostomy) for nutrition administration and proximal bowel decompression [
• Bowel diversion (e.g., ileostomy, colostomy) for distal bowel decompression [
• Total parenteral nutrition (TPN) when appropriate for malnutrition as a result of intestinal failure from intestinal dysmotility
• Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN because of complications (e.g., liver dysfunction and cholestasis, lack of adequate central venous access, recurrent central line-associated bloodstream infections) [
• Referral to cardiologist and monitoring for pulmonary hypertension, aortic dilatation, and patent ductus arteriosus
• Referral to neurologist for evaluation for abnormal cerebral vasculature [
## Surveillance
The prognosis for individuals with MMIHS in light of its variable genetic causes has not been well elucidated. Data on individuals prior to molecular diagnosis suggests a poor and often fatal prognosis within the first year of life.
The evaluation and management are primarily supportive. Specialized centers offer multidisciplinary medical and surgical models of care including comprehensive TPN management and multivisceral transplantation.
Goals of bladder management include bladder decompression and subsequent monitoring and prevention of kidney failure.
Goals of bowel management include providing means of nutrition in the setting of intestinal dysmotility via enteral or parenteral means while monitoring for nutritional failure and TPN-associated complications (line infections, liver disease).
## Agents/Circumstances to Avoid
Treatment/medications to be avoided or limited include those that diminish bowel and bladder motility.
## Therapies Under Investigation
Search
## Genetic Counseling of Family Members of an Individual with Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) caused by pathogenic variants in
MMIHS caused by biallelic pathogenic variants in
MMIHS caused by a heterozygous pathogenic variant in
Some individuals diagnosed with autosomal dominant MMIHS have the disorder as the result of a
Some individuals diagnosed with MMIHS inherited a pathogenic variant from a parent. The severity of clinical findings may vary within a family; a parent may be asymptomatic or have a milder phenotype [
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and gonadal mosaicism have been reported in
* A parent with somatic and gonadal mosaicism for an
The family history of some individuals diagnosed with autosomal dominant MMIHS may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic expression, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the MMIHS-related pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the autosomal dominant MMIHS-related pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
Clinical severity and phenotype may differ between family members with the same MMIHS-related pathogenic variant; thus, age of onset and/or progression may not be predictable in heterozygous sibs.
If the MMIHS-related pathogenic variant detected in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
If the parents have not been tested for the MMIHS-related pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for MMIHS because of the possibility of parental gonadal mosaicism or reduced penetrance in a heterozygous parent.
The parents of an affected individual are presumed to be heterozygous for an MMIHS-related pathogenic variant.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an MMIHS-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are not at risk for MMIHS.
If both parents are known to be heterozygous for an MMIHS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are not at risk for MMIHS.
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Abdominal or bladder ultrasound and contrast enema if the pathogenic variant(s) in the family are not known. Evidence of megacystis (on the abdominal or bladder ultrasound) and microcolon (on the contrast enema) are highly suggestive of MMIHS.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having an MMIHS-related pathogenic variant.
It is appropriate to offer molecular genetic testing for reproductive partners of individuals known to be heterozygous for a pathogenic variant associated with autosomal recessive MMIHS, particularly if consanguinity is likely.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Some individuals diagnosed with autosomal dominant MMIHS have the disorder as the result of a
• Some individuals diagnosed with MMIHS inherited a pathogenic variant from a parent. The severity of clinical findings may vary within a family; a parent may be asymptomatic or have a milder phenotype [
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and gonadal mosaicism have been reported in
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and gonadal mosaicism have been reported in
• * A parent with somatic and gonadal mosaicism for an
• The family history of some individuals diagnosed with autosomal dominant MMIHS may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic expression, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the MMIHS-related pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and gonadal mosaicism have been reported in
• * A parent with somatic and gonadal mosaicism for an
• If a parent of the proband is affected and/or is known to have the autosomal dominant MMIHS-related pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Clinical severity and phenotype may differ between family members with the same MMIHS-related pathogenic variant; thus, age of onset and/or progression may not be predictable in heterozygous sibs.
• If the MMIHS-related pathogenic variant detected in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
• If the parents have not been tested for the MMIHS-related pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for MMIHS because of the possibility of parental gonadal mosaicism or reduced penetrance in a heterozygous parent.
• The parents of an affected individual are presumed to be heterozygous for an MMIHS-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an MMIHS-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are not at risk for MMIHS.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an MMIHS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are not at risk for MMIHS.
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Abdominal or bladder ultrasound and contrast enema if the pathogenic variant(s) in the family are not known. Evidence of megacystis (on the abdominal or bladder ultrasound) and microcolon (on the contrast enema) are highly suggestive of MMIHS.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having an MMIHS-related pathogenic variant.
• It is appropriate to offer molecular genetic testing for reproductive partners of individuals known to be heterozygous for a pathogenic variant associated with autosomal recessive MMIHS, particularly if consanguinity is likely.
## Mode of Inheritance
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) caused by pathogenic variants in
MMIHS caused by biallelic pathogenic variants in
MMIHS caused by a heterozygous pathogenic variant in
## Autosomal Dominant Inheritance – Risk to Family Members
Some individuals diagnosed with autosomal dominant MMIHS have the disorder as the result of a
Some individuals diagnosed with MMIHS inherited a pathogenic variant from a parent. The severity of clinical findings may vary within a family; a parent may be asymptomatic or have a milder phenotype [
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and gonadal mosaicism have been reported in
* A parent with somatic and gonadal mosaicism for an
The family history of some individuals diagnosed with autosomal dominant MMIHS may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic expression, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the MMIHS-related pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the autosomal dominant MMIHS-related pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
Clinical severity and phenotype may differ between family members with the same MMIHS-related pathogenic variant; thus, age of onset and/or progression may not be predictable in heterozygous sibs.
If the MMIHS-related pathogenic variant detected in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
If the parents have not been tested for the MMIHS-related pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for MMIHS because of the possibility of parental gonadal mosaicism or reduced penetrance in a heterozygous parent.
• Some individuals diagnosed with autosomal dominant MMIHS have the disorder as the result of a
• Some individuals diagnosed with MMIHS inherited a pathogenic variant from a parent. The severity of clinical findings may vary within a family; a parent may be asymptomatic or have a milder phenotype [
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and gonadal mosaicism have been reported in
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and gonadal mosaicism have been reported in
• * A parent with somatic and gonadal mosaicism for an
• The family history of some individuals diagnosed with autosomal dominant MMIHS may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic expression, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the MMIHS-related pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and gonadal mosaicism have been reported in
• * A parent with somatic and gonadal mosaicism for an
• If a parent of the proband is affected and/or is known to have the autosomal dominant MMIHS-related pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Clinical severity and phenotype may differ between family members with the same MMIHS-related pathogenic variant; thus, age of onset and/or progression may not be predictable in heterozygous sibs.
• If the MMIHS-related pathogenic variant detected in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
• If the parents have not been tested for the MMIHS-related pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for MMIHS because of the possibility of parental gonadal mosaicism or reduced penetrance in a heterozygous parent.
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for an MMIHS-related pathogenic variant.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an MMIHS-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are not at risk for MMIHS.
If both parents are known to be heterozygous for an MMIHS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are not at risk for MMIHS.
• The parents of an affected individual are presumed to be heterozygous for an MMIHS-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an MMIHS-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are not at risk for MMIHS.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an MMIHS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are not at risk for MMIHS.
## Related Genetic Counseling Issues
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Abdominal or bladder ultrasound and contrast enema if the pathogenic variant(s) in the family are not known. Evidence of megacystis (on the abdominal or bladder ultrasound) and microcolon (on the contrast enema) are highly suggestive of MMIHS.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having an MMIHS-related pathogenic variant.
It is appropriate to offer molecular genetic testing for reproductive partners of individuals known to be heterozygous for a pathogenic variant associated with autosomal recessive MMIHS, particularly if consanguinity is likely.
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Abdominal or bladder ultrasound and contrast enema if the pathogenic variant(s) in the family are not known. Evidence of megacystis (on the abdominal or bladder ultrasound) and microcolon (on the contrast enema) are highly suggestive of MMIHS.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having an MMIHS-related pathogenic variant.
• It is appropriate to offer molecular genetic testing for reproductive partners of individuals known to be heterozygous for a pathogenic variant associated with autosomal recessive MMIHS, particularly if consanguinity is likely.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
## Chapter Notes
Lusine Ambartsumyan's
Lusine Ambartsumyan specializes in the diagnosis and management of individuals with Hirschsprung disease, anorectal malformation, refractory constipation, neurogenic bowel, gastroparesis, chronic intestinal pseudo-obstruction, achalasia, and scleroderma. Her clinical and research interests include mechanisms of fecal continence in children with functional and organic defecation disorders, specifically children with anorectal malformations, neurogenic bowel, and postsurgical Hirschsprung disease.
Countless patients and families who have entrusted our gastrointestinal motility program with their care.
1 August 2024 (sw) Comprehensive update posted live
9 May 2019 (sw) Review posted live
5 December 2018 (la) Original submission
• 1 August 2024 (sw) Comprehensive update posted live
• 9 May 2019 (sw) Review posted live
• 5 December 2018 (la) Original submission
## Author Notes
Lusine Ambartsumyan's
Lusine Ambartsumyan specializes in the diagnosis and management of individuals with Hirschsprung disease, anorectal malformation, refractory constipation, neurogenic bowel, gastroparesis, chronic intestinal pseudo-obstruction, achalasia, and scleroderma. Her clinical and research interests include mechanisms of fecal continence in children with functional and organic defecation disorders, specifically children with anorectal malformations, neurogenic bowel, and postsurgical Hirschsprung disease.
## Acknowledgments
Countless patients and families who have entrusted our gastrointestinal motility program with their care.
## Revision History
1 August 2024 (sw) Comprehensive update posted live
9 May 2019 (sw) Review posted live
5 December 2018 (la) Original submission
• 1 August 2024 (sw) Comprehensive update posted live
• 9 May 2019 (sw) Review posted live
• 5 December 2018 (la) Original submission
## References
## Literature Cited
|
[] |
9/5/2019
|
1/8/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mn1-ctt
|
mn1-ctt
|
[
"Transcriptional activator MN1",
"MN1",
"MN1 C-Terminal Truncation Syndrome"
] |
Christopher CY Mak, Jasmine LF Fung, Mianne Lee, Angela E Lin, Jeanne Amiel, Dan Doherty, Christopher T Gordon, Brian HY Chung
|
Summary Individuals with No consensus clinical diagnostic criteria for MCTT syndrome have been published. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic variant in MCTT syndrome is an autosomal dominant disorder typically caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for
Intellectual disability (ID) with severe expressive language delay
Hypotonia
Delays in motor development
Hearing loss (conductive or sensorineural)
Distinctive craniofacial features (See
Brain Imaging Features in Individuals with MCTT Syndrome
Based on 11 MRIs reviewed at one center [
Observed in insula; can sometimes extend more broadly in perisylvian region.
The diagnosis of
(1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive craniofacial or brain MRI findings described in
Note: To date all described variants have been C-terminal truncating variants at the 3' end of exon 1 or in exon 2.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Intellectual disability (ID) with severe expressive language delay
• Hypotonia
• Delays in motor development
• Hearing loss (conductive or sensorineural)
• Distinctive craniofacial features (See
## Suggestive Findings
Intellectual disability (ID) with severe expressive language delay
Hypotonia
Delays in motor development
Hearing loss (conductive or sensorineural)
Distinctive craniofacial features (See
Brain Imaging Features in Individuals with MCTT Syndrome
Based on 11 MRIs reviewed at one center [
Observed in insula; can sometimes extend more broadly in perisylvian region.
• Intellectual disability (ID) with severe expressive language delay
• Hypotonia
• Delays in motor development
• Hearing loss (conductive or sensorineural)
• Distinctive craniofacial features (See
## Establishing the Diagnosis
The diagnosis of
(1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive craniofacial or brain MRI findings described in
Note: To date all described variants have been C-terminal truncating variants at the 3' end of exon 1 or in exon 2.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
Note: To date all described variants have been C-terminal truncating variants at the 3' end of exon 1 or in exon 2.
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
To date, 25 individuals have been identified with a germline (
Clinical Features of
Based on
Delay in gross motor development included hypotonia; at least four of 22 children walked independently by age two to three years. Others required orthotics or a wheelchair for mobilization. As for fine motor and self-help skills, most individuals require help with writing, feeding, or dressing [
No genotype-phenotype correlations have been identified.
MCTT syndrome is referred to as CEBALID (
To date, 25 individuals with MCTT syndrome have been reported [
## Clinical Description
To date, 25 individuals have been identified with a germline (
Clinical Features of
Based on
Delay in gross motor development included hypotonia; at least four of 22 children walked independently by age two to three years. Others required orthotics or a wheelchair for mobilization. As for fine motor and self-help skills, most individuals require help with writing, feeding, or dressing [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
MCTT syndrome is referred to as CEBALID (
## Prevalence
To date, 25 individuals with MCTT syndrome have been reported [
## Genetically Related (Allelic) Disorders
Truncating variants in the N-terminal third of
Contiguous gene deletions of various sizes containing
## Differential Diagnosis
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Dental eval
Oral-maxillofacial eval
Dental anomalies (e.g., conical teeth, crowded teeth, malocclusion)
Palate for submucous cleft assoc w/bifid uvula
Cranial exam & skull radiographs for craniosynostosis
CT if indicated
Brain MRI to identify polymicrogyria (possibly assoc w/seizure risk) & persistent trigeminal artery (possible risks for neurosurgical procedures involving skull base & pituitary)
EEG, if seizures present
Incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
No consistent behavior problems reporte
Some may experience frustration due to poor verbal communication.
Spinal involvement (lordosis, scoliosis, kyphosis)
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Assess for conductive &/or sensorineural hearing loss.
If present, refer to otolaryngologist.
Community or
Social work involvement for parental support.
ASD = atrial septal defect; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; VSD = ventricular septal defects
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none demonstrated effective specifically for this disorder.
Education of parents/caregivers
Incl stretching to help avoid contractures & falls
Consider need for positioning & mobility devices, disability parking placard.
Hearing aids may be helpful; per audiologist.
See also
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive, self-injurious, or destructive behavior can be addressed by a pediatric psychiatrist, developmental pediatrician, or psychologist with particular interest in management of these types of behaviors.
Recommended Surveillance for Individuals with
OT = occupational therapy; PT = physical therapy
See
Search
• Dental eval
• Oral-maxillofacial eval
• Dental anomalies (e.g., conical teeth, crowded teeth, malocclusion)
• Palate for submucous cleft assoc w/bifid uvula
• Cranial exam & skull radiographs for craniosynostosis
• CT if indicated
• Brain MRI to identify polymicrogyria (possibly assoc w/seizure risk) & persistent trigeminal artery (possible risks for neurosurgical procedures involving skull base & pituitary)
• EEG, if seizures present
• Incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• No consistent behavior problems reporte
• Some may experience frustration due to poor verbal communication.
• Spinal involvement (lordosis, scoliosis, kyphosis)
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Assess for conductive &/or sensorineural hearing loss.
• If present, refer to otolaryngologist.
• Community or
• Social work involvement for parental support.
• Many ASMs may be effective; none demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Incl stretching to help avoid contractures & falls
• Consider need for positioning & mobility devices, disability parking placard.
• Hearing aids may be helpful; per audiologist.
• See also
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Dental eval
Oral-maxillofacial eval
Dental anomalies (e.g., conical teeth, crowded teeth, malocclusion)
Palate for submucous cleft assoc w/bifid uvula
Cranial exam & skull radiographs for craniosynostosis
CT if indicated
Brain MRI to identify polymicrogyria (possibly assoc w/seizure risk) & persistent trigeminal artery (possible risks for neurosurgical procedures involving skull base & pituitary)
EEG, if seizures present
Incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
No consistent behavior problems reporte
Some may experience frustration due to poor verbal communication.
Spinal involvement (lordosis, scoliosis, kyphosis)
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Assess for conductive &/or sensorineural hearing loss.
If present, refer to otolaryngologist.
Community or
Social work involvement for parental support.
ASD = atrial septal defect; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; VSD = ventricular septal defects
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Dental eval
• Oral-maxillofacial eval
• Dental anomalies (e.g., conical teeth, crowded teeth, malocclusion)
• Palate for submucous cleft assoc w/bifid uvula
• Cranial exam & skull radiographs for craniosynostosis
• CT if indicated
• Brain MRI to identify polymicrogyria (possibly assoc w/seizure risk) & persistent trigeminal artery (possible risks for neurosurgical procedures involving skull base & pituitary)
• EEG, if seizures present
• Incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• No consistent behavior problems reporte
• Some may experience frustration due to poor verbal communication.
• Spinal involvement (lordosis, scoliosis, kyphosis)
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Assess for conductive &/or sensorineural hearing loss.
• If present, refer to otolaryngologist.
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none demonstrated effective specifically for this disorder.
Education of parents/caregivers
Incl stretching to help avoid contractures & falls
Consider need for positioning & mobility devices, disability parking placard.
Hearing aids may be helpful; per audiologist.
See also
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive, self-injurious, or destructive behavior can be addressed by a pediatric psychiatrist, developmental pediatrician, or psychologist with particular interest in management of these types of behaviors.
• Many ASMs may be effective; none demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Incl stretching to help avoid contractures & falls
• Consider need for positioning & mobility devices, disability parking placard.
• Hearing aids may be helpful; per audiologist.
• See also
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive, self-injurious, or destructive behavior can be addressed by a pediatric psychiatrist, developmental pediatrician, or psychologist with particular interest in management of these types of behaviors.
## Surveillance
Recommended Surveillance for Individuals with
OT = occupational therapy; PT = physical therapy
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Molecular genetic testing is recommended to confirm the genetic status of the parents and to allow reliable recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
* A parent with somatic and germline mosaicism for an
If a parent of the proband has the
If the
The majority of probands reported to date with MCTT syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
Each child of an individual with MCTT syndrome has a 50% chance of inheriting the
Individuals with MCTT syndrome are not known to reproduce; however, many are not yet of reproductive age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Molecular genetic testing is recommended to confirm the genetic status of the parents and to allow reliable recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• If a parent of the proband has the
• If the
• The majority of probands reported to date with MCTT syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
• Each child of an individual with MCTT syndrome has a 50% chance of inheriting the
• Individuals with MCTT syndrome are not known to reproduce; however, many are not yet of reproductive age.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
Molecular genetic testing is recommended to confirm the genetic status of the parents and to allow reliable recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
* A parent with somatic and germline mosaicism for an
If a parent of the proband has the
If the
The majority of probands reported to date with MCTT syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
Each child of an individual with MCTT syndrome has a 50% chance of inheriting the
Individuals with MCTT syndrome are not known to reproduce; however, many are not yet of reproductive age.
• Molecular genetic testing is recommended to confirm the genetic status of the parents and to allow reliable recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• If a parent of the proband has the
• If the
• The majority of probands reported to date with MCTT syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
• Each child of an individual with MCTT syndrome has a 50% chance of inheriting the
• Individuals with MCTT syndrome are not known to reproduce; however, many are not yet of reproductive age.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
## Molecular Genetics
MN1 C-Terminal Truncation Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MN1 C-Terminal Truncation Syndrome (
All
Truncated MN1 impairs the binding of the E3 ubiquitin ligase RING1; therefore, C-terminal deletion may interfere with the interaction of MN1 with molecules related to the ubiquitin-mediated proteasome pathway, increasing the amount of abnormal protein. This increase would lead to the dysregulation of
Notable
Variants listed in the table have been provided by the authors.
Fusion of
## Molecular Pathogenesis
All
Truncated MN1 impairs the binding of the E3 ubiquitin ligase RING1; therefore, C-terminal deletion may interfere with the interaction of MN1 with molecules related to the ubiquitin-mediated proteasome pathway, increasing the amount of abnormal protein. This increase would lead to the dysregulation of
Notable
Variants listed in the table have been provided by the authors.
## Cancer and Benign Tumors
Fusion of
## Chapter Notes
Author's website:
Dr Brian Hon-Yin Chung is Clinical Associate Professor / Honorary Consultant in the Department of Pædiatrics and Adolescent Medicine and the Department of Obstetrics & Gynæcology of the University of Hong Kong. Dr Chung takes care of patients and families with genetic disorders. A clinical geneticist and academic paediatrician by training, he focuses on accurate delineation of the clinical phenotype/natural history of genetic syndromes and how genetic and epigenetic factors contribute to disease susceptibility, using state-of-the-art genomic technologies.
We are extremely grateful to the families for their participation, and our collaborators for their valuable contribution to our knowledge about these disorders.
13 August 2020 (bp) Review posted live
22 April 2020 (bc) Original submission
• 13 August 2020 (bp) Review posted live
• 22 April 2020 (bc) Original submission
## Author Notes
Author's website:
Dr Brian Hon-Yin Chung is Clinical Associate Professor / Honorary Consultant in the Department of Pædiatrics and Adolescent Medicine and the Department of Obstetrics & Gynæcology of the University of Hong Kong. Dr Chung takes care of patients and families with genetic disorders. A clinical geneticist and academic paediatrician by training, he focuses on accurate delineation of the clinical phenotype/natural history of genetic syndromes and how genetic and epigenetic factors contribute to disease susceptibility, using state-of-the-art genomic technologies.
## Acknowledgments
We are extremely grateful to the families for their participation, and our collaborators for their valuable contribution to our knowledge about these disorders.
## Revision History
13 August 2020 (bp) Review posted live
22 April 2020 (bc) Original submission
• 13 August 2020 (bp) Review posted live
• 22 April 2020 (bc) Original submission
## References
## Literature Cited
Facial features of individuals with C-terminal truncating variants in
Reproduced with permission from
Partial rhombencephalosynapsis in patients with C-terminal truncating
Reproduced with permission from
Persistent trigeminal artery and prominent posterior clinoid process in patients with C-terminal truncating
A. Carotid and basilar arteries (axial view): persistent trigeminal artery flow-voids (dark signal) connecting the carotid (C) and basilar (B) artery flow-voids (arrows). The persistent trigeminal arteries are unilateral in individuals 11 and 17, and bilateral in individual 13. Individual 24, with an early truncating variant, does not have persistent trigeminal arteries (shown for comparison).
B. Prominent posterior clinoid process (sagittal view): abnormal tissue just superior to the posterior pituitary bright spot and continuous with the posterior clinoid process (arrowheads). Individual 24, without abnormal tissue, is shown for comparison.
Reproduced with permission from
|
[
"A Burford, A Mackay, S Popov, M Vinci, D Carvalho, M Clarke, E Izquierdo, A Avery, TS Jacques, WJ Ingram, AS Moore. The ten-year evolutionary trajectory of a highly recurrent paediatric high grade neuroepithelial tumour with MN1: BEND2 fusion.. Sci Rep. 2018;8:1032",
"J Kaplanis, KE Samocha, L Wiel, Z Zhang, KJ Arvai, RY Eberhardt, G Gallone, SH Lelieveld, HC Martin, JF McRae, PJ Short, RI Torene, E de Boer, P Danecek, EJ Gardner, N Huang, J Lord, I Martincorena, R Pfundt, MRF Reijnders, A Yeung, HG Yntema. Deciphering Developmental Disorders Study, Vissers LELM, Juusola J, Wright CF, Brunner HG, Firth HV, FitzPatrick DR, Barrett JC, Hurles ME, Gilissen C, Retterer K. Evidence for 28 genetic disorders discovered by combining healthcare and research data.. Nature. 2020;586:757-62",
"CCY Mak, D Doherty, AE Lin, N Vegas, MT Cho, G Viot, C Dimartino, JD Weisfeld-Adams, D Lessel, S Joss, C Li, C Gonzaga-Jauregui, YA Zarate, N Ehmke, D Horn, C Troyer, SG Kant, Y Lee, GE Ishak, G Leung, A Barone Pritchard, S Yang, EG Bend, F Filippini, C Roadhouse, N Lebrun, MG Mehaffey, PM Martin, B Apple, F Millan, O Puk, MJV Hoffer, LB Henderson, R McGowan, IM Wentzensen, S Pei, FR Zahir, M Yu, WT Gibson, A Seman, M Steeves, JR Murrell, S Luettgen, E Francisco, TM Strom, L Amlie-Wolf, AM Kaindl, WG Wilson, S Halbach, L Basel-Salmon, N Lev-El, J Denecke, LELM Vissers, K Radtke, J Chelly, E Zackai, JM Friedman, MJ Bamshad, DA Nickerson, RR Reid, K Devriendt, JH Chae, E Stolerman, C McDougall, Z Powis, T Bienvenu, TY Tan, N Orenstein, WB Dobyns, JT Shieh, M Choi, D Waggoner, KW Gripp, MJ Parker, J Stoler, S Lyonnet, V Cormier-Daire, D Viskochil, TL Hoffman, J Amiel, BHY Chung, CT Gordon. MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.. Brain. 2020;143:55-68",
"JF McRae, S Clayton, TW Fitzgerald, J Kaplanis, E Prigmore, D Rajan, A Sifrim, S Aitken, N Akawi, M Alvi. Prevalence and architecture of de novo mutations in developmental disorders.. Nature. 2017;542:433-8",
"N Miyake, H Takahashi, K Nakamura, B Isidor, Y Hiraki, E Koshimizu, M Shiina, K Sasaki, H Suzuki, R Abe, Y Kimura, T Akiyama, SI Tomizawa, T Hirose, K Hamanaka, S Miyatake, S Mitsuhashi, T Mizuguchi, A Takata, K Obo, M Kato, K Ogata, N Matsumoto. Gain-of-function MN1 truncation variants cause a recognizable syndrome with craniofacial and brain abnormalities.. Am J Hum Genet. 2020;106:13-25",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"M Rossi, D El-Khechen, MH Black, KD Farwell Hagman, S Tang, Z Powis. Outcomes of diagnostic exome sequencing in patients with diagnosed or suspected autism spectrum disorders.. Pediatr Neurol. 2017;70:34-43.e2",
"H Shao, J Cen, S Chen, H Qiu, J Pan. Myeloid neoplasms with t (12; 22)(p13; q12)/MN1-EVT6: a systematic review of 12 cases.. Ann Hematol. 2018;97:417-24"
] |
13/8/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
mngie
|
mngie
|
[
"Mitochondrial Neurogastrointestinal Encephalopathy Syndrome",
"MNGIE Syndrome",
"Thymidine Phosphorylase Deficiency",
"MNGIE Syndrome",
"Thymidine Phosphorylase Deficiency",
"Mitochondrial Neurogastrointestinal Encephalopathy Syndrome",
"Thymidine phosphorylase",
"TYMP",
"Mitochondrial Neurogastrointestinal Encephalopathy Disease"
] |
Mitochondrial Neurogastrointestinal Encephalopathy Disease
|
Michio Hirano
|
Summary Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is characterized by progressive gastrointestinal dysmotility (manifesting as early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and/or distention, and diarrhea); cachexia; ptosis/ophthalmoplegia or ophthalmoparesis; leukoencephalopathy; and demyelinating peripheral neuropathy (manifesting as paresthesias (tingling, numbness, and pain) and symmetric and distal weakness more prominently affecting the lower extremities). The order in which manifestations appear is unpredictable. Onset is usually between the first and fifth decades; in about 60% of individuals, symptoms begin before age 20 years. The clinical diagnosis of MNGIE disease is based on the presence of severe gastrointestinal dysmotility, cachexia, ptosis, external ophthalmoplegia, sensorimotor neuropathy, asymptomatic leukoencephalopathy as observed on brain MRI, and family history consistent with autosomal recessive inheritance. The diagnosis of MNGIE disease can be established in a proband by detection of one of the following: (1) biallelic pathogenic variants in MNGIE disease is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes and therefore carry one mutated allele; heterozygotes are asymptomatic. Unless an individual with MNGIE disease has offspring with either an affected individual or a carrier, his/her offspring will be obligate heterozygotes for a pathogenic variant in
|
## Diagnosis
MNGIE (
Severe gastrointestinal (GI) dysmotility
Cachexia
Ptosis
External ophthalmoplegia
Sensorimotor neuropathy (usually mixed axonal and demyelinating)
Note: Although magnetic resonance spectroscopy (MRS) can show increases in lactate within the white matter, it is not a sensitive diagnostic test.
The diagnosis of MNGIE disease
Molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Individuals with enzymatically confirmed MNGIE disease [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
•
• Severe gastrointestinal (GI) dysmotility
• Cachexia
• Ptosis
• External ophthalmoplegia
• Sensorimotor neuropathy (usually mixed axonal and demyelinating)
• Severe gastrointestinal (GI) dysmotility
• Cachexia
• Ptosis
• External ophthalmoplegia
• Sensorimotor neuropathy (usually mixed axonal and demyelinating)
• Note: Although magnetic resonance spectroscopy (MRS) can show increases in lactate within the white matter, it is not a sensitive diagnostic test.
• Severe gastrointestinal (GI) dysmotility
• Cachexia
• Ptosis
• External ophthalmoplegia
• Sensorimotor neuropathy (usually mixed axonal and demyelinating)
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
MNGIE (
Severe gastrointestinal (GI) dysmotility
Cachexia
Ptosis
External ophthalmoplegia
Sensorimotor neuropathy (usually mixed axonal and demyelinating)
Note: Although magnetic resonance spectroscopy (MRS) can show increases in lactate within the white matter, it is not a sensitive diagnostic test.
•
• Severe gastrointestinal (GI) dysmotility
• Cachexia
• Ptosis
• External ophthalmoplegia
• Sensorimotor neuropathy (usually mixed axonal and demyelinating)
• Severe gastrointestinal (GI) dysmotility
• Cachexia
• Ptosis
• External ophthalmoplegia
• Sensorimotor neuropathy (usually mixed axonal and demyelinating)
• Note: Although magnetic resonance spectroscopy (MRS) can show increases in lactate within the white matter, it is not a sensitive diagnostic test.
• Severe gastrointestinal (GI) dysmotility
• Cachexia
• Ptosis
• External ophthalmoplegia
• Sensorimotor neuropathy (usually mixed axonal and demyelinating)
## Establishing the Diagnosis
The diagnosis of MNGIE disease
Molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Individuals with enzymatically confirmed MNGIE disease [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
MNGIE disease is characterized by the following major manifestations: gastrointestinal dysmotility, cachexia, progressive external ophthalmoplegia with or without ptosis, peripheral neuropathy, and leukoencephalopathy.
Gestation and delivery are normal. The earliest reported age of onset is five months; onset is usually between the first and fifth decades. In about 60% of individuals, symptoms begin before age 20 years (mean age at onset: 18 years) [
Prior to the onset of symptoms, many individuals with MNGIE disease are healthy, but usually have a long history of subtle fatigability, mild gastrointestinal symptoms, or thin body habitus.
The order in which manifestations appear is unpredictable; however, in a review of 102 patients, the first symptoms were gastrointestinal (~57%), ptosis/ophthalmoplegia (~19%), peripheral neuropathy (~14%), and myopathy (~5%) [
Late-onset MNGIE disease occurs in individuals harboring pathogenic
Weight loss and cachexia coincide with the onset of GI symptoms. The average weight loss is about 15 kg [
Duodenal pathology can demonstrate focal muscle atrophy or absence with increased nerve numbers, serosal granulomas, and focal loss of Auerbach's plexus with fibrosis [
Mitochondrial DNA depletion, mitochondrial proliferation, and smooth cell atrophy are observed in the external layer of the muscularis propria in the stomach and in the small intestine [
Loss of the pacemaker cells that stimulate gut contraction (interstitial cells of Cajal) is also noted in the small bowel [
The segmental demyelination is hypothesized to be caused by the uneven distribution of mtDNA abnormalities (depletion, single-nucleotide variants, deletions, duplications) along the nerve. Areas with the highest concentration of these pathogenic variants may be predisposed to demyelination.
Electrodiagnostic features can include decreased motor and sensory nerve conduction velocities, prolonged F-wave latency, and partial conduction block. Myopathic changes are common.
Histologically, demyelination and remyelination (onion bulb formation) are observed. Loss of large myelinated fibers is common.
Active hepatic cirrhosis with increased liver enzymes and macrovesicular steatosis
Anemia
Early-onset sensorineural hearing loss involving either the cochlea or eighth cranial nerve.
Diverticula, which may become infected (diverticulitis) or perforate, causing peritonitis, which may be fatal.
Hypergonadotropic hypogonadism [
Significantly increased CSF protein (typically 60 - >100 mg/dL; normal: 15 - 45 mg/dL)
Lactic acidemia (increased serum concentration of lactate without a change in the pH) and hyperalaninemia are common. Lactic acidosis (increased serum lactate concentration associated with a decrease in blood pH) is unusual, but is more likely to occur in the presence of renal or hepatic impairment.
Evidence of mitochondrial dysfunction manifest by any of the following:
Histologic abnormalities of a mitochondrial myopathy including ragged-red fibers (Gomori trichrome) and defects in single or multiple OXPHOS enzyme complexes. The most common defect is in cytochrome
Note: Normal muscle histopathology can be observed [
Acquired mitochondrial DNA (mtDNA) deletions/duplications detected in any tissue by Southern blot analysis and long-range PCR
Mitochondrial DNA depletion detected by quantitation of mtDNA relative to nuclear DNA
Site-specific mtDNA single-nucleotide variants detected in blood and tissues
Other metabolic abnormalities including increased urine concentrations of deoxyuridine and thymidine. These compounds are not detectable in controls or in individuals who are heterozygous for a
Post-mortem increases in nucleosides in all tissues [
Late-onset disease occurs in individuals harboring
MNGIE disease was first described as congenital oculo-skeletal myopathy with abnormal muscle and liver mitochondria. Other names for MNGIE disease include polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction (POLIP); oculogastrointestinal muscular dystrophy (OGIMD); and mitochondrial myopathy with sensorimotor polyneuropathy, ophthalmoplegia, and pseudo-obstruction (MEPOP).
MNGIE disease is rare. The prevalence is unknown. More than 120 individuals with features consistent with MNGIE disease have been reported since it was first described.
No ethnic predilection for MNGIE disease has been observed; it occurs in individuals of mixed European, Turkish, Puerto Rican, Ashkenazi Jewish, Iranian Jewish, German American, Asian, Spanish, and African American heritage.
Parental consanguinity is common, occurring in nearly half the families in some reports [
• Active hepatic cirrhosis with increased liver enzymes and macrovesicular steatosis
• Anemia
• Early-onset sensorineural hearing loss involving either the cochlea or eighth cranial nerve.
• Diverticula, which may become infected (diverticulitis) or perforate, causing peritonitis, which may be fatal.
• Hypergonadotropic hypogonadism [
• Significantly increased CSF protein (typically 60 - >100 mg/dL; normal: 15 - 45 mg/dL)
• Lactic acidemia (increased serum concentration of lactate without a change in the pH) and hyperalaninemia are common. Lactic acidosis (increased serum lactate concentration associated with a decrease in blood pH) is unusual, but is more likely to occur in the presence of renal or hepatic impairment.
• Evidence of mitochondrial dysfunction manifest by any of the following:
• Histologic abnormalities of a mitochondrial myopathy including ragged-red fibers (Gomori trichrome) and defects in single or multiple OXPHOS enzyme complexes. The most common defect is in cytochrome
• Note: Normal muscle histopathology can be observed [
• Acquired mitochondrial DNA (mtDNA) deletions/duplications detected in any tissue by Southern blot analysis and long-range PCR
• Mitochondrial DNA depletion detected by quantitation of mtDNA relative to nuclear DNA
• Site-specific mtDNA single-nucleotide variants detected in blood and tissues
• Other metabolic abnormalities including increased urine concentrations of deoxyuridine and thymidine. These compounds are not detectable in controls or in individuals who are heterozygous for a
• Post-mortem increases in nucleosides in all tissues [
• Histologic abnormalities of a mitochondrial myopathy including ragged-red fibers (Gomori trichrome) and defects in single or multiple OXPHOS enzyme complexes. The most common defect is in cytochrome
• Note: Normal muscle histopathology can be observed [
• Acquired mitochondrial DNA (mtDNA) deletions/duplications detected in any tissue by Southern blot analysis and long-range PCR
• Mitochondrial DNA depletion detected by quantitation of mtDNA relative to nuclear DNA
• Site-specific mtDNA single-nucleotide variants detected in blood and tissues
• Other metabolic abnormalities including increased urine concentrations of deoxyuridine and thymidine. These compounds are not detectable in controls or in individuals who are heterozygous for a
• Post-mortem increases in nucleosides in all tissues [
• Histologic abnormalities of a mitochondrial myopathy including ragged-red fibers (Gomori trichrome) and defects in single or multiple OXPHOS enzyme complexes. The most common defect is in cytochrome
• Note: Normal muscle histopathology can be observed [
• Acquired mitochondrial DNA (mtDNA) deletions/duplications detected in any tissue by Southern blot analysis and long-range PCR
• Mitochondrial DNA depletion detected by quantitation of mtDNA relative to nuclear DNA
• Site-specific mtDNA single-nucleotide variants detected in blood and tissues
• Other metabolic abnormalities including increased urine concentrations of deoxyuridine and thymidine. These compounds are not detectable in controls or in individuals who are heterozygous for a
• Post-mortem increases in nucleosides in all tissues [
## Clinical Description
MNGIE disease is characterized by the following major manifestations: gastrointestinal dysmotility, cachexia, progressive external ophthalmoplegia with or without ptosis, peripheral neuropathy, and leukoencephalopathy.
Gestation and delivery are normal. The earliest reported age of onset is five months; onset is usually between the first and fifth decades. In about 60% of individuals, symptoms begin before age 20 years (mean age at onset: 18 years) [
Prior to the onset of symptoms, many individuals with MNGIE disease are healthy, but usually have a long history of subtle fatigability, mild gastrointestinal symptoms, or thin body habitus.
The order in which manifestations appear is unpredictable; however, in a review of 102 patients, the first symptoms were gastrointestinal (~57%), ptosis/ophthalmoplegia (~19%), peripheral neuropathy (~14%), and myopathy (~5%) [
Late-onset MNGIE disease occurs in individuals harboring pathogenic
Weight loss and cachexia coincide with the onset of GI symptoms. The average weight loss is about 15 kg [
Duodenal pathology can demonstrate focal muscle atrophy or absence with increased nerve numbers, serosal granulomas, and focal loss of Auerbach's plexus with fibrosis [
Mitochondrial DNA depletion, mitochondrial proliferation, and smooth cell atrophy are observed in the external layer of the muscularis propria in the stomach and in the small intestine [
Loss of the pacemaker cells that stimulate gut contraction (interstitial cells of Cajal) is also noted in the small bowel [
The segmental demyelination is hypothesized to be caused by the uneven distribution of mtDNA abnormalities (depletion, single-nucleotide variants, deletions, duplications) along the nerve. Areas with the highest concentration of these pathogenic variants may be predisposed to demyelination.
Electrodiagnostic features can include decreased motor and sensory nerve conduction velocities, prolonged F-wave latency, and partial conduction block. Myopathic changes are common.
Histologically, demyelination and remyelination (onion bulb formation) are observed. Loss of large myelinated fibers is common.
Active hepatic cirrhosis with increased liver enzymes and macrovesicular steatosis
Anemia
Early-onset sensorineural hearing loss involving either the cochlea or eighth cranial nerve.
Diverticula, which may become infected (diverticulitis) or perforate, causing peritonitis, which may be fatal.
Hypergonadotropic hypogonadism [
Significantly increased CSF protein (typically 60 - >100 mg/dL; normal: 15 - 45 mg/dL)
Lactic acidemia (increased serum concentration of lactate without a change in the pH) and hyperalaninemia are common. Lactic acidosis (increased serum lactate concentration associated with a decrease in blood pH) is unusual, but is more likely to occur in the presence of renal or hepatic impairment.
Evidence of mitochondrial dysfunction manifest by any of the following:
Histologic abnormalities of a mitochondrial myopathy including ragged-red fibers (Gomori trichrome) and defects in single or multiple OXPHOS enzyme complexes. The most common defect is in cytochrome
Note: Normal muscle histopathology can be observed [
Acquired mitochondrial DNA (mtDNA) deletions/duplications detected in any tissue by Southern blot analysis and long-range PCR
Mitochondrial DNA depletion detected by quantitation of mtDNA relative to nuclear DNA
Site-specific mtDNA single-nucleotide variants detected in blood and tissues
Other metabolic abnormalities including increased urine concentrations of deoxyuridine and thymidine. These compounds are not detectable in controls or in individuals who are heterozygous for a
Post-mortem increases in nucleosides in all tissues [
• Active hepatic cirrhosis with increased liver enzymes and macrovesicular steatosis
• Anemia
• Early-onset sensorineural hearing loss involving either the cochlea or eighth cranial nerve.
• Diverticula, which may become infected (diverticulitis) or perforate, causing peritonitis, which may be fatal.
• Hypergonadotropic hypogonadism [
• Significantly increased CSF protein (typically 60 - >100 mg/dL; normal: 15 - 45 mg/dL)
• Lactic acidemia (increased serum concentration of lactate without a change in the pH) and hyperalaninemia are common. Lactic acidosis (increased serum lactate concentration associated with a decrease in blood pH) is unusual, but is more likely to occur in the presence of renal or hepatic impairment.
• Evidence of mitochondrial dysfunction manifest by any of the following:
• Histologic abnormalities of a mitochondrial myopathy including ragged-red fibers (Gomori trichrome) and defects in single or multiple OXPHOS enzyme complexes. The most common defect is in cytochrome
• Note: Normal muscle histopathology can be observed [
• Acquired mitochondrial DNA (mtDNA) deletions/duplications detected in any tissue by Southern blot analysis and long-range PCR
• Mitochondrial DNA depletion detected by quantitation of mtDNA relative to nuclear DNA
• Site-specific mtDNA single-nucleotide variants detected in blood and tissues
• Other metabolic abnormalities including increased urine concentrations of deoxyuridine and thymidine. These compounds are not detectable in controls or in individuals who are heterozygous for a
• Post-mortem increases in nucleosides in all tissues [
• Histologic abnormalities of a mitochondrial myopathy including ragged-red fibers (Gomori trichrome) and defects in single or multiple OXPHOS enzyme complexes. The most common defect is in cytochrome
• Note: Normal muscle histopathology can be observed [
• Acquired mitochondrial DNA (mtDNA) deletions/duplications detected in any tissue by Southern blot analysis and long-range PCR
• Mitochondrial DNA depletion detected by quantitation of mtDNA relative to nuclear DNA
• Site-specific mtDNA single-nucleotide variants detected in blood and tissues
• Other metabolic abnormalities including increased urine concentrations of deoxyuridine and thymidine. These compounds are not detectable in controls or in individuals who are heterozygous for a
• Post-mortem increases in nucleosides in all tissues [
• Histologic abnormalities of a mitochondrial myopathy including ragged-red fibers (Gomori trichrome) and defects in single or multiple OXPHOS enzyme complexes. The most common defect is in cytochrome
• Note: Normal muscle histopathology can be observed [
• Acquired mitochondrial DNA (mtDNA) deletions/duplications detected in any tissue by Southern blot analysis and long-range PCR
• Mitochondrial DNA depletion detected by quantitation of mtDNA relative to nuclear DNA
• Site-specific mtDNA single-nucleotide variants detected in blood and tissues
• Other metabolic abnormalities including increased urine concentrations of deoxyuridine and thymidine. These compounds are not detectable in controls or in individuals who are heterozygous for a
• Post-mortem increases in nucleosides in all tissues [
## Genotype-Phenotype Correlations
Late-onset disease occurs in individuals harboring
## Nomenclature
MNGIE disease was first described as congenital oculo-skeletal myopathy with abnormal muscle and liver mitochondria. Other names for MNGIE disease include polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction (POLIP); oculogastrointestinal muscular dystrophy (OGIMD); and mitochondrial myopathy with sensorimotor polyneuropathy, ophthalmoplegia, and pseudo-obstruction (MEPOP).
## Prevalence
MNGIE disease is rare. The prevalence is unknown. More than 120 individuals with features consistent with MNGIE disease have been reported since it was first described.
No ethnic predilection for MNGIE disease has been observed; it occurs in individuals of mixed European, Turkish, Puerto Rican, Ashkenazi Jewish, Iranian Jewish, German American, Asian, Spanish, and African American heritage.
Parental consanguinity is common, occurring in nearly half the families in some reports [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
MNGIE (
Because of the rapid appearance of neuropathic symptoms over several months in some individuals, chronic inflammatory demyelinating polyneuropathy (CIDP) has been misdiagnosed [
However, when the diagnostic criteria for MNGIE disease are strictly applied, thymidine phosphorylase activity and molecular genetic testing of
Autosomal dominant progressive external ophthalmoplegia, caused by:
Mutation of
Mutation of
Mutation of
Mutation of
A larger array of mtDNA diseases caused by single-nucleotide variants (SNVs) (For reviews see
Mitochondrial myopathy with mtDNA depletion caused by pathogenic variants in
Mitochondrial hepatopathy and encephalopathy with mtDNA depletion caused by pathogenic variants in
Multisystemic diseases with mtDNA depletion caused by mutation of:
Although pathogenic variants in
• Autosomal dominant progressive external ophthalmoplegia, caused by:
• Mutation of
• Mutation of
• Mutation of
• Mutation of
• Mutation of
• Mutation of
• Mutation of
• Mutation of
• A larger array of mtDNA diseases caused by single-nucleotide variants (SNVs) (For reviews see
• Mitochondrial myopathy with mtDNA depletion caused by pathogenic variants in
• Mitochondrial hepatopathy and encephalopathy with mtDNA depletion caused by pathogenic variants in
• Multisystemic diseases with mtDNA depletion caused by mutation of:
• Mutation of
• Mutation of
• Mutation of
• Mutation of
## Management
To establish the extent of disease and needs in a proband with MNGIE (
EMG/NCV
Brain MRI
EKG
Ophthalmologic evaluation
Audiologic evaluation
Assessment of hepatic function, renal function, plasma concentrations of amino acids, and serum concentration of lactate and pyruvate
GI evaluation, which depends on the symptoms and may include abdominal films, abdominal CT, upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, and antroduodenal manometry. Radiologic studies may show hypoperistalsis, gastroparesis, dilated duodenum, and diverticulosis. Small bowel manometry shows reduced amplitude of contractions.
Consultation with a clinical geneticist and/or genetic counselor
Cooperation among multiple specialties including neurology, clinical genetics, nutrition, gastroenterology, pain management, psychiatry, and physical/occupational therapy helps with timely detection and treatment of the various aspects of multiorgan dysfunction. Once symptoms appear, treatment is primarily supportive.
Management of GI dysfunction can include the following:
Early attention to swallowing difficulties and airway protection, especially in the most severely affected individuals
Trial of dromperidone for nausea and vomiting
Nutritional support including (when necessary) bolus feedings, gastrostomy tube placement, and total parenteral nutrition
Antibiotic therapy for intestinal bacterial overgrowth, a complication of dysmotility
Celiac plexus block with bupivicaine. This has been successful in reducing pain by interrupting visceral afferent pain sensation and increasing GI motility by inhibiting sympathetic efferent activity to the upper abdominal viscera and much of the small bowel [
Complex medication regimens that include amitriptyline, nortriptyline, and gabapentin for relief of neuropathic symptoms, which are difficult to treat
Specialized schooling arrangements, typically necessary for children and young adults
Physical therapy and occupational therapy to help preserve mobility. Activity as tolerated should be encouraged.
Establishing the correct diagnosis of MNGIE disease may help avoid unnecessary exploratory abdominal surgeries, risks associated with anesthesia, and inappropriate therapies.
The approximately 20% of individuals with MNGIE disease who have hepatopathy may be at increased risk for worsening hepatic dysfunction caused by medications metabolized by the liver and as a result of total parenteral nutrition. Therefore, medications that are primarily metabolized in the liver should be used with caution.
Attention to swallowing abnormalities associated with oropharyngeal muscle dysfunction may help decrease the risk for aspiration pneumonia.
Early attention to diverticulosis can help prevent complications such as ruptured diverticula and fatal peritonitis.
Breath test to screen for bacterial overgrowth is recommended.
Surveillance should be individualized based on symptoms and organs affected.
Avoid drugs that interfere with mitochondrial function; these include valproate, phenytoin, chloramphenicol, tetracycline, and certain antipsychotic medications [
Medications primarily metabolized in the liver should be used with caution [
It is appropriate to evaluate apparently asymptomatic or minimally symptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.
Evaluations can include:
Molecular genetic testing if the
Measurements of thymidine phosphorylase enzyme (see
See
Normalization of intracellular thymidine concentrations could reduce the rate of the mtDNA damage, which progressively increases in an individual over time. Possible future treatments include decreasing plasma thymidine concentration by reducing renal reabsorption of thymidine (i.e., blocking the Na+/thymidine transporter), by dialysis, and by enzyme replacement therapy (ERT).
Approaches to ERT include allogeneic stem cell transplantation (AHSCT) [
AHSCT produced nearly full biochemical correction of the deoxythymidine and deoxyuridine imbalances in blood and clinical improvements after successful engraftment of donor cells; however, high morbidity and mortality (16/25 patients died after AHSCT) precludes general use of this therapy for MNGIE disease [
Polymeric enzyme-loaded nanoparticles are being explored for use in MNGIE disease but have not been used in humans [
Platelet transfusion produced only transient reductions in blood nucleosides [
Search
Supplements like coenzyme Q
Although plasma concentration of thymidine can be reduced by hemodialysis, the plasma concentration becomes elevated again in about three hours [
• EMG/NCV
• Brain MRI
• EKG
• Ophthalmologic evaluation
• Audiologic evaluation
• Assessment of hepatic function, renal function, plasma concentrations of amino acids, and serum concentration of lactate and pyruvate
• GI evaluation, which depends on the symptoms and may include abdominal films, abdominal CT, upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, and antroduodenal manometry. Radiologic studies may show hypoperistalsis, gastroparesis, dilated duodenum, and diverticulosis. Small bowel manometry shows reduced amplitude of contractions.
• Consultation with a clinical geneticist and/or genetic counselor
• Early attention to swallowing difficulties and airway protection, especially in the most severely affected individuals
• Trial of dromperidone for nausea and vomiting
• Nutritional support including (when necessary) bolus feedings, gastrostomy tube placement, and total parenteral nutrition
• Antibiotic therapy for intestinal bacterial overgrowth, a complication of dysmotility
• Celiac plexus block with bupivicaine. This has been successful in reducing pain by interrupting visceral afferent pain sensation and increasing GI motility by inhibiting sympathetic efferent activity to the upper abdominal viscera and much of the small bowel [
• Complex medication regimens that include amitriptyline, nortriptyline, and gabapentin for relief of neuropathic symptoms, which are difficult to treat
• Specialized schooling arrangements, typically necessary for children and young adults
• Physical therapy and occupational therapy to help preserve mobility. Activity as tolerated should be encouraged.
• Molecular genetic testing if the
• Measurements of thymidine phosphorylase enzyme (see
• AHSCT produced nearly full biochemical correction of the deoxythymidine and deoxyuridine imbalances in blood and clinical improvements after successful engraftment of donor cells; however, high morbidity and mortality (16/25 patients died after AHSCT) precludes general use of this therapy for MNGIE disease [
• Polymeric enzyme-loaded nanoparticles are being explored for use in MNGIE disease but have not been used in humans [
• Platelet transfusion produced only transient reductions in blood nucleosides [
## Evaluations at Initial Diagnosis
To establish the extent of disease and needs in a proband with MNGIE (
EMG/NCV
Brain MRI
EKG
Ophthalmologic evaluation
Audiologic evaluation
Assessment of hepatic function, renal function, plasma concentrations of amino acids, and serum concentration of lactate and pyruvate
GI evaluation, which depends on the symptoms and may include abdominal films, abdominal CT, upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, and antroduodenal manometry. Radiologic studies may show hypoperistalsis, gastroparesis, dilated duodenum, and diverticulosis. Small bowel manometry shows reduced amplitude of contractions.
Consultation with a clinical geneticist and/or genetic counselor
• EMG/NCV
• Brain MRI
• EKG
• Ophthalmologic evaluation
• Audiologic evaluation
• Assessment of hepatic function, renal function, plasma concentrations of amino acids, and serum concentration of lactate and pyruvate
• GI evaluation, which depends on the symptoms and may include abdominal films, abdominal CT, upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, and antroduodenal manometry. Radiologic studies may show hypoperistalsis, gastroparesis, dilated duodenum, and diverticulosis. Small bowel manometry shows reduced amplitude of contractions.
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Cooperation among multiple specialties including neurology, clinical genetics, nutrition, gastroenterology, pain management, psychiatry, and physical/occupational therapy helps with timely detection and treatment of the various aspects of multiorgan dysfunction. Once symptoms appear, treatment is primarily supportive.
Management of GI dysfunction can include the following:
Early attention to swallowing difficulties and airway protection, especially in the most severely affected individuals
Trial of dromperidone for nausea and vomiting
Nutritional support including (when necessary) bolus feedings, gastrostomy tube placement, and total parenteral nutrition
Antibiotic therapy for intestinal bacterial overgrowth, a complication of dysmotility
Celiac plexus block with bupivicaine. This has been successful in reducing pain by interrupting visceral afferent pain sensation and increasing GI motility by inhibiting sympathetic efferent activity to the upper abdominal viscera and much of the small bowel [
Complex medication regimens that include amitriptyline, nortriptyline, and gabapentin for relief of neuropathic symptoms, which are difficult to treat
Specialized schooling arrangements, typically necessary for children and young adults
Physical therapy and occupational therapy to help preserve mobility. Activity as tolerated should be encouraged.
• Early attention to swallowing difficulties and airway protection, especially in the most severely affected individuals
• Trial of dromperidone for nausea and vomiting
• Nutritional support including (when necessary) bolus feedings, gastrostomy tube placement, and total parenteral nutrition
• Antibiotic therapy for intestinal bacterial overgrowth, a complication of dysmotility
• Celiac plexus block with bupivicaine. This has been successful in reducing pain by interrupting visceral afferent pain sensation and increasing GI motility by inhibiting sympathetic efferent activity to the upper abdominal viscera and much of the small bowel [
• Complex medication regimens that include amitriptyline, nortriptyline, and gabapentin for relief of neuropathic symptoms, which are difficult to treat
• Specialized schooling arrangements, typically necessary for children and young adults
• Physical therapy and occupational therapy to help preserve mobility. Activity as tolerated should be encouraged.
## Prevention of Secondary Complications
Establishing the correct diagnosis of MNGIE disease may help avoid unnecessary exploratory abdominal surgeries, risks associated with anesthesia, and inappropriate therapies.
The approximately 20% of individuals with MNGIE disease who have hepatopathy may be at increased risk for worsening hepatic dysfunction caused by medications metabolized by the liver and as a result of total parenteral nutrition. Therefore, medications that are primarily metabolized in the liver should be used with caution.
Attention to swallowing abnormalities associated with oropharyngeal muscle dysfunction may help decrease the risk for aspiration pneumonia.
Early attention to diverticulosis can help prevent complications such as ruptured diverticula and fatal peritonitis.
## Surveillance
Breath test to screen for bacterial overgrowth is recommended.
Surveillance should be individualized based on symptoms and organs affected.
## Agents/Circumstances to Avoid
Avoid drugs that interfere with mitochondrial function; these include valproate, phenytoin, chloramphenicol, tetracycline, and certain antipsychotic medications [
Medications primarily metabolized in the liver should be used with caution [
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic or minimally symptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.
Evaluations can include:
Molecular genetic testing if the
Measurements of thymidine phosphorylase enzyme (see
See
• Molecular genetic testing if the
• Measurements of thymidine phosphorylase enzyme (see
## Therapies Under Investigation
Normalization of intracellular thymidine concentrations could reduce the rate of the mtDNA damage, which progressively increases in an individual over time. Possible future treatments include decreasing plasma thymidine concentration by reducing renal reabsorption of thymidine (i.e., blocking the Na+/thymidine transporter), by dialysis, and by enzyme replacement therapy (ERT).
Approaches to ERT include allogeneic stem cell transplantation (AHSCT) [
AHSCT produced nearly full biochemical correction of the deoxythymidine and deoxyuridine imbalances in blood and clinical improvements after successful engraftment of donor cells; however, high morbidity and mortality (16/25 patients died after AHSCT) precludes general use of this therapy for MNGIE disease [
Polymeric enzyme-loaded nanoparticles are being explored for use in MNGIE disease but have not been used in humans [
Platelet transfusion produced only transient reductions in blood nucleosides [
Search
• AHSCT produced nearly full biochemical correction of the deoxythymidine and deoxyuridine imbalances in blood and clinical improvements after successful engraftment of donor cells; however, high morbidity and mortality (16/25 patients died after AHSCT) precludes general use of this therapy for MNGIE disease [
• Polymeric enzyme-loaded nanoparticles are being explored for use in MNGIE disease but have not been used in humans [
• Platelet transfusion produced only transient reductions in blood nucleosides [
## Other
Supplements like coenzyme Q
Although plasma concentration of thymidine can be reduced by hemodialysis, the plasma concentration becomes elevated again in about three hours [
## Genetic Counseling
MNGIE disease is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
MNGIE disease is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder
## Carrier Detection
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
## Resources
United Kingdom
United Kingdom
•
•
•
•
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
## Molecular Genetics
Mitochondrial Neurogastrointestinal Encephalopathy Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Mitochondrial Neurogastrointestinal Encephalopathy Disease (
MNGIE (
In MNGIE disease, increases in deoxythymidine and deoxyuridine with relative deficiency of deoxycytidine cause imbalances in mitochondrial deoxynucleotide 5’-triphosphate (dNTP) pools with relative excess of deoxythymidine triphosphate (dTTP) and paucity of deoxycytidine triphosphate (dCTP), producing mtDNA instability [
The mitochondrial dNTP pool is sequestered within the mitochondria.
Mitochondrial DNA is more dependent on thymidine salvage than nuclear DNA, which depends primarily on
Mitochondrial DNA has a limited capability to repair damage as compared to nuclear DNA.
Since mtDNA continues to replicate throughout an individual's life, various tissues throughout the body develop abnormalities over time as a result of progressive oxidative phosphorylation (OXPHOS) impairment. Accumulation of mtDNA pathogenic variants can be observed in fibroblasts and tissues of individuals with MNGIE disease as well in HeLa cells cultured in the presence of increased thymidine [
Thymidine-deficient mice (TP -/-) appear normal and do not show features of MNGIE disease [
See
Thymidine phosphorylase was originally mistakenly identified as a "growth factor" abundant in platelets; therefore, it was named "platelet-derived endothelial cell growth factor" (PD-ECGF or ECGF1). The misconception that thymidine phosphorylase (TP) is a growth factor is based on [
• The mitochondrial dNTP pool is sequestered within the mitochondria.
• Mitochondrial DNA is more dependent on thymidine salvage than nuclear DNA, which depends primarily on
• Mitochondrial DNA has a limited capability to repair damage as compared to nuclear DNA.
## Molecular Pathogenesis
MNGIE (
In MNGIE disease, increases in deoxythymidine and deoxyuridine with relative deficiency of deoxycytidine cause imbalances in mitochondrial deoxynucleotide 5’-triphosphate (dNTP) pools with relative excess of deoxythymidine triphosphate (dTTP) and paucity of deoxycytidine triphosphate (dCTP), producing mtDNA instability [
The mitochondrial dNTP pool is sequestered within the mitochondria.
Mitochondrial DNA is more dependent on thymidine salvage than nuclear DNA, which depends primarily on
Mitochondrial DNA has a limited capability to repair damage as compared to nuclear DNA.
Since mtDNA continues to replicate throughout an individual's life, various tissues throughout the body develop abnormalities over time as a result of progressive oxidative phosphorylation (OXPHOS) impairment. Accumulation of mtDNA pathogenic variants can be observed in fibroblasts and tissues of individuals with MNGIE disease as well in HeLa cells cultured in the presence of increased thymidine [
Thymidine-deficient mice (TP -/-) appear normal and do not show features of MNGIE disease [
See
Thymidine phosphorylase was originally mistakenly identified as a "growth factor" abundant in platelets; therefore, it was named "platelet-derived endothelial cell growth factor" (PD-ECGF or ECGF1). The misconception that thymidine phosphorylase (TP) is a growth factor is based on [
• The mitochondrial dNTP pool is sequestered within the mitochondria.
• Mitochondrial DNA is more dependent on thymidine salvage than nuclear DNA, which depends primarily on
• Mitochondrial DNA has a limited capability to repair damage as compared to nuclear DNA.
## Chapter Notes
Michio Hirano, MD (2016-present)John M Shoffner, MD; Georgia State University (2005-2016)
14 January 2016 (me) Comprehensive update posted live
11 May 2010 (me) Comprehensive update posted live
22 April 2005 (me) Review posted live
16 September 2004 (jms) Original submission
• 14 January 2016 (me) Comprehensive update posted live
• 11 May 2010 (me) Comprehensive update posted live
• 22 April 2005 (me) Review posted live
• 16 September 2004 (jms) Original submission
## Author History
Michio Hirano, MD (2016-present)John M Shoffner, MD; Georgia State University (2005-2016)
## Revision History
14 January 2016 (me) Comprehensive update posted live
11 May 2010 (me) Comprehensive update posted live
22 April 2005 (me) Review posted live
16 September 2004 (jms) Original submission
• 14 January 2016 (me) Comprehensive update posted live
• 11 May 2010 (me) Comprehensive update posted live
• 22 April 2005 (me) Review posted live
• 16 September 2004 (jms) Original submission
## References
## Literature Cited
|
[
"RS Bedlack, T Vu, S Hammans, SA Sparr, B Myers, J Morgenlander, M Hirano. MNGIE neuropathy: five cases mimicking chronic inflammatory demyelinating polyneuropathy.. Muscle Nerve 2004;29:364-8",
"NS Brown, R Bicknell. Thymidine phosphorylase, 2-deoxy-D-ribose and angiogenesis.. Biochem J 1998;334:1-8",
"FJ Carod-Artal, MD Herrero, MC Lara, E Lopez-Gallardo, E Ruiz-Pesini, R Marti, J Montoya. Cognitive dysfunction and hypogonadotropic hypogonadism in a Brazilian patient with mitochondrial neurogastrointestinal encephalomyopathy and a novel ECGF1 mutation.. Eur J Neurol 2007;14:581-5",
"N Celebi, A Sahin, O Canbay, F Uzümcügil, U Aypar. Abdominal pain related to mitochondrial neurogastrointestinal encephalomyopathy syndrome may benefit from splanchnic nerve blockade.. Paediatr Anaesth 2006;16:1073-6",
"M Debouverie, M Wagner, X Ducrocq, Y Grignon, B Mousson, M Weber. Rev Neurol (Paris) 1997;153:547-53",
"C De Vocht, A Ranquin, R Willaert, JA Van Ginderachter, T Vanhaecke, V Rogiers, W Versées, P Van Gelder, J Steyaert. Assessment of stability, toxicity and immunogenicity of new polymeric nanoreactors for use in enzyme replacement therapy of MNGIE.. J Control Release 2009;137:246-54",
"LD Fairbanks, AM Marinaki, EA Carrey, SR Hammans, JA Duley. Deoxyuridine accumulation in urine in thymidine phosphorylase deficiency (MNGIE).. J Inherit Metab Dis 2002;25:603-4",
"A Finkenstedt, M Schranz, S Bosch, D Karall, SS Burgi, C Ensinger, M Drach, JA Mayr, AR Janecke, W Vogel, D Nachbaur, H Zoller. MNGIE syndrome: Liver cirrhosis should be ruled out prior to bone marrow transplantation.. JIMD Reports 2013;10:41-4",
"B Garcia-Diaz, C Garone, E Barca, H Mojahed, P Gutierrez, G Pizzorno, K Tanji, F Arias-Mendoza, CM Quinzii, M Hirano. Deoxynucleoside stress exacerbates the phenotype of a mouse model of mitochondrial neurogastrointestinal encephalopathy.. Brain 2014;137:1337-49",
"C Garone, S Tadesse, M Hirano. Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy.. Brain 2011;134:3326-32",
"C Giordano, M Sebastiani, R De Giorgio, C Travaglini, A Tancredi, ML Valentino, M Bellan, A Cossarizza, M Hirano, G d'Amati, V Carelli. Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion.. Am J Pathol 2008;173:1120-8",
"C Giordano, M Sebastiani, G Plazzi, C Travaglini, P Sale, M Pinti, A Tancredi, R Liguori, P Montagna, M Bellan, ML Valentino, A Cossarizza, M Hirano, G d'Amati, V Carelli. Mitochondrial neurogastrointestinal encephalomyopathy: evidence of mitochondrial DNA depletion in the small intestine.. Gastroenterology 2006;130:893-901",
"K Hagiwara, G Stenman, H Honda, P Sahlin, A Andersson, K Miyazono, CH Heldin, F Ishikawa, F Takaku. Organization and chromosomal localization of the human platelet-derived endothelial cell growth factor gene.. Mol Cell Biol 1991;11:2125-32",
"JP Halter, W Michael, M Schupbach, H Mandel, C Casali, K Orchard, M Collin, D Valcarcel, A Rovelli, M Filosto, MT Dotti, G Marotta, G Pintos, P Barba, A Accarino, C Ferra, I Illa, Y Beguin, JA Bakker, JJ Boelens, IF de Coo, K Fay, CM Sue, D Nachbaur, H Zoller, C Sobreira, B Pinto Simoes, SR Hammans, D Savage, R Marti, PF Chinnery, R Elhasid, A Gratwohl, M Hirano. Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy.. Brain 2015;138:2847-58",
"H Hamano, T Ohta, Y Takekawa, K Kouda, Y Shinohara. Rinsho Shinkeigaku 1997;37:917-22",
"CO Hanemann, C Bergmann, J Senderek, K Zerres, AD Sperfeld. Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation.. Arch Neurol 2003;60:605-9",
"M Haraguchi, H Tsujimoto, M Fukushima, I Higuchi, H Kuribayashi, H Utsumi, A Nakayama, Y Hashizume, J Hirato, H Yoshida, H Hara, S Hamano, H Kawaguchi, T Furukawa, K Miyazono, F Ishikawa, H Toyoshima, T Kaname, M Komatsu, ZS Chen, T Gotanda, T Tachiwada, T Sumizawa, K Miyadera, M Osame, H Yoshida, T Noda, Y Yamada, S Akiyama. Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.. Mol Cell Biol 2002;22:5212-21",
"M Hirano, R Martí, C Casali, S Tadesse, T Uldrick, B Fine, DM Escolar, ML Valentino, I Nishino, C Hesdorffer, J Schwartz, RG Hawks, DL Martone, MS Cairo, S DiMauro, M Stanzani, JH Garvin, DG Savage. Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE.. Neurology 2006;67:1458-60",
"M Hirano, Y Nishigaki, R Marti. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a disease of two genomes.. Neurologist 2004;10:8-17",
"M Hirano, G Silvestri, DM Blake, A Lombes, C Minetti, E Bonilla, AP Hays, RE Lovelace, I Butler, TE Bertorini. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder.. Neurology 1994;44:721-7",
"IH Kalkan, O Tayfur, E Oztas, Y Beyazit, H Yildiz, B Tunc. A novel finding in MNGIE (mitochondrial neurogastrointestinal encephalomyopathy): hypergonadotropic hypogonadism.. Hormones 2012;11:377-9",
"J Kaukonen, JK Juselius, V Tiranti, A Kyttala, M Zeviani, GP Comi, S Keranen, L Peltonen, A Suomalainen. Role of adenine nucleotide translocator 1 in mtDNA maintenance.. Science 2000;289:782-5",
"C Kornblum, TJ Nicholls, TB Haack, S Scholer, V Peeva, K Danhauser, K Hallmann, G Zsurka, J Rorbach, A Iuso, T Wieland, M Sciacco, D Ronchi, GP Comi, M Moggio, CM Quinzii, S DiMauro, SE Calvo, VK Mootha, T Klopstock, TM Strom, T Meitinger, M Minczuk, WS Kunz, H Prokisch. Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease.. Nat Genet. 2013;45:214-9",
"MC Lara, B Weiss, I Illa, P Madoz, L Massuet, AL Andreu, ML Valentino, Y Anikster, M Hirano, R Martí. Infusion of platelets transiently reduces nucleoside overload in MNGIE.. Neurology 2006;67:1461-3",
"LC López, HO Akman, A Garcia-Cazorla, B Dorado, R Marti, I Nishino, S Tadesse, G Pizzorno, DC Shungu, E Bonilla, K Tanji, M Hirano. Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase deficient mice.. Hum Mol Genet. 2009;18:714-22",
"H Mandel, R Szargel, V Labay, O Elpeleg, A Saada, A Shalata, Y Anbinder, D Berkowitz, C Hartman, M Barak, S Eriksson, N Cohen. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.. Nat Genet 2001;29:337-41",
"R Martí, Y Nishigaki, M Hirano. Elevated plasma deoxyuridine in patients with thymidine phosphorylase deficiency.. Biochem Biophys Res Commun 2003;303:14-8",
"R Martí, A Spinazzola, S Tadesse, I Nishino, Y Nishigaki, M Hirano. Definitive diagnosis of mitochondrial neurogastrointestinal encephalomyopathy by biochemical assays.. Clin Chem 2004;50:120-4",
"R Martí, JJ Verschuuren, A Buchman, I Hirano, S Tadesse, AB van Kuilenburg, AH van Gennip, BJ Poorthuis, M Hirano. Late-onset MNGIE due to partial loss of thymidine phosphorylase activity.. Ann Neurol. 2005;58:649-52",
"R Massa, A Tessa, M Margollicci, V Micheli, A Romigi, G Tozzi, C Terracciano, F Piemonte, G Bernardi, FM Santorelli. Late-onset MNGIE without peripheral neuropathy due to incomplete loss of thymidine phosphorylase activity.. Neuromuscular disorders 2009;19:837-40",
"NF Moran, MD Bain, MM Muqit, BE Bax. Carrier erythrocyte entrapped thymidine phosphorylase therapy for MNGIE.. Neurology 2008;71:686-8",
"Y Nishigaki, R Marti, WC Copeland, M Hirano. Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency.. J Clin Invest 2003;111:1913-21",
"I Nishino, A Spinazzola, M Hirano. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.. Science 1999;283:689-92",
"I Nishino, A Spinazzola, A Papadimitriou, S Hammans, I Steiner, CD Hahn, AM Connolly, A Verloes, J Guimaraes, I Maillard, H Hamano, MA Donati, CE Semrad, JA Russell, AL Andreu, GM Hadjigeorgiou, TH Vu, S Tadesse, TG Nygaard, I Nonaka, I Hirano, E Bonilla, LP Rowland, S DiMauro, M Hirano. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.. Ann Neurol 2000;47:792-800",
"MC Peedikayil, EI Kagevi, E Abufarhaneh, MD Alsayed, HA Alzahrani. Mitochondrial neurogastrointestinal encephalomyopathy treated with stem cell transplantation: a case report and review of literature.. Hematol Oncol Stem Cell Ther. 2015;8:85-90",
"AR Perez-Atayde, V Fox, JE Teitelbaum, DA Anthony, R Fadic, L Kalsner, M Rivkin, DR Johns, GF Cox. Mitochondrial neurogastrointestinal encephalomyopathy: diagnosis by rectal biopsy.. Am J Surg Pathol 1998;22:1141-7",
"S Rahman, IP Hargreaves. Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE.. Neurology 2007;68:1872",
"A Saada, A Shaag, H Mandel, Y Nevo, S Eriksson, O Elpeleg. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.. Nat Genet 2001;29:342-4",
"G Said, C Lacroix, V Plante-Bordeneuve, B Messing, A Slama, P Crenn, A Nivelon-Chevallier, L Bedenne, P Soichot, E Manceau, D Rigaud, A Guiochon-Mantel, C Matuchansky. Clinicopathological aspects of the neuropathy of neurogastrointestinal encephalomyopathy (MNGIE) in four patients including two with a Charcot-Marie-Tooth presentation.. J Neurol 2005;252:655-62",
"EA Schon, S DiMauro, M Hirano. Human mitochondrial DNA: roles of inherited and somatic mutations.. Nat Rev Genet. 2012;13:878-90",
"A Spinazzola, C Viscomi, E Fernandez-Vizarra, F Carrara, P D'Adamo, S Calvo, RM Marsano, C Donnini, H Weiher, P Strisciuglio, R Parini, E Sarzi, A Chan, S DiMauro, A Rotig, P Gasparini, I Ferrero, VK Mootha, V Tiranti, M Zeviani. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.. Nat Genet 2006;38:570-5",
"S Song, LJ Wheeler, CK Mathews. Deoxyribonucleotide pool imbalance stimulates deletions in HeLa cell mitochondrial DNA.. J Biol Chem 2003;278:43893-6",
"JN Spelbrink, FY Li, V Tiranti, K Nikali, QP Yuan, M Tariq, S Wanrooij, N Garrido, G Comi, L Morandi, L Santoro, A Toscano, GM Fabrizi, H Somer, R Croxen, D Beeson, J Poulton, A Suomalainen, HT Jacobs, M Zeviani, C Larsson. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria.. Nat Genet 2001;28:223-31",
"A Spinazzola, R Marti, I Nishino, AL Andreu, A Naini, S Tadesse, I Pela, E Zammarchi, MA Donati, JA Oliver, M Hirano. Altered thymidine metabolism due to defects of thymidine phosphorylase.. J Biol Chem 2002;277:4128-33",
"K Szigeti, LJ Wong, CL Perng, GM Saifi, K Eldin, AM Adesina, DL Cass, M Hirano, JR Lupski, F Scaglia. MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation.. J Med Genet 2004;41:125-9",
"JE Teitelbaum, CB Berde, S Nurko, C Buonomo, AR Perez-Atayde, VL Fox. Diagnosis and management of MNGIE syndrome in children: case report and review of the literature.. J Pediatr Gastroenterol Nutr 2002;35:377-83",
"ML Valentino, R Martí, S Tadesse, LC López, JL Manes, J Lyzak, A Hahn, V Carelli, M Hirano. Thymidine and deoxyuridine accumulate in tissues of patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).. FEBS Lett 2007;581:3410-4",
"G Van Goethem, B Dermaut, A Lofgren, JJ Martin, C Van Broeckhoven. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.. Nat Genet 2001;28:211-2",
"J Vissing, K Ravn, ER Danielsen, M Duno, F Wibrand, RA Wevers, M Schwartz. Multiple mtDNA deletions with features of MNGIE.. Neurology 2002;59:926-9",
"H Yavuz, A Ozel, M Christensen, E Christensen, M Schwartz, M Elmaci, J Vissing. Treatment of mitochondrial neurogastrointestinal encephalomyopathy with dialysis.. Arch Neurol 2007;64:435-8",
"V Zimmer, W Feiden, G Becker, A Zimmer, W Reith, J Raedle, F Lammert, S Zeuzem, M Hirano, M Menges. Absence of the interstitial cell of Cajal network in mitochondrial neurogastrointestinal encephalomyopathy.. Neurogastroenterol Motil 2009;21:627-31"
] |
22/4/2005
|
14/1/2016
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mody-ov
|
mody-ov
|
[
"MODY Overview",
"MODY Overview",
"ATP-binding cassette sub-family C member 8",
"ATP-sensitive inward rectifier potassium channel 11",
"Bile salt-activated lipase",
"DCC-interacting protein 13-alpha",
"Hepatocyte nuclear factor 1-alpha",
"Hepatocyte nuclear factor 1-beta",
"Hepatocyte nuclear factor 4-alpha",
"Hexokinase-4",
"Insulin",
"Krueppel-like factor 11",
"Neurogenic differentiation factor 1",
"Paired box protein Pax-4",
"Pancreas/duodenum homeobox protein 1",
"Tyrosine-protein kinase Blk",
"ABCC8",
"APPL1",
"BLK",
"CEL",
"GCK",
"HNF1A",
"HNF1B",
"HNF4A",
"INS",
"KCNJ11",
"KLF11",
"NEUROD1",
"PAX4",
"PDX1",
"Maturity Onset Diabetes of the Young",
"Overview"
] |
Maturity-Onset Diabetes of the Young Overview
|
Rochelle Naylor, Amy Knight Johnson, Daniela del Gaudio
|
Summary The purpose of this overview is to: Describe the Review the Provide an Inform (when possible) Inform
|
## Clinical Characteristics of MODY
Maturity-onset diabetes of the young (MODY) is a group of inherited disorders of non-autoimmune diabetes mellitus which usually present in adolescence or young adulthood.
A clinical diagnosis of MODY can be suspected in individuals with:
Early-onset diabetes in adolescence or young adulthood (typically age <35 years);
Features atypical for type 1 diabetes mellitus including the following:
Absence of pancreatic islet autoantibodies [
Evidence of endogenous insulin production beyond the honeymoon period (i.e., 3-5 years after the onset of diabetes)
Measurable C-peptide in the presence of hyperglycemia (C-peptide ≥0.60 ng/mL or 0.2 nmol/L) [
Low insulin requirement for treatment (i.e., <0.5 U/kg/d)
Lack of ketoacidosis when insulin is omitted from treatment
Features atypical for type 2 diabetes mellitus including the following:
Onset of diabetes before age 45 years
Lack of significant obesity
Lack of acanthosis nigricans
Normal triglyceride levels and/or normal or elevated high-density lipoprotein cholesterol (HDL-C)
Mild, stable fasting hyperglycemia that does not progress or respond appreciably to pharmacologic therapy
Extreme sensitivity to sulfonylureas
Extrapancreatic features (e.g., renal, hepatic, gastrointestinal)
A personal history or family history of neonatal diabetes or neonatal hypoglycemia
A family history of diabetes consistent with autosomal dominant inheritance that contrasts with type 1 diabetes and type 2 diabetes in the following ways:
Type 1 diabetes can run in families but is often sporadic: only 2%-6% of individuals with type 1 diabetes have an affected parent [
Type 2 diabetes often runs in families: shared risk alleles and shared environment can lead to occurrence of type 2 diabetes in multiple family members. Family history that helps distinguish between type 2 diabetes and MODY are onset of diabetes after age 45 years in association with obesity (type 2 diabetes) versus onset of diabetes before age 35 years and lack of obesity (MODY).
Note: (1) A clinical prediction tool that can be used to calculate an individual's probability of having MODY also provides a rational approach to molecular genetic testing [
Prevalence of MODY. Although estimates of prevalence vary by country, between children and adults, and by method of ascertainment, MODY is thought to account for at least 1%-3% of all diabetes [
The prevalence of MODY in racial and ethnic minorities may be underrepresented as many individuals with MODY remain undiagnosed [
• Early-onset diabetes in adolescence or young adulthood (typically age <35 years);
• Features atypical for type 1 diabetes mellitus including the following:
• Absence of pancreatic islet autoantibodies [
• Evidence of endogenous insulin production beyond the honeymoon period (i.e., 3-5 years after the onset of diabetes)
• Measurable C-peptide in the presence of hyperglycemia (C-peptide ≥0.60 ng/mL or 0.2 nmol/L) [
• Low insulin requirement for treatment (i.e., <0.5 U/kg/d)
• Lack of ketoacidosis when insulin is omitted from treatment
• Absence of pancreatic islet autoantibodies [
• Evidence of endogenous insulin production beyond the honeymoon period (i.e., 3-5 years after the onset of diabetes)
• Measurable C-peptide in the presence of hyperglycemia (C-peptide ≥0.60 ng/mL or 0.2 nmol/L) [
• Low insulin requirement for treatment (i.e., <0.5 U/kg/d)
• Lack of ketoacidosis when insulin is omitted from treatment
• Features atypical for type 2 diabetes mellitus including the following:
• Onset of diabetes before age 45 years
• Lack of significant obesity
• Lack of acanthosis nigricans
• Normal triglyceride levels and/or normal or elevated high-density lipoprotein cholesterol (HDL-C)
• Onset of diabetes before age 45 years
• Lack of significant obesity
• Lack of acanthosis nigricans
• Normal triglyceride levels and/or normal or elevated high-density lipoprotein cholesterol (HDL-C)
• Mild, stable fasting hyperglycemia that does not progress or respond appreciably to pharmacologic therapy
• Extreme sensitivity to sulfonylureas
• Extrapancreatic features (e.g., renal, hepatic, gastrointestinal)
• A personal history or family history of neonatal diabetes or neonatal hypoglycemia
• A family history of diabetes consistent with autosomal dominant inheritance that contrasts with type 1 diabetes and type 2 diabetes in the following ways:
• Type 1 diabetes can run in families but is often sporadic: only 2%-6% of individuals with type 1 diabetes have an affected parent [
• Type 2 diabetes often runs in families: shared risk alleles and shared environment can lead to occurrence of type 2 diabetes in multiple family members. Family history that helps distinguish between type 2 diabetes and MODY are onset of diabetes after age 45 years in association with obesity (type 2 diabetes) versus onset of diabetes before age 35 years and lack of obesity (MODY).
• Type 1 diabetes can run in families but is often sporadic: only 2%-6% of individuals with type 1 diabetes have an affected parent [
• Type 2 diabetes often runs in families: shared risk alleles and shared environment can lead to occurrence of type 2 diabetes in multiple family members. Family history that helps distinguish between type 2 diabetes and MODY are onset of diabetes after age 45 years in association with obesity (type 2 diabetes) versus onset of diabetes before age 35 years and lack of obesity (MODY).
• Absence of pancreatic islet autoantibodies [
• Evidence of endogenous insulin production beyond the honeymoon period (i.e., 3-5 years after the onset of diabetes)
• Measurable C-peptide in the presence of hyperglycemia (C-peptide ≥0.60 ng/mL or 0.2 nmol/L) [
• Low insulin requirement for treatment (i.e., <0.5 U/kg/d)
• Lack of ketoacidosis when insulin is omitted from treatment
• Onset of diabetes before age 45 years
• Lack of significant obesity
• Lack of acanthosis nigricans
• Normal triglyceride levels and/or normal or elevated high-density lipoprotein cholesterol (HDL-C)
• Type 1 diabetes can run in families but is often sporadic: only 2%-6% of individuals with type 1 diabetes have an affected parent [
• Type 2 diabetes often runs in families: shared risk alleles and shared environment can lead to occurrence of type 2 diabetes in multiple family members. Family history that helps distinguish between type 2 diabetes and MODY are onset of diabetes after age 45 years in association with obesity (type 2 diabetes) versus onset of diabetes before age 35 years and lack of obesity (MODY).
## Genetic Causes of MODY
To date it has been proposed that pathogenic variants in at least 14 genes cause MODY. The genes and associated clinical features are summarized in
The four most common causes of MODY are the following:
Approximately 20% of all MODY has been attributed to pathogenic variants in ten other genes – some of which were designated before the availability of large-scale genetic testing and thus may be incorrectly associated with MODY. Molecular genetic testing of large numbers of individuals with possible MODY as well as other investigations (e.g., functional studies and/or segregation of variants with the disease) are needed to determine the significance of variants previously inferred to be pathogenic based on other methods.
A portion of MODY may be caused by pathogenic variants in yet-to-be-identified genes or complex molecular alterations in the known MODY-related genes that were not detected by previous genetic testing methods [
Maturity-Onset Diabetes of the Young (MODY): Genes and Associated Clinical Features
Pancreatic atrophy → exocrine pancreatic insufficiency
Fibrosis & lipomatosis → diabetes
Stable, mild fasting hyperglycemia at birth
Typically asymptomatic; diagnosis often incidental
Transient neonatal hyperinsulinemic hypoglycemia in some
Progressive insulin secretory defect
OGTT frequently needed to make an early diagnosis
Renal glycosuria
IUGR
Renal anomalies
Urogenital tract anomalies
Pancreatic hypoplasia
Birth weight >800 g above normal
Transient neonatal hyperinsulinemic hypoglycemia common
Progressive insulin secretory defect
IUGR = intrauterine growth restriction; OGTT = oral glucose tolerance test
Pathogenic variants in this gene are also associated with
Pathogenic variants in this gene are also associated with
Should be considered in affected individuals responsive to sulfonylurea who test negative for
Two
Some variants in
One individual had a large
Depending on the population studied
~1.8% of
~1.2% of
Related to overall glycemic control [
~33% of
~1.9% of
Individuals with
Penetrance in
Of the kidney structural defects, the most common are renal cysts, which can be evident prenatally as isolated bilateral hyperechogenic kidneys [
Kidney functional defects include renal magnesium wasting, which can lead to life-threatening hypomagnesemia, and hyperuricemia, which can manifest as early-onset gout.
Early-onset diabetes mellitus is the most common extrarenal manifestation and usually presents after the identification of childhood-onset kidney disease. The mean age of onset of diabetes is 24 years [
Additional findings can include pancreatic atrophy, genital tract abnormalities in females, abnormal liver function, and primary hyperparathyroidism [
• Pancreatic atrophy → exocrine pancreatic insufficiency
• Fibrosis & lipomatosis → diabetes
• Stable, mild fasting hyperglycemia at birth
• Typically asymptomatic; diagnosis often incidental
• Transient neonatal hyperinsulinemic hypoglycemia in some
• Progressive insulin secretory defect
• OGTT frequently needed to make an early diagnosis
• Renal glycosuria
• IUGR
• Renal anomalies
• Urogenital tract anomalies
• Pancreatic hypoplasia
• Birth weight >800 g above normal
• Transient neonatal hyperinsulinemic hypoglycemia common
• Progressive insulin secretory defect
## Evaluation Strategy to Identify the Genetic Cause of MODY in a Proband
Establishing a specific genetic cause of MODY in an individual whose clinical findings suggest MODY (see
Establishing the specific genetic cause of MODY usually involves a medical history, family history, physical examination, diabetes-related laboratory testing, and molecular genetic testing.
Other than findings consistent with gout (suggestive of
In
High-sensitivity C-reactive protein (hsCRP) is useful as values are lower in
Single-gene testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because of the clinical and genetic heterogeneity of MODY, the genetic cause of MODY in a person with the distinctive clinical findings described in
When the phenotypic and laboratory findings are consistent with one or more genetic causes of MODY (
For an introduction to multigene panels click
In individuals with distinguishing phenotypic features suggestive of a contiguous gene deletion, such as the
To estimate the breakpoints and size of a whole-gene deletion detected by gene-targeted deletion/duplication analysis
For an introduction to comprehensive genomic testing click
• In
• High-sensitivity C-reactive protein (hsCRP) is useful as values are lower in
• In individuals with distinguishing phenotypic features suggestive of a contiguous gene deletion, such as the
• To estimate the breakpoints and size of a whole-gene deletion detected by gene-targeted deletion/duplication analysis
## Option 1
When the phenotypic and laboratory findings are consistent with one or more genetic causes of MODY (
## Option 2
For an introduction to multigene panels click
In individuals with distinguishing phenotypic features suggestive of a contiguous gene deletion, such as the
To estimate the breakpoints and size of a whole-gene deletion detected by gene-targeted deletion/duplication analysis
• In individuals with distinguishing phenotypic features suggestive of a contiguous gene deletion, such as the
• To estimate the breakpoints and size of a whole-gene deletion detected by gene-targeted deletion/duplication analysis
## Option 3
For an introduction to comprehensive genomic testing click
## Management of MODY Based on Genetic Cause
MODY: Management by Genetic Cause
X
X
Commonly needed
X
GLP-1 = glucagon-like peptide-1; OAD = oral antidiabetic agents
Depending on genotype of the fetus (see
Patients with
May require only small doses of insulin
At the level of glycemic control observed in
Fetal genotype:
Fetal outcome:
If the fetus has inherited the maternal GCK pathogenic variant, the fetus will produce normal amounts of insulin and grow normally. Current recommendations do not support use of insulin in the mother.
If the fetus has not inherited the maternal GCK pathogenic variant, the fetus will respond to maternal hyperglycemia with excess insulin production resulting in excess growth. While current recommendations are to treat the mother with insulin to decrease the risk of macrosomia, data to support these recommendations are limited.
Note: While more data currently support fetal genotype-based treatment, some advocate treating all women with GCK-MODY with insulin early in pregnancy [
Additional considerations:
Glycemic excursions are difficult to manage with insulin in GCK-MODY as exogenous insulin will suppress endogenous insulin secretion and counter-regulation occurs at a lower blood glucose value [
If the fetus inherits a GCK pathogenic variant from the father or has a de novo GCK pathogenic variant, the fetus will have decreased insulin secretion leading to lower birth weight.
Influence of Parental and Fetal Genotype on Fetal Growth and Recommended Management of the Mother during a Pregnancy at Risk for
When the fetal genotype is not known, it can be inferred from abdominal circumference on second trimester fetal ultrasound.
Assessed by second-trimester ultrasound [
Individuals with
In the US, glyburide is the most commonly used sulfonylurea for
Because individuals with
Over time the glycemic control of sulfonylureas may deteriorate in individuals with
Because of the increased risk of cardiovascular disease (despite the accompanying elevated levels of HDL and low levels of high-sensitivity C- reactive protein (hsCRP), persons with
Hyperglycemia during pregnancy in a woman with
Of note, the background risk for birth defects in the general population is approximately 3%-4%. Women who have pre-pregnancy insulin-dependent diabetes are at increased risk of having a child with a birth defect (~6%-8% risk). Women with non-insulin dependent diabetes prior to pregnancy are also at risk greater than the general population of having a baby with a birth defect; however, their risk is less than that of women who have insulin-dependent diabetes prior to pregnancy.
Appropriate glycemic control during pregnancy may reduce (though does not eliminate) the risk of having a child with a birth defect and also decrease the risk of having a child with neonatal diabetes-related complications (e.g., macrosomia, hypoglycemia, and electrolyte abnormalities). In a meta-analysis by
To screen for fetal birth defects in pregnant women with diabetes, prenatal high-resolution ultrasound with fetal echocardiogram is recommended; referral to a maternal-fetal medicine specialist may also be considered.
See
• If the fetus has inherited the maternal GCK pathogenic variant, the fetus will produce normal amounts of insulin and grow normally. Current recommendations do not support use of insulin in the mother.
• If the fetus has not inherited the maternal GCK pathogenic variant, the fetus will respond to maternal hyperglycemia with excess insulin production resulting in excess growth. While current recommendations are to treat the mother with insulin to decrease the risk of macrosomia, data to support these recommendations are limited.
• Note: While more data currently support fetal genotype-based treatment, some advocate treating all women with GCK-MODY with insulin early in pregnancy [
• Glycemic excursions are difficult to manage with insulin in GCK-MODY as exogenous insulin will suppress endogenous insulin secretion and counter-regulation occurs at a lower blood glucose value [
• If the fetus inherits a GCK pathogenic variant from the father or has a de novo GCK pathogenic variant, the fetus will have decreased insulin secretion leading to lower birth weight.
## Risk Assessment and Surveillance of At-Risk Relatives for Early Detection and Treatment of MODY
The advantages of early clarification of the genetic status of asymptomatic family members at risk for MODY:
Routine surveillance to identify hyperglycemia enables prompt and appropriate treatment based on the type of MODY (
For those at increased risk, early intervention reduces the long-term risk of hyperglycemia-related microvascular and macrovascular complications [
Families with individuals with MODY as well as the much more common type 1 and type 2 diabetes [
Studies have shown that family members at risk for MODY are generally in favor of early predictive genetic testing [
Maturity-onset diabetes of the young (MODY) is generally inherited in an autosomal dominant manner.
Note: Biallelic pathogenic variants in
Risk Assessment of Family Members of a Proband with Maturity-Onset Diabetes of the Young (MODY)
Affected & heterozygous for MODY-related pathogenic or likely pathogenic variant OR
Apparently asymptomatic & heterozygous due to reduced penetrance or variable expressivity OR
Not heterozygous because either:
Pathogenic or likely pathogenic variant was
Parental germline mosaicism
Molecular genetic testing
If familial pathogenic or likely pathogenic variant is identified, surveillance for early manifestations of MODY (See
If familial pathogenic or likely pathogenic variant is not identified, monitoring consistent w/standard of care for general population
If one parent of the proband is affected/heterozygous: 50% risk to sibs of inheriting variant / being at risk for MODY
If the proband has a known MODY-related pathogenic variant that is not detectable in leukocyte DNA of either parent: ~1% recurrence risk to sibs due to the theoretic possibility of parental germline mosaicism
The proportion of cases caused by a
When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely
• Routine surveillance to identify hyperglycemia enables prompt and appropriate treatment based on the type of MODY (
• For those at increased risk, early intervention reduces the long-term risk of hyperglycemia-related microvascular and macrovascular complications [
• Families with individuals with MODY as well as the much more common type 1 and type 2 diabetes [
• Affected & heterozygous for MODY-related pathogenic or likely pathogenic variant OR
• Apparently asymptomatic & heterozygous due to reduced penetrance or variable expressivity OR
• Not heterozygous because either:
• Pathogenic or likely pathogenic variant was
• Parental germline mosaicism
• Pathogenic or likely pathogenic variant was
• Parental germline mosaicism
• Pathogenic or likely pathogenic variant was
• Parental germline mosaicism
• If familial pathogenic or likely pathogenic variant is identified, surveillance for early manifestations of MODY (See
• If familial pathogenic or likely pathogenic variant is not identified, monitoring consistent w/standard of care for general population
• If one parent of the proband is affected/heterozygous: 50% risk to sibs of inheriting variant / being at risk for MODY
• If the proband has a known MODY-related pathogenic variant that is not detectable in leukocyte DNA of either parent: ~1% recurrence risk to sibs due to the theoretic possibility of parental germline mosaicism
## Mode of Inheritance
Maturity-onset diabetes of the young (MODY) is generally inherited in an autosomal dominant manner.
Note: Biallelic pathogenic variants in
## Risk to Family Members
Risk Assessment of Family Members of a Proband with Maturity-Onset Diabetes of the Young (MODY)
Affected & heterozygous for MODY-related pathogenic or likely pathogenic variant OR
Apparently asymptomatic & heterozygous due to reduced penetrance or variable expressivity OR
Not heterozygous because either:
Pathogenic or likely pathogenic variant was
Parental germline mosaicism
Molecular genetic testing
If familial pathogenic or likely pathogenic variant is identified, surveillance for early manifestations of MODY (See
If familial pathogenic or likely pathogenic variant is not identified, monitoring consistent w/standard of care for general population
If one parent of the proband is affected/heterozygous: 50% risk to sibs of inheriting variant / being at risk for MODY
If the proband has a known MODY-related pathogenic variant that is not detectable in leukocyte DNA of either parent: ~1% recurrence risk to sibs due to the theoretic possibility of parental germline mosaicism
The proportion of cases caused by a
When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely
• Affected & heterozygous for MODY-related pathogenic or likely pathogenic variant OR
• Apparently asymptomatic & heterozygous due to reduced penetrance or variable expressivity OR
• Not heterozygous because either:
• Pathogenic or likely pathogenic variant was
• Parental germline mosaicism
• Pathogenic or likely pathogenic variant was
• Parental germline mosaicism
• Pathogenic or likely pathogenic variant was
• Parental germline mosaicism
• If familial pathogenic or likely pathogenic variant is identified, surveillance for early manifestations of MODY (See
• If familial pathogenic or likely pathogenic variant is not identified, monitoring consistent w/standard of care for general population
• If one parent of the proband is affected/heterozygous: 50% risk to sibs of inheriting variant / being at risk for MODY
• If the proband has a known MODY-related pathogenic variant that is not detectable in leukocyte DNA of either parent: ~1% recurrence risk to sibs due to the theoretic possibility of parental germline mosaicism
## Resources
United Kingdom
United Kingdom
•
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
## Chapter Notes
24 May 2018 (bp) Review posted live
5 September 2017 (ddg) Original submission
• 24 May 2018 (bp) Review posted live
• 5 September 2017 (ddg) Original submission
## Revision History
24 May 2018 (bp) Review posted live
5 September 2017 (ddg) Original submission
• 24 May 2018 (bp) Review posted live
• 5 September 2017 (ddg) Original submission
## References
ABMG Board of Directors. ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. Genet Med. 2015;17:68-9. [
• ABMG Board of Directors. ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. Genet Med. 2015;17:68-9. [
## Published Guidelines / Policy Statements
ABMG Board of Directors. ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. Genet Med. 2015;17:68-9. [
• ABMG Board of Directors. ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. Genet Med. 2015;17:68-9. [
## Literature Cited
|
[] |
24/5/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mona
|
mona
|
[
"Torg Syndrome",
"Torg-Winchester Syndrome",
"MMP2-Related Multicentric Osteolysis",
"Nodulosis",
"and Arthropathy",
"Torg Syndrome",
"Torg-Winchester Syndrome",
"72 kDa type IV collagenase",
"MMP2",
"Multicentric Osteolysis Nodulosis and Arthropathy"
] |
Multicentric Osteolysis Nodulosis and Arthropathy
|
Gandham SriLakshmi Bhavani, Hitesh Shah, Anju Shukla, Katta Mohan Girisha
|
Summary Multicentric osteolysis nodulosis and arthropathy (MONA) is a skeletal dysplasia characterized by progressive osteolysis (particularly of the carpal and tarsal bones), osteoporosis, subcutaneous nodules on the palms and soles, and progressive arthropathy (joint contractures, pain, swelling, and stiffness). Other manifestations include coarse facies, pigmented skin lesions, cardiac defects, and corneal opacities. Onset is usually between ages six months and six years (range: birth to 11 years). The diagnosis of MONA is established in a proband with characteristic clinical and radiographic findings and either biallelic pathogenic variants in MONA is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the
|
## Diagnosis
Formal diagnostic criteria have not been established for multicentric osteolysis nodulosis and arthropathy (MONA).
MONA
Joint disease manifest predominantly as pain, swelling, and contractures of the small joints of the hands and feet in early childhood (See
Subcutaneous nodules, usually on the palms and soles (See
Coarse facial features
Gingival hypertrophy
Progressive osteopenia and osteolysis with early and predominant involvement of the bones of the hands (see
Thin cortices of the long bones (see
Milder and similar changes in other bones
The diagnosis of MONA
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multicentric Osteolysis Nodulosis and Arthropathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Analysis of matrix metalloproteinase 2 enzyme activity can be performed by the electrophoretic technique gelatin zymography on body fluids and/or cell or tissue extracts [
• Joint disease manifest predominantly as pain, swelling, and contractures of the small joints of the hands and feet in early childhood (See
• Subcutaneous nodules, usually on the palms and soles (See
• Coarse facial features
• Gingival hypertrophy
• Progressive osteopenia and osteolysis with early and predominant involvement of the bones of the hands (see
• Thin cortices of the long bones (see
• Milder and similar changes in other bones
• For an introduction to multigene panels click
## Suggestive Findings
MONA
Joint disease manifest predominantly as pain, swelling, and contractures of the small joints of the hands and feet in early childhood (See
Subcutaneous nodules, usually on the palms and soles (See
Coarse facial features
Gingival hypertrophy
Progressive osteopenia and osteolysis with early and predominant involvement of the bones of the hands (see
Thin cortices of the long bones (see
Milder and similar changes in other bones
• Joint disease manifest predominantly as pain, swelling, and contractures of the small joints of the hands and feet in early childhood (See
• Subcutaneous nodules, usually on the palms and soles (See
• Coarse facial features
• Gingival hypertrophy
• Progressive osteopenia and osteolysis with early and predominant involvement of the bones of the hands (see
• Thin cortices of the long bones (see
• Milder and similar changes in other bones
## Establishing the Diagnosis
The diagnosis of MONA
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multicentric Osteolysis Nodulosis and Arthropathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Analysis of matrix metalloproteinase 2 enzyme activity can be performed by the electrophoretic technique gelatin zymography on body fluids and/or cell or tissue extracts [
• For an introduction to multigene panels click
## Molecular Genetic Testing
Testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Multicentric Osteolysis Nodulosis and Arthropathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Analysis of Enzyme Activity
Analysis of matrix metalloproteinase 2 enzyme activity can be performed by the electrophoretic technique gelatin zymography on body fluids and/or cell or tissue extracts [
## Clinical Characteristics
Multicentric osteolysis nodulosis and arthropathy (MONA) is a skeletal dysplasia characterized by progressive osteolysis (particularly of the carpal and tarsal bones), osteoporosis, subcutaneous nodules on the palms and soles, and progressive arthropathy (contractures, pain, joint swelling/stiffness). Other manifestations include pigmented lesions on the skin, coarse facies, corneal opacities, and cardiac defects.
Most affected children are apparently normal at birth. Onset is usually between ages six months and six years [
To date, 51 individuals have been identified with biallelic pathogenic variants in
Multicentric Osteolysis Nodulosis and Arthropathy: Frequency of Select Features
Knees show swelling and contractures in the majority (
Wrists, ankles, and elbows are also involved.
Over time all affected individuals need assistance with mobility. Those with more severe manifestations are wheelchair bound between ages three and 12 years [
Other cutaneous manifestations include hyperpigmentation and thickening. Serpiginous hyperpigmented cutaneous lesions are present in a few individuals (
In some individuals excessive skin folds in the hands and feet have resulted from destruction of underlying bones (
Scoliosis and kyphosis are observed in some individuals [
Corneal opacities are occasionally observed; however, vision is preserved.
No genotype-phenotype correlations have been observed.
In addition to MONA, this phenotype has been reported in the literature as Torg syndrome, Winchester-Torg (or Torg-Winchester) syndrome, and nodulosis-arthropathy-osteolysis (NAO) syndrome. All of these conditions have been shown to be caused by biallelic pathogenic variants in
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
The prevalence for this rare skeletal dysplasia is not available at present. To date 51 individuals (from 31 families) with molecularly proven MONA have been reported.
• Scoliosis and kyphosis are observed in some individuals [
• Corneal opacities are occasionally observed; however, vision is preserved.
## Clinical Description
Multicentric osteolysis nodulosis and arthropathy (MONA) is a skeletal dysplasia characterized by progressive osteolysis (particularly of the carpal and tarsal bones), osteoporosis, subcutaneous nodules on the palms and soles, and progressive arthropathy (contractures, pain, joint swelling/stiffness). Other manifestations include pigmented lesions on the skin, coarse facies, corneal opacities, and cardiac defects.
Most affected children are apparently normal at birth. Onset is usually between ages six months and six years [
To date, 51 individuals have been identified with biallelic pathogenic variants in
Multicentric Osteolysis Nodulosis and Arthropathy: Frequency of Select Features
Knees show swelling and contractures in the majority (
Wrists, ankles, and elbows are also involved.
Over time all affected individuals need assistance with mobility. Those with more severe manifestations are wheelchair bound between ages three and 12 years [
Other cutaneous manifestations include hyperpigmentation and thickening. Serpiginous hyperpigmented cutaneous lesions are present in a few individuals (
In some individuals excessive skin folds in the hands and feet have resulted from destruction of underlying bones (
Scoliosis and kyphosis are observed in some individuals [
Corneal opacities are occasionally observed; however, vision is preserved.
• Scoliosis and kyphosis are observed in some individuals [
• Corneal opacities are occasionally observed; however, vision is preserved.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been observed.
## Nomenclature
In addition to MONA, this phenotype has been reported in the literature as Torg syndrome, Winchester-Torg (or Torg-Winchester) syndrome, and nodulosis-arthropathy-osteolysis (NAO) syndrome. All of these conditions have been shown to be caused by biallelic pathogenic variants in
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
The prevalence for this rare skeletal dysplasia is not available at present. To date 51 individuals (from 31 families) with molecularly proven MONA have been reported.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of Multicentric Osteolysis Nodulosis and Arthropathy (MONA)
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance
Two families have been reported to date [
## Management
To establish the extent of disease and needs in an individual diagnosed with multicentric osteolysis nodulosis and arthropathy (MONA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Multicentric Osteolysis Nodulosis and Arthropathy
Complete skeletal survey
Eval by orthopedic surgeon, rheumatologist, & PT to assess joint range of motion
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; PT = physical therapist
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment is supportive.
Treatment of Manifestations in Individuals with Multicentric Osteolysis Nodulosis and Arthropathy
PT may slow rate of development of contractures & prolong mobility.
Aids to ensure mobility (wheelchair & walking aids) may be needed as disease progresses.
NSAIDs may not provide sufficient relief.
Bisphosphonate therapy may or may not be helpful in controlling skeletal pain [
Referral to rheumatologist or pain clinic may be beneficial to develop an individual pain mgmt plan.
At present no specific therapy can alleviate the progressive osteopenia.
Assure that daily requirements of vitamin D & calcium are met.
Pamidronate is probably not effective [
Steroids & immunosuppressants have been used w/o much benefit & are best avoided given the side effects [
NSAID = nonsteroidal anti-inflammatory drug; PT = physical therapy
Recommended Surveillance for Individuals with Multicentric Osteolysis Nodulosis and Arthropathy
Avoid physical trauma to reduce the risk of fractures.
See
No information on pregnancy management and outcomes is available.
Search
• Complete skeletal survey
• Eval by orthopedic surgeon, rheumatologist, & PT to assess joint range of motion
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• PT may slow rate of development of contractures & prolong mobility.
• Aids to ensure mobility (wheelchair & walking aids) may be needed as disease progresses.
• NSAIDs may not provide sufficient relief.
• Bisphosphonate therapy may or may not be helpful in controlling skeletal pain [
• Referral to rheumatologist or pain clinic may be beneficial to develop an individual pain mgmt plan.
• At present no specific therapy can alleviate the progressive osteopenia.
• Assure that daily requirements of vitamin D & calcium are met.
• Pamidronate is probably not effective [
• Steroids & immunosuppressants have been used w/o much benefit & are best avoided given the side effects [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with multicentric osteolysis nodulosis and arthropathy (MONA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Multicentric Osteolysis Nodulosis and Arthropathy
Complete skeletal survey
Eval by orthopedic surgeon, rheumatologist, & PT to assess joint range of motion
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; PT = physical therapist
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Complete skeletal survey
• Eval by orthopedic surgeon, rheumatologist, & PT to assess joint range of motion
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment is supportive.
Treatment of Manifestations in Individuals with Multicentric Osteolysis Nodulosis and Arthropathy
PT may slow rate of development of contractures & prolong mobility.
Aids to ensure mobility (wheelchair & walking aids) may be needed as disease progresses.
NSAIDs may not provide sufficient relief.
Bisphosphonate therapy may or may not be helpful in controlling skeletal pain [
Referral to rheumatologist or pain clinic may be beneficial to develop an individual pain mgmt plan.
At present no specific therapy can alleviate the progressive osteopenia.
Assure that daily requirements of vitamin D & calcium are met.
Pamidronate is probably not effective [
Steroids & immunosuppressants have been used w/o much benefit & are best avoided given the side effects [
NSAID = nonsteroidal anti-inflammatory drug; PT = physical therapy
• PT may slow rate of development of contractures & prolong mobility.
• Aids to ensure mobility (wheelchair & walking aids) may be needed as disease progresses.
• NSAIDs may not provide sufficient relief.
• Bisphosphonate therapy may or may not be helpful in controlling skeletal pain [
• Referral to rheumatologist or pain clinic may be beneficial to develop an individual pain mgmt plan.
• At present no specific therapy can alleviate the progressive osteopenia.
• Assure that daily requirements of vitamin D & calcium are met.
• Pamidronate is probably not effective [
• Steroids & immunosuppressants have been used w/o much benefit & are best avoided given the side effects [
## Surveillance
Recommended Surveillance for Individuals with Multicentric Osteolysis Nodulosis and Arthropathy
## Agents/Circumstances to Avoid
Avoid physical trauma to reduce the risk of fractures.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
No information on pregnancy management and outcomes is available.
## Therapies Under Investigation
Search
## Genetic Counseling
Multicentric osteolysis nodulosis and arthropathy (MONA) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
The age of onset and manifestations may vary in sibs with the same biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• The age of onset and manifestations may vary in sibs with the same biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Multicentric osteolysis nodulosis and arthropathy (MONA) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
The age of onset and manifestations may vary in sibs with the same biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• The age of onset and manifestations may vary in sibs with the same biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Multicentric Osteolysis Nodulosis and Arthropathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Multicentric Osteolysis Nodulosis and Arthropathy (
Pathogenic variants include deletions and missense, nonsense, and splice site variants. Most pathogenic variants are private and homozygous. Most
The study of osteoblast cell lines from
Somatic
## Molecular Pathogenesis
Pathogenic variants include deletions and missense, nonsense, and splice site variants. Most pathogenic variants are private and homozygous. Most
The study of osteoblast cell lines from
## Cancer and Benign Tumors
Somatic
## Chapter Notes
Dr Katta M Girisha, MD, DM is a clinical geneticist with special interest in skeletal dysplasia and genomic diagnosis of rare diseases.
Website:
Indian Council of Medical Research – Clinical and molecular evaluation of inherited arthropathies and multiple vertebral segmentation defects (BMS 54/2/2013)
Department of Science and Technology – Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development (SB/SO/HS/005/2014)
30 March 2023 (sw) Revision: "
9 September 2021 (sw) Comprehensive update posted live
14 July 2016 (bp) Review posted live
22 February 2016 (kmg) Original submission
• 30 March 2023 (sw) Revision: "
• 9 September 2021 (sw) Comprehensive update posted live
• 14 July 2016 (bp) Review posted live
• 22 February 2016 (kmg) Original submission
## Author Notes
Dr Katta M Girisha, MD, DM is a clinical geneticist with special interest in skeletal dysplasia and genomic diagnosis of rare diseases.
Website:
## Acknowledgments
Indian Council of Medical Research – Clinical and molecular evaluation of inherited arthropathies and multiple vertebral segmentation defects (BMS 54/2/2013)
Department of Science and Technology – Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development (SB/SO/HS/005/2014)
## Revision History
30 March 2023 (sw) Revision: "
9 September 2021 (sw) Comprehensive update posted live
14 July 2016 (bp) Review posted live
22 February 2016 (kmg) Original submission
• 30 March 2023 (sw) Revision: "
• 9 September 2021 (sw) Comprehensive update posted live
• 14 July 2016 (bp) Review posted live
• 22 February 2016 (kmg) Original submission
## References
## Literature Cited
Hands of different children with MONA showing joint contractures and swelling of the digits at age 4 years (A), 5 years (B), 7 years (C,D), 9 years (E), 10 years (F), 13 years (G,H), and 15 years (I).
From
Feet of different individuals with MONA at ages 5 years (A), 6 years (B,C), 7 years (D,E), 9 years (F), 10 years (G), 13 years (H,I), and 15 years (J). Subcutaneous nodules are seen in A, B, C, F, G (arrows).
From
Swollen knee joints in children with MONA at age 6 years (A), 7 years (B), and 13 years (C,D). Note serpiginous hyperpigmented skin lesions in C and D.
From
Radiographs of the hands of different children with MONA at age 4 years (A), 5 years (B), 6 years (C,D), 7 years (E), 9 years (F), 10 years (G), 11 years (H), and 13 years (I,J). All have diffuse osteopenia and cortical thinning, most striking in the metacarpals. In (C), (D), and (G-J), carpal bones are small, irregular, and poorly ossified, consistent with osteolysis, with varying degrees of collapse of the carpal rows. Contractures are seen most prominently in (C), (I), and (J).
From
Radiographs of the feet of affected individuals at ages 5 years (A), 6 years (B), 7 years (C), 9 years (D), and 13 years (E). All cases demonstrate diffuse osteopenia. Small tarsal bones for age with irregular margins, particularly in (C) and (E), are reflective of osteolysis.
From
Radiographs of the long bones of the upper extremities in affected individuals at ages 6 years (A, B) and 13 years (C, D, E). All cases demonstrate decreased bone mineralization with cortical thinning.
From
|
[
"SM Al-Mayouf, M Majeed, C Hugosson, S Bahabri. New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome.. Am J Med Genet. 2000;93:5-10",
"J Azzollini, D Rovina, C Gervasini, I Parenti, A Fratoni, MV Cubellis, A Cerri, L Pietrogrande, L Larizza. Functional characterisation of a novel mutation affecting the catalytic domain of MMP2 in siblings with multicentric osteolysis, nodulosis and arthropathy.. J Hum Genet. 2014;59:631-7",
"B Bader-Meunier, L Bonafé, S Fraitag, S Breton, C Bodemer, G. Baujat. Mutation in MMP2 gene may result in scleroderma-like skin thickening.. Ann Rheum Dis. 2016;75",
"GS Bhavani, H Shah, A Shukla, N Gupta, K Gowrishankar, AP Rao, M Kabra, M Agarwal, P Ranganath, AV Ekbote, SR Phadke, A Kamath, A Dalal, KM Girisha. Clinical and mutation profile of multicentric osteolysis nodulosis and arthropathy.. Am J Med Genet A. 2016;170A:410-7",
"FC Castberg, S Kjaergaard, RA Mosig, M Lobl, C Martignetti, JA Martignetti, C Myrup, M Zak. Multicentric osteolysis with nodulosis and arthropathy (MONA) with cardiac malformation, mimicking polyarticular juvenile idiopathic arthritis: case report and literature review.. Eur J Pediatr. 2013;172:1657-63",
"IJHM de Vos, ASW Wong, TJM Welting, BJ Coull, MAM van Steensel. Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling.. Am J Med Genet A. 2019;179:1652-64",
"AV Ekbote, S Danda, A Zankl, K Mandal, T Maguire, K Ungerer. Patient with mutation in the matrix metalloproteinase 2 (MMP2) gene - a case report and review of the literature.. J Clin Res Pediatr Endocrinol. 2014;6:40-6",
"H Elsebaie, MA Mansour, SM Elsayed, S Mahmoud, TA El-Sobky. Multicentric Osteolysis, Nodulosis, and Arthropathy in two unrelated children with matrix metalloproteinase 2 variants: Genetic-skeletal correlations.. Bone Rep. 2021;15",
"BR Evans, RA Mosig, M Lobl, CR Martignetti, C Camacho, V Grum-Tokars, MJ Glucksman, JA Martignetti. Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome.. Am J Hum Genet. 2012;91:572-6",
"F Gok, LM Crettol, Y Alanay, B Hacihamdioglu, M Kocaoglu, L Bonafe, S Ozen. Clinical and radiographic findings in two brothers affected with a novel mutation in matrix metalloproteinase 2 gene.. Eur J Pediatr. 2010;169:363-7",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"SY Jeong, BY Kim, HJ Kim, JA Yang, OH Kim. A novel homozygous MMP2 mutation in a patient with Torg-Winchester syndrome.. J Hum Genet. 2010;55:764-6",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"L Kröger, T Löppönen, L Ala-Kokko, H Kröger, HM Jauhonen, K Lehti, J Jääskeläinen. A novel mutation in the matrix metallopeptidase 2 coding gene associated with intrafamilial variability of multicentric osteolysis, nodulosis, and arthropathy.. Mol Genet Genomic Med. 2019;7",
"JA Martignetti, AA Aqeel, WA Sewairi, CE Boumah, M Kambouris, SA Mayouf, KV Sheth, WA Eid, O Dowling, J Harris, MJ Glucksman, S Bahabri, BF Meyer, RJ Desnick. Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.. Nat Genet. 2001;28:261-5",
"RA Mosig, O Dowling, A DiFeo, MC Ramirez, IC Parker, E Abe, J Diouri, AA Aqeel, JD Wylie, SA Oblander, J Madri, P Bianco, SS Apte, M Zaidi, SB Doty, RJ Majeska, MB Schaffler, JA Martignetti. Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth.. Hum Mol Genet. 2007;16:1113-23",
"SR Phadke, M Ramirez, A Difeo, JA Martignetti, KM Girisha. Torg-Winchester syndrome: lack of efficacy of pamidronate therapy.. Clin Dysmorphol. 2007;16:95-100",
"K Pichler, D Karall, D Kotzot, E Steichen-Gersdorf, A Rümmele-Waibel, L Mittaz-Crettol, J Wanschitz, L Bonafé, K Maurer, A Superti-Furga, S Scholl-Bürgi. Bisphosphonates in multicentric osteolysis, nodulosis and arthropathy (MONA) spectrum disorder - an alternative therapeutic approach.. Sci Rep. 2016;6:34017",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"C Rouzier, R Vanatka, S Bannwarth, N Philip, A Coussement, V Paquis-Flucklinger, JC Lambert. A novel homozygous MMP2 mutation in a family with Winchester syndrome.. Clin Genet. 2006;69:271-6",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"SA Temtamy, S Ismail, MS Aglan, AM Ashour, LA Hosny, TH El-Badry, EH Aboul-Ezz, K Amr, E Fateen, T Maguire, K Ungerer, A Zankl. A report of three patients with MMP2 associated hereditary osteolysis.. Genet Couns. 2012;23:175-84",
"B Tuysuz, R Mosig, G Altun, S Sancak, MJ Glucksman, JA Martignetti. A novel matrix metalloproteinase 2 (MMP2) terminal hemopexin domain mutation in a family with multicentric osteolysis with nodulosis and arthritis with cardiac defects.. Eur J Hum Genet. 2009;17:565-72",
"S Unger, CR Ferreira, GR Mortier, H Ali, DR Bertola, A Calder, DH Cohn, V Cormier-Daire, KM Girisha, C Hall, D Krakow, O Makitie, S Mundlos, G Nishimura, SP Robertson, R Savarirayan, D Sillence, M Simon, VR Sutton, ML Warman, A Superti-Furga. Nosology of genetic skeletal disorders: 2023 revision.. Am J Med Genet A. 2023",
"A Zankl, L Bonafé, V Calcaterra, M Di Rocco, A Superti-Furga. Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2.. Clin Genet. 2005;67:261-6",
"A Zankl, L Pachman, A Poznanski, L Bonafé, F Wang, Y Shusterman, DA Fishman, A Superti-Furga. Torg syndrome is caused by inactivating mutations in MMP2 and is allelic to NAO and Winchester syndrome.. J Bone Miner Res. 2007;22:329-33"
] |
14/7/2016
|
9/9/2021
|
30/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mono7-mds
|
mono7-mds
|
[
"Familial Monosomy 7 Syndrome"
] |
Familial Monosomy 7 Syndrome ─ RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Jennifer JD Morrissette, Gerald Wertheim, Timothy Olson
|
Summary Familial monosomy 7 is characterized by early-childhood onset of bone marrow insufficiency/failure associated with increased risk for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). In all reported individuals, the monosomy 7 is believed to be an acquired cytogenetic abnormality within hematopoietic cells due to as-yet poorly defined inherited genetic predisposition. Identification of peripheral blood leukocytes with monosomy 7 usually precedes bone marrow failure/MDS/AML by a few months to years. Nearly all individuals reported with familial monosomy 7 have died of their disease. Note: Only a minority of individuals with bone marrow failure/MDS/AML with monosomy 7 have familial monosomy 7. Detection of cells with monosomy 7 during evaluation of a hematologic abnormality or malignancy or in the context of chromosomal studies in the diagnosis of unrelated conditions needs to be confirmed with bone marrow cytogenetic and interphase FISH studies. A bone marrow karyotype of 45,XX,-7 in females or 45,XY,-7 in males, often mosaic with normal cells (i.e., 46,XX in females and 46,XY in males), confirms the presence of monosomy 7. Of note, individuals with a family history of monosomy 7 (e.g., an affected sib) may initially have a normal karyotype in peripheral blood and/or bone marrow and later transition to mosaic monosomy 7 in peripheral blood and/or bone marrow. The mode of inheritance of familial monosomy 7 is unknown.
|
## Diagnosis
Familial monosomy 7
Values consistent with laboratory age-related standards for:
Red cell macrocytosis
Increased hemoglobin F concentration
Evidence of bone marrow insufficiency manifesting as any combination of:
Thrombocytopenia
Neutropenia
Anemia
Bone marrow aplasia
Note: Severe aplastic anemia has been defined as follows:
Granulocyte count <500/mL
Platelet count <20,000/mL
Reticulocyte count <1% after correction for hematocrit
Bone marrow biopsy with <25% of the normal cellularity for age
Myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML)
Monosomy 7 in peripheral blood and/or bone marrow cells
The diagnosis of familial monosomy 7
Monosomy 7 cells identified on peripheral blood examination or any of the following: bone marrow insufficiency, MDS, AML
Monosomy 7 cell line identified on bone marrow examination
Family member with characteristic hematologic findings and demonstration of monosomy 7
Exclusion of other hematologic disorders with known clonal acquisition of monosomy 7 (e.g., normal chromosome breakage studies and telomere length assay; see
Note: Because monosomy 7 is typically sporadic, the proband is usually considered to be a simplex case (i.e., a single occurrence in a family) until an additional family member is found to have characteristic findings. Typically these asymptomatic family members have an unremarkable prior medical history; laboratory findings in these individuals are likely to include macrocytic red blood cells (MCV >94 fL), increased concentrations of hemoglobin F, and low normal platelet counts.
Cytogenetic and molecular testing approaches can include
Note: (1) Individuals with familial monosomy 7 may initially have a normal karyotype in peripheral blood and/or bone marrow and over time transition to mosaic monosomy 7 in peripheral blood and/or bone marrow. Thus, normal cytogenetic studies in either peripheral blood or bone marrow at the onset of hematologic disease do not eliminate the possibility of subsequent loss of a chromosome 7 associated with bone marrow failure, MDS, and/or AML. (2) In some individuals, treatment with steroids, which inhibit the growth of cells in culture, can mask the cytogenetic identification of monosomy 7. However, monosomy 7 would be identifiable by fluorescence in situ hybridization (FISH) or microarray analysis; therefore, FISH or microarray is favored when performing longitudinal assessment of clonal percentage.
Note: A pre-onset monosomy is not detectable with the presently available deletion/duplication methodology. Thus, a sib of a person with known monosomy 7 should be under continuous surveillance for emergence of hematologic anomalies.
Molecular Genetic Testing Used in Familial Monosomy 7 Syndrome
See
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
Additional acquired cytogenetic abnormalities have been seen. Occasionally, rearrangement of chromosome 7 material results in retention of the short arm (7p) and loss of the long arm (7q) resulting in monosomy of 7q (sometimes called "partial monosomy 7").
Minimal detection for mosaicism depends on laboratory cut-off values; typical range: 20%-30%.
Minimal detection for mosaicism depends on laboratory cut-off values; typical range: 10%-20%.
• Values consistent with laboratory age-related standards for:
• Red cell macrocytosis
• Increased hemoglobin F concentration
• Red cell macrocytosis
• Increased hemoglobin F concentration
• Evidence of bone marrow insufficiency manifesting as any combination of:
• Thrombocytopenia
• Neutropenia
• Anemia
• Bone marrow aplasia
• Note: Severe aplastic anemia has been defined as follows:
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
• Thrombocytopenia
• Neutropenia
• Anemia
• Bone marrow aplasia
• Note: Severe aplastic anemia has been defined as follows:
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
• Myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML)
• Monosomy 7 in peripheral blood and/or bone marrow cells
• Red cell macrocytosis
• Increased hemoglobin F concentration
• Thrombocytopenia
• Neutropenia
• Anemia
• Bone marrow aplasia
• Note: Severe aplastic anemia has been defined as follows:
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
• Monosomy 7 cells identified on peripheral blood examination or any of the following: bone marrow insufficiency, MDS, AML
• Monosomy 7 cell line identified on bone marrow examination
• Family member with characteristic hematologic findings and demonstration of monosomy 7
• Exclusion of other hematologic disorders with known clonal acquisition of monosomy 7 (e.g., normal chromosome breakage studies and telomere length assay; see
## Suggestive Findings
Familial monosomy 7
Values consistent with laboratory age-related standards for:
Red cell macrocytosis
Increased hemoglobin F concentration
Evidence of bone marrow insufficiency manifesting as any combination of:
Thrombocytopenia
Neutropenia
Anemia
Bone marrow aplasia
Note: Severe aplastic anemia has been defined as follows:
Granulocyte count <500/mL
Platelet count <20,000/mL
Reticulocyte count <1% after correction for hematocrit
Bone marrow biopsy with <25% of the normal cellularity for age
Myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML)
Monosomy 7 in peripheral blood and/or bone marrow cells
• Values consistent with laboratory age-related standards for:
• Red cell macrocytosis
• Increased hemoglobin F concentration
• Red cell macrocytosis
• Increased hemoglobin F concentration
• Evidence of bone marrow insufficiency manifesting as any combination of:
• Thrombocytopenia
• Neutropenia
• Anemia
• Bone marrow aplasia
• Note: Severe aplastic anemia has been defined as follows:
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
• Thrombocytopenia
• Neutropenia
• Anemia
• Bone marrow aplasia
• Note: Severe aplastic anemia has been defined as follows:
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
• Myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML)
• Monosomy 7 in peripheral blood and/or bone marrow cells
• Red cell macrocytosis
• Increased hemoglobin F concentration
• Thrombocytopenia
• Neutropenia
• Anemia
• Bone marrow aplasia
• Note: Severe aplastic anemia has been defined as follows:
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
• Granulocyte count <500/mL
• Platelet count <20,000/mL
• Reticulocyte count <1% after correction for hematocrit
• Bone marrow biopsy with <25% of the normal cellularity for age
## Establishing the Diagnosis
The diagnosis of familial monosomy 7
Monosomy 7 cells identified on peripheral blood examination or any of the following: bone marrow insufficiency, MDS, AML
Monosomy 7 cell line identified on bone marrow examination
Family member with characteristic hematologic findings and demonstration of monosomy 7
Exclusion of other hematologic disorders with known clonal acquisition of monosomy 7 (e.g., normal chromosome breakage studies and telomere length assay; see
Note: Because monosomy 7 is typically sporadic, the proband is usually considered to be a simplex case (i.e., a single occurrence in a family) until an additional family member is found to have characteristic findings. Typically these asymptomatic family members have an unremarkable prior medical history; laboratory findings in these individuals are likely to include macrocytic red blood cells (MCV >94 fL), increased concentrations of hemoglobin F, and low normal platelet counts.
Cytogenetic and molecular testing approaches can include
Note: (1) Individuals with familial monosomy 7 may initially have a normal karyotype in peripheral blood and/or bone marrow and over time transition to mosaic monosomy 7 in peripheral blood and/or bone marrow. Thus, normal cytogenetic studies in either peripheral blood or bone marrow at the onset of hematologic disease do not eliminate the possibility of subsequent loss of a chromosome 7 associated with bone marrow failure, MDS, and/or AML. (2) In some individuals, treatment with steroids, which inhibit the growth of cells in culture, can mask the cytogenetic identification of monosomy 7. However, monosomy 7 would be identifiable by fluorescence in situ hybridization (FISH) or microarray analysis; therefore, FISH or microarray is favored when performing longitudinal assessment of clonal percentage.
Note: A pre-onset monosomy is not detectable with the presently available deletion/duplication methodology. Thus, a sib of a person with known monosomy 7 should be under continuous surveillance for emergence of hematologic anomalies.
Molecular Genetic Testing Used in Familial Monosomy 7 Syndrome
See
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
Additional acquired cytogenetic abnormalities have been seen. Occasionally, rearrangement of chromosome 7 material results in retention of the short arm (7p) and loss of the long arm (7q) resulting in monosomy of 7q (sometimes called "partial monosomy 7").
Minimal detection for mosaicism depends on laboratory cut-off values; typical range: 20%-30%.
Minimal detection for mosaicism depends on laboratory cut-off values; typical range: 10%-20%.
• Monosomy 7 cells identified on peripheral blood examination or any of the following: bone marrow insufficiency, MDS, AML
• Monosomy 7 cell line identified on bone marrow examination
• Family member with characteristic hematologic findings and demonstration of monosomy 7
• Exclusion of other hematologic disorders with known clonal acquisition of monosomy 7 (e.g., normal chromosome breakage studies and telomere length assay; see
## Clinical Characteristics
Familial monosomy 7 is typically characterized by early-childhood onset of evidence of bone marrow insufficiency/failure associated with increased risk for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (reviewed in
Penetrance for familial monosomy 7 is unknown.
Before the advent of chromosome banding, chromosomes were grouped by size and morphology (location of the centromere) because it was not possible to distinguish individual chromosomes. Using this system, chromosome 7 is categorized as a "C-group" chromosome (C-group chromosomes: 6-12 and X); thus, familial "C-group monosomy" reported prior to 1972 is presumed to be familial monosomy 7.
Familial monosomy 7 is rare; 14 kindreds have been reported in the literature.
## Clinical Description
Familial monosomy 7 is typically characterized by early-childhood onset of evidence of bone marrow insufficiency/failure associated with increased risk for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (reviewed in
## Penetrance
Penetrance for familial monosomy 7 is unknown.
## Nomenclature
Before the advent of chromosome banding, chromosomes were grouped by size and morphology (location of the centromere) because it was not possible to distinguish individual chromosomes. Using this system, chromosome 7 is categorized as a "C-group" chromosome (C-group chromosomes: 6-12 and X); thus, familial "C-group monosomy" reported prior to 1972 is presumed to be familial monosomy 7.
## Prevalence
Familial monosomy 7 is rare; 14 kindreds have been reported in the literature.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Although rare, sporadic myelodysplastic syndrome (MDS) has been described in children; monosomy 7 is seen in 25%-30% of such cases. Although most MDS associated with monosomy 7 is not familial, these individuals also had a poor response to therapy and were candidates for bone marrow transplantation.
Monosomy 7 can also be seen in sporadic acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms. Although the discovery of monosomy 7 in these individuals portends a poor outcome, the majority are not associated with the familial entity.
Monosomy 7 has been reported in multiple family members with the following disorders:
Cerebellar ataxia/atrophy-pancytopenia syndrome (OMIM
Familial platelet disorder with propensity to AML (FPD/AML) (OMIM
Monosomy 7 has been reported in individuals with the following disorders:
Aplastic anemia (OMIM
Juvenile myelomonocytic leukemia (JMML) (OMIM
Paroxysmal nocturnal hemoglobinuria (PNH) (OMIM
• Cerebellar ataxia/atrophy-pancytopenia syndrome (OMIM
• Familial platelet disorder with propensity to AML (FPD/AML) (OMIM
• Aplastic anemia (OMIM
• Juvenile myelomonocytic leukemia (JMML) (OMIM
• Paroxysmal nocturnal hemoglobinuria (PNH) (OMIM
•
•
•
## Management
Urgent referral to an oncologist for evaluation of cytopenias and bone marrow abnormalities that appear prior to the development of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) is indicated. Laboratory studies for hematologic status and hemoglobin F levels, as well as cytogenetic studies in unstimulated peripheral blood are recommended.
Consultation with a clinical geneticist and/or genetic counselor is recommended.
The goal of management in familial monosomy 7 is early diagnosis so that definitive therapy with bone marrow transplantation (BMT) can be initiated prior to the emergence of a leukemic clone. Once transformation into AML occurs, the probability that BMT will fail to cure the disease increases significantly.
Any child or young adult with detectable monosomy 7 in combination with cytopenias and marrow dysplasia should, therefore, proceed to BMT as soon as possible, unless rising blast count warrants cytoreductive chemotherapy prior to transplant. Since BMT is the only effective treatment for the management of hematologic disease and the familial status of the disorder may not be known, rigorous evaluation of related donors is strongly suggested.
The suitability of sibs who are potential bone marrow donors may be evaluated with appropriate hematologic and cytogenetic studies to rule out bone marrow disease associated with familial monosomy 7. However, given that the underlying germline pathogenic variant may not be known, a matched sib donor may not be an ideal candidate (unless much older than the affected individual and with no evidence of hematologic disorders) and an unrelated donor may be more suitable.
Monosomy 7 in children with
Individuals with monosomy 7 and certain underlying bone marrow failure syndromes including
If transplant therapy is not pursued due to lack of donor availability or family preference, annual monitoring of bone marrow karyotype and FISH for chromosome 7, hematologic status, and hemoglobin F levels should be coordinated by specialists in oncology and bone marrow transplantation. The goal is to identify bone marrow abnormalities (cytopenias and bone marrow dysplasia) prior to the development of AML or MDS by annual monitoring of cytogenetic studies in unstimulated peripheral blood, hematologic status, and hemoglobin F levels.
Because the goal of management in familial monosomy 7 is early diagnosis for initiation of BMT prior to the emergence of a leukemic clone, it is appropriate to evaluate relatives at risk including sibs and potentially maternal first cousins, based on kindreds described in
In sibs and cousins of individuals with a history of familial monosomy 7, signs and symptoms that cannot be accounted for otherwise should be evaluated by their physicians as potential early indications of the cytopenias and bone marrow dysplasia which appear prior to the development of AML or MDS.
See
Search
## Evaluations Following Initial Diagnosis
Urgent referral to an oncologist for evaluation of cytopenias and bone marrow abnormalities that appear prior to the development of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) is indicated. Laboratory studies for hematologic status and hemoglobin F levels, as well as cytogenetic studies in unstimulated peripheral blood are recommended.
Consultation with a clinical geneticist and/or genetic counselor is recommended.
## Treatment of Manifestations
The goal of management in familial monosomy 7 is early diagnosis so that definitive therapy with bone marrow transplantation (BMT) can be initiated prior to the emergence of a leukemic clone. Once transformation into AML occurs, the probability that BMT will fail to cure the disease increases significantly.
Any child or young adult with detectable monosomy 7 in combination with cytopenias and marrow dysplasia should, therefore, proceed to BMT as soon as possible, unless rising blast count warrants cytoreductive chemotherapy prior to transplant. Since BMT is the only effective treatment for the management of hematologic disease and the familial status of the disorder may not be known, rigorous evaluation of related donors is strongly suggested.
The suitability of sibs who are potential bone marrow donors may be evaluated with appropriate hematologic and cytogenetic studies to rule out bone marrow disease associated with familial monosomy 7. However, given that the underlying germline pathogenic variant may not be known, a matched sib donor may not be an ideal candidate (unless much older than the affected individual and with no evidence of hematologic disorders) and an unrelated donor may be more suitable.
Monosomy 7 in children with
## Prevention of Secondary Complications
Individuals with monosomy 7 and certain underlying bone marrow failure syndromes including
## Surveillance
If transplant therapy is not pursued due to lack of donor availability or family preference, annual monitoring of bone marrow karyotype and FISH for chromosome 7, hematologic status, and hemoglobin F levels should be coordinated by specialists in oncology and bone marrow transplantation. The goal is to identify bone marrow abnormalities (cytopenias and bone marrow dysplasia) prior to the development of AML or MDS by annual monitoring of cytogenetic studies in unstimulated peripheral blood, hematologic status, and hemoglobin F levels.
## Evaluation of Relatives at Risk
Because the goal of management in familial monosomy 7 is early diagnosis for initiation of BMT prior to the emergence of a leukemic clone, it is appropriate to evaluate relatives at risk including sibs and potentially maternal first cousins, based on kindreds described in
In sibs and cousins of individuals with a history of familial monosomy 7, signs and symptoms that cannot be accounted for otherwise should be evaluated by their physicians as potential early indications of the cytopenias and bone marrow dysplasia which appear prior to the development of AML or MDS.
See
## Therapies Under Investigation
Search
## Genetic Counseling
The mode of inheritance of familial monosomy 7 is unclear. Autosomal dominant disease with reduced penetrance or an imprinting disorder have been suggested.
In one kindred, eight of 14 first cousins (the offspring of 3 sisters) developed aplastic anemia or acute myeloid leukemia (AML); in those with cytogenetic studies, the karyotype evolved to monosomy 7 (or group C monosomy) [
See Management,
The optimal time for estimating genetic risk is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
At this time prenatal testing is not possible as mutation of a specific gene responsible for familial monosomy 7 is unknown. Monosomy 7 is not expected to be present in tissues sampled prenatally.
• The optimal time for estimating genetic risk is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
The mode of inheritance of familial monosomy 7 is unclear. Autosomal dominant disease with reduced penetrance or an imprinting disorder have been suggested.
In one kindred, eight of 14 first cousins (the offspring of 3 sisters) developed aplastic anemia or acute myeloid leukemia (AML); in those with cytogenetic studies, the karyotype evolved to monosomy 7 (or group C monosomy) [
## Risk to Family Members
## Related Genetic Counseling Issues
See Management,
The optimal time for estimating genetic risk is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for estimating genetic risk is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing
At this time prenatal testing is not possible as mutation of a specific gene responsible for familial monosomy 7 is unknown. Monosomy 7 is not expected to be present in tissues sampled prenatally.
## Resources
No specific resources for Familial Monosomy 7 Syndrome have been identified by
## Molecular Genetics
OMIM Entries for Familial Monosomy 7 Syndrome (
In familial monosomy 7 affected individuals are predisposed to acquiring monosomy 7 or partial deletion of the long arm of chromosome 7 in hematopoietic cells. It is not known whether other tissues may also be affected.
Hematologic malignancies (e.g., MDS or AML) result from the loss of the minimal segment(s) on the long arm of chromosome 7, with most involving regions between 7q21.3 and 7q34 [
The loss of chromosome 7 or segmental loss of 7q is thought to delete a tumor suppressor locus [
In a recently reported family, a germline pathogenic variant in
Pathogenic variants in
Monosomy 7 represents a small proportion of chromosome aberrations found in AML, but is a common finding in therapy-related AML after alkylator chemotherapy.
## Molecular Pathogenesis
In familial monosomy 7 affected individuals are predisposed to acquiring monosomy 7 or partial deletion of the long arm of chromosome 7 in hematopoietic cells. It is not known whether other tissues may also be affected.
Hematologic malignancies (e.g., MDS or AML) result from the loss of the minimal segment(s) on the long arm of chromosome 7, with most involving regions between 7q21.3 and 7q34 [
The loss of chromosome 7 or segmental loss of 7q is thought to delete a tumor suppressor locus [
In a recently reported family, a germline pathogenic variant in
Pathogenic variants in
Monosomy 7 represents a small proportion of chromosome aberrations found in AML, but is a common finding in therapy-related AML after alkylator chemotherapy.
## References
## Literature Cited
## Chapter Notes
We would like to thank Hope H Punnett, PhD and Carol E Anderson, MD for critical reading of the manuscript.
Jean-Pierre de Chadarévian, MD, FRCP(C), St Christopher’s Hospital for Children (2009-2016)E Anders Kolb, MD; Nemours/Alfred I DuPont Hospital for Children (2009-2016)Jennifer JD Morrissette, PhD, FACMG (2009-present)Timothy Olson, MD, PhD (2016-present)Gerald Wertheim, MD, PhD (2016-present)
19 November 2020 (ma) Chapter retired: does not reflect current use of genetic testing
21 January 2016 (me) Comprehensive update posted live
7 February 2013 (me) Comprehensive update posted live
8 July 2010 (me) Review posted live
13 November 2009 (jm) Original submission
• 19 November 2020 (ma) Chapter retired: does not reflect current use of genetic testing
• 21 January 2016 (me) Comprehensive update posted live
• 7 February 2013 (me) Comprehensive update posted live
• 8 July 2010 (me) Review posted live
• 13 November 2009 (jm) Original submission
## Acknowledgments
We would like to thank Hope H Punnett, PhD and Carol E Anderson, MD for critical reading of the manuscript.
## Author History
Jean-Pierre de Chadarévian, MD, FRCP(C), St Christopher’s Hospital for Children (2009-2016)E Anders Kolb, MD; Nemours/Alfred I DuPont Hospital for Children (2009-2016)Jennifer JD Morrissette, PhD, FACMG (2009-present)Timothy Olson, MD, PhD (2016-present)Gerald Wertheim, MD, PhD (2016-present)
## Revision History
19 November 2020 (ma) Chapter retired: does not reflect current use of genetic testing
21 January 2016 (me) Comprehensive update posted live
7 February 2013 (me) Comprehensive update posted live
8 July 2010 (me) Review posted live
13 November 2009 (jm) Original submission
• 19 November 2020 (ma) Chapter retired: does not reflect current use of genetic testing
• 21 January 2016 (me) Comprehensive update posted live
• 7 February 2013 (me) Comprehensive update posted live
• 8 July 2010 (me) Review posted live
• 13 November 2009 (jm) Original submission
|
[
"D Aktas, A Koc, K Boduroglu, G Hicsonmez, E Tuncbilek. Myelodysplastic syndrome associated with monosomy 7 in a child with Bloom syndrome.. Cancer Genet Cytogenet. 2000;116:44-6",
"H Asou, H Matsui, Y Ozaki, A Nagamachi, M Nakamura, D Aki, T Inaba. Identification of a common microdeletion cluster in 7q21.3 subband among patients with myeloid leukemia and myelodysplastic syndrome.. Biochem Biophys Res Commun. 2009;383:245-51",
"C Bödör, A Renneville, M Smith, A Charazac, S Iqbal, P Etancelin, J Cavenagh, MJ Barnett, K Kramarzová, B Krishnan, A Matolcsy, C Preudhomme, J Fitzgibbon, C Owen. Germ-line GATA2 p.Thr354Met mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival.. Haematologica. 2012;97:890-4",
"CR Chitambar, WA Robinson, LM Glode. Familial leukemia and aplastic anemia associated with monosomy 7.. Am J Med 1983;75:756-62",
"K Choong, MH Freedman, D Chitayat, EN Kelly, G Taylor, A Zipursky. Juvenile myelomonocytic leukemia and Noonan syndrome.. J Pediatr Hematol Oncol. 1999;21:523-7",
"D Cigognini, G Corneo, E Fermo, A Zanella, P Tripputi. HIC gene, a candidate suppressor gene within a minimal region of loss at 7q31.1 in myeloid neoplasms.. Leuk Res. 2007;31:477-82",
"NP Curtiss, JM Bonifas, JO Lauchle, JD Balkman, CP Kratz, BM Emerling, ED Green, MM Le Beau, KM Shannon. Isolation and analysis of candidate myeloid tumor suppressor genes from a commonly deleted segment of 7q22.. Genomics. 2005;85:600-7",
"S Gaitonde, R Boumendjel, R Angeles, D. Rondelli. Familial childhood monosomy 7 and associated myelodysplasia.. J Pediatr Hematol Oncol. 2010;32:e236-7",
"H Hasle, TA Alonzo, A Auvrignon, C Behar, M Chang, U Creutzig, A Fischer, E Forestier, A Fynn, OA Haas, J Harbott, CJ Harrison, NA Heerema, MM van den Heuvel-Eibrink, GJ Kaspers, F Locatelli, P Noellke, S Polychronopoulou, Y Ravindranath, B Razzouk, D Reinhardt, NN Savva, B Stark, S Suciu, I Tsukimoto, DK Webb, D Wojcik, WG Woods, M Zimmermann, CM Niemeyer, SC Raimondi. Monosomy 7 and deletion 7q in children and adolescents with acute myeloid leukemia: an international retrospective study.. Blood 2007;109:4641-7",
"H Hasle, JH Olsen. Cancer in relatives of children with myelodysplastic syndrome, acute and chronic myeloid leukaemia.. Br J Haematol. 1997;97:127-31",
"MC Jongmans, RP Kuiper, CL Carmichael, EJ Wilkins, N Dors, A Carmagnac, AY Schouten-van Meeteren, X Li, M Stankovic, E Kamping, H Bengtsson, EF Schoenmakers, AG van Kessel, PM Hoogerbrugge, CN Hahn, PP Brons, HS Scott, N Hoogerbrugge. Novel RUNX1 mutations in familial platelet disorder with enhanced risk for acute myeloid leukemia: clues for improved identification of the FPD/AML syndrome.. Leukemia. 2010;24:242-6",
"JF Kelleher, TV Carbone. Monosomy 7 syndrome in an infant with neurofibromatosis.. Am J Pediatr Hematol Oncol. 1991;13:338-41",
"CP Kratz, CM Niemeyer, RP Castleberry, M Cetin, E Bergsträsser, PD Emanuel, H Hasle, G Kardos, C Klein, S Kojima, J Stary, M Trebo, M Zecca, BD Gelb, M Tartaglia, ML Loh. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.. Blood. 2005;106:2183-5",
"A Lawrie, DA Stevenson, TN Doig, MA Vickers, DJ Culligan. Acute myeloid leukemia presenting in a mother and daughter pair with the identical acquired karyotypic abnormality consisting of inversion 3q21q26 and monosomy 7: a review of possible mechanisms.. Cancer Genet. 2012;205:599-602",
"FP Li, F Hecht, B Kaiser-McCaw, PV Baranko, NU Potter. Ataxia-pancytopenia: syndrome of cerebellar ataxia, hypoplastic anemia, monosomy 7, and acute myelogenous leukemia.. Cancer Genet Cytogenet. 1981;4:189-96",
"FP Li, NU Potter, GR Buchanan, G Vawter, J Whang-Peng, RB Rosen. A family with acute leukemia, hypoplastic anemia and cerebellar ataxia: association with bone marrow C-monosomy.. Am J Med. 1978;65:933-40",
"E Liew, C Owen. Familial myelodysplastic syndromes: a review of the literature.. Haematologica. 2011;96:1536-42",
"JM Maris, SR Wiersma, N Mahgoub, P Thompson, RJ Geyer, CG Hurwitz, BJ Lange, KM Shannon. Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1.. Cancer 1997;79:1438-46",
"E Maserati, A Minelli, G Menna, MP Cecchini, ME Bernardo, G Rossi, P De Filippi, F Lo Curto, C Danesino, F Locatelli, F Pasquali. Familial myelodysplastic syndromes, monosomy 7/trisomy 8, and mutator effects.. Cancer Genet Cytogenet. 2004;148:155-8",
"A Minelli, E Maserati, G Giudici, S Tosi, C Olivieri, L Bonvini, P De Filippi, A Biondi, F Lo Curto, F Pasquali, C Danesino. Familial partial monosomy 7 and myelodysplasia: different parental origin of the monosomy 7 suggests action of a mutator gene.. Cancer Genet Cytogenet 2001;124:147-51",
"A Minelli, E Maserati, G Rossi, ME Bernardo, P De Stefano, MP Cecchini, R Valli, V Albano, P Pierani, A Leszl, L Sainati, F Lo Curto, C Danesino, F Locatelli, F Pasquali. Familial platelet disorder with propensity to acute myelogenous leukemia: genetic heterogeneity and progression to leukemia via acquisition of clonal chromosome anomalies.. Genes Chromosomes Cancer. 2004;40:165-71",
"T Pabst, M Eyholzer, S Haefliger, J Schardt, BU Mueller. Somatic CEBPA mutations are a frequent second event in families with germline mutations and familial acute myeloid leukemia.. J Clin Oncol 2008;26:5088-93",
"G Porta, E Maserati, E Mattarucchi, A Minelli, B Pressato, R Valli, M Zecca, ME Bernardo, F Lo Curto, F Locatelli, C Danesino, F Pasquali. Monosomy 7 in myeloid malignancies: parental origin and monitoring by real-time quantitative PCR.. Leukemia. 2007;21:1833-5",
"KM Shannon, AG Turhan, SS Chang, AM Bowcock, PC Rogers, WL Carroll, MJ Cowan, BE Glader, CJ Eaves, AC Eaves, YW Kan. Familial bone marrow monosomy 7: evidence that the predisposing locus is not on the long arm of chromosome 7.. J Clin Invest 1989;84:984-9"
] |
8/7/2010
|
21/1/2016
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
monosomy7-ov
|
monosomy7-ov
|
[
"Monosomy 7 Predisposition Syndromes",
"Overview"
] |
Monosomy 7 Predisposition Syndromes Overview
|
Timothy S Olson, Kathryn E Dickerson, Taizo A Nakano, Marcin Wlodarski
|
Summary The purpose of this overview is to: Describe the Review the Provide an Review the Inform (when possible) Provide a basic view of
|
## Clinical Characteristics of Monosomy 7 Predisposition Syndromes
Monosomy 7 predisposition syndromes are typically characterized by childhood or young-adult onset of bone marrow insufficiency associated with an increased risk for severe cytopenias, variable adaptive immune deficiency, bone marrow aplasia, myelodysplastic syndrome (MDS), and/or acute myeloid leukemia (AML) [
Systemic anomalies associated with monosomy 7 predisposition syndromes can include multiple organ system involvement and delays in growth and neurodevelopment (see
Disorders that predispose to monosomy 7 were included in the 2016 revision of the World Health Organization (WHO) classification of myeloid neoplasms and AML, in a new category: "myeloid neoplasms with germline predisposition" [
Note: Individuals meet WHO 2016 criteria for MDS [
Note: (1) Individuals with monosomy 7 predisposition syndromes may initially have a normal karyotype in peripheral blood and/or bone marrow and over time transition to develop clonal monosomy 7 in peripheral blood and/or bone marrow. Thus, normal cytogenetic studies in either peripheral blood or bone marrow at the onset of hematologic disease do not eliminate the possibility of subsequent loss of a chromosome 7 associated with bone marrow failure, MDS, and/or AML. (2) In some individuals, treatment with steroids, which inhibit the growth of cells in culture, can mask the cytogenetic identification of monosomy 7. However, monosomy 7 would be identifiable by fluorescence in situ hybridization (FISH) or microarray analysis; therefore, FISH or microarray is preferred when performing longitudinal assessment of clonal percentage.
In individuals with monosomy 7 and progressive features of MDS or AML, prognosis is poor without aggressive chemotherapy and hematopoietic stem cell transplantation [
Some individuals diagnosed in early childhood with a monosomy 7 predisposition syndrome in the absence of advanced MDS or AML may exhibit regression and resolution of the monosomy 7 clone(s) [
## Clinical Description
Monosomy 7 predisposition syndromes are typically characterized by childhood or young-adult onset of bone marrow insufficiency associated with an increased risk for severe cytopenias, variable adaptive immune deficiency, bone marrow aplasia, myelodysplastic syndrome (MDS), and/or acute myeloid leukemia (AML) [
Systemic anomalies associated with monosomy 7 predisposition syndromes can include multiple organ system involvement and delays in growth and neurodevelopment (see
Disorders that predispose to monosomy 7 were included in the 2016 revision of the World Health Organization (WHO) classification of myeloid neoplasms and AML, in a new category: "myeloid neoplasms with germline predisposition" [
Note: Individuals meet WHO 2016 criteria for MDS [
Note: (1) Individuals with monosomy 7 predisposition syndromes may initially have a normal karyotype in peripheral blood and/or bone marrow and over time transition to develop clonal monosomy 7 in peripheral blood and/or bone marrow. Thus, normal cytogenetic studies in either peripheral blood or bone marrow at the onset of hematologic disease do not eliminate the possibility of subsequent loss of a chromosome 7 associated with bone marrow failure, MDS, and/or AML. (2) In some individuals, treatment with steroids, which inhibit the growth of cells in culture, can mask the cytogenetic identification of monosomy 7. However, monosomy 7 would be identifiable by fluorescence in situ hybridization (FISH) or microarray analysis; therefore, FISH or microarray is preferred when performing longitudinal assessment of clonal percentage.
In individuals with monosomy 7 and progressive features of MDS or AML, prognosis is poor without aggressive chemotherapy and hematopoietic stem cell transplantation [
Some individuals diagnosed in early childhood with a monosomy 7 predisposition syndrome in the absence of advanced MDS or AML may exhibit regression and resolution of the monosomy 7 clone(s) [
## Causes of Monosomy 7 Predisposition Syndromes
Monosomy 7 Predisposition Syndromes: Genes and Clinical Features
AD = autosomal dominant; AML = acute myeloid leukemia; AR = autosomal recessive; DCML = dendritic cell, monocyte, and B and natural killer cell lymphoid deficiency; DD = developmental delay; MDS = myelodysplastic syndrome; MOI = mode of inheritance; XL = X-linked
Genes are listed alphabetically
Listed genes represent the most common genetic causes of Fanconi anemia (FA). For other genes associated with this phenotype (>20 genes have been identified), see
Although additional genes have been associated with Noonan syndrome, only those listed here have been definitively linked to monosomy 7.
Although 20 genes in addition to
Too few cases described to determine age of onset
## Evaluation Strategies to Identify the Genetic Cause of Monosomy 7 Predisposition in a Proband
Establishing a specific genetic cause for predisposition to monosomy 7:
Can aid in discussions of prognosis (which are beyond the scope of this
Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
Short stature is seen in many conditions including Shwachman-Diamond syndrome, Fanconi anemia, and MIRAGE syndrome
Microcephaly is seen in Fanconi anemia, ligase 4 syndrome, and
Café au lait macules may be seen in Fanconi anemia and neurofibromatosis I. Axillary freckling and cutaneous neurofibromas are specific to neurofibromatosis 1.
Cardiac murmurs may be identified in Fanconi anemia and rasopathies due to underlying congenital heart disease.
Lymphedema and pulmonary auscultation abnormalities may be features of
Cerebellar ataxia is seen in
Bruising and petechiae may be associated with any monosomy 7 predisposition syndrome after onset of severe cytopenias; however prolonged bleeding in the absence of severe thrombocytopenia or advanced MDS or AML may be suggestive of
Hepatosplenomegaly is infrequently present in early-stage MDS, but is associated with advanced myeloid malignancy; however, rasopathies associated with monosomy 7 and myeloproliferative diseases are most commonly associated with hepatosplenomegaly.
Skeletal dysplasia may be a feature of Shwachman-Diamond syndrome.
Early-childhood deaths and/or maternal history of miscarriages
Early-onset or atypical cancer diagnoses. Excessive toxicity associated with cancer treatment
Syndromic features/congenital anomalies
Consanguinity
Neonatal transient cytopenias
Bone marrow failure or immune deficiencies
Lymphedema
History of atypical and/or prolonged bleeding
Severe developmental delay and other neurologic abnormalities
Fanconi anemia chromosome breakage studies (mitomycin C / diepoxybutane)
Telomere length analysis
Note: Skin (considered gold standard) or buccal fibroblasts are the preferred tissue type for germline molecular testing for individuals suspected to have a monosomy 7 predisposition syndrome due to somatic revertant mutation or functional deletion of germline pathogenic variants through chromosome loss or loss of heterozygosity that can occur in bone marrow and blood cells from individuals with monosomy 7. In situations where rapid therapy decision making is required, molecular genetic testing may be initially performed on blood or bone marrow samples, and subsequently performed on cultured skin fibroblasts which may take longer to obtain results.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Can aid in discussions of prognosis (which are beyond the scope of this
• Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
• Short stature is seen in many conditions including Shwachman-Diamond syndrome, Fanconi anemia, and MIRAGE syndrome
• Microcephaly is seen in Fanconi anemia, ligase 4 syndrome, and
• Café au lait macules may be seen in Fanconi anemia and neurofibromatosis I. Axillary freckling and cutaneous neurofibromas are specific to neurofibromatosis 1.
• Cardiac murmurs may be identified in Fanconi anemia and rasopathies due to underlying congenital heart disease.
• Lymphedema and pulmonary auscultation abnormalities may be features of
• Cerebellar ataxia is seen in
• Bruising and petechiae may be associated with any monosomy 7 predisposition syndrome after onset of severe cytopenias; however prolonged bleeding in the absence of severe thrombocytopenia or advanced MDS or AML may be suggestive of
• Hepatosplenomegaly is infrequently present in early-stage MDS, but is associated with advanced myeloid malignancy; however, rasopathies associated with monosomy 7 and myeloproliferative diseases are most commonly associated with hepatosplenomegaly.
• Skeletal dysplasia may be a feature of Shwachman-Diamond syndrome.
• Early-childhood deaths and/or maternal history of miscarriages
• Early-onset or atypical cancer diagnoses. Excessive toxicity associated with cancer treatment
• Syndromic features/congenital anomalies
• Consanguinity
• Neonatal transient cytopenias
• Bone marrow failure or immune deficiencies
• Lymphedema
• History of atypical and/or prolonged bleeding
• Severe developmental delay and other neurologic abnormalities
• Fanconi anemia chromosome breakage studies (mitomycin C / diepoxybutane)
• Telomere length analysis
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Differential Diagnosis of Monosomy 7 Predisposition Syndromes
The differential diagnosis of monosomy 7 predisposition syndromes includes:
Sporadic monosomy 7 MDS/AML refers to monosomy 7 MDS/AML that arises without evidence of germline genetic predisposition and in the absence of other predisposing medical conditions or treatments. Monosomy 7 MDS/AML that occurs in older adults is typically considered to be sporadic (i.e., the result of a chance occurrence of a disorder or abnormality that is not expected to recur in a family) and is associated with clonal hematopoiesis of indeterminate potential, a common age-related phenomenon [
Monosomy 7 is the most common somatic cytogenetic abnormality identified in persons with secondary MDS/AML who were previously diagnosed with an acquired bone marrow failure disorder (e.g., acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria) [
Monosomy 7 occurs in 27%-32% of therapy-related myeloid neoplasms [
Additionally, germline variants in genes encoding proteins involved in the glutathione S-transferase pathway and other drug metabolism pathways have been identified to alter susceptibility to therapy-related monosomy 7 [
Other germline predisposition disorders in which MDS and leukemia have been reported without a specific association with monosomy 7 are summarized in
Disorders that Predispose to Myeloid Neoplasms without Monosomy 7
AD = autosomal dominant; AML = acute myeloid leukemia; AR = autosomal recessive; DD = developmental delay; MDS = myelodysplastic syndrome; MOI = mode of inheritance; XL = X-linked
Eleven additional ribosomal proteins have been associated with autosomal dominant Diamond-Blackfan anemia, though each at lower frequencies than the genes included in
## Sporadic Monosomy 7 MDS/AML
Sporadic monosomy 7 MDS/AML refers to monosomy 7 MDS/AML that arises without evidence of germline genetic predisposition and in the absence of other predisposing medical conditions or treatments. Monosomy 7 MDS/AML that occurs in older adults is typically considered to be sporadic (i.e., the result of a chance occurrence of a disorder or abnormality that is not expected to recur in a family) and is associated with clonal hematopoiesis of indeterminate potential, a common age-related phenomenon [
## Secondary Monosomy 7 Arising from Acquired Bone Marrow Failure
Monosomy 7 is the most common somatic cytogenetic abnormality identified in persons with secondary MDS/AML who were previously diagnosed with an acquired bone marrow failure disorder (e.g., acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria) [
## Monosomy 7 Secondary to Prior Cancer Therapy
Monosomy 7 occurs in 27%-32% of therapy-related myeloid neoplasms [
Additionally, germline variants in genes encoding proteins involved in the glutathione S-transferase pathway and other drug metabolism pathways have been identified to alter susceptibility to therapy-related monosomy 7 [
## Germline Genetic Disorders Associated with Myeloid Neoplasms Not Specifically Associated with Monosomy 7
Other germline predisposition disorders in which MDS and leukemia have been reported without a specific association with monosomy 7 are summarized in
Disorders that Predispose to Myeloid Neoplasms without Monosomy 7
AD = autosomal dominant; AML = acute myeloid leukemia; AR = autosomal recessive; DD = developmental delay; MDS = myelodysplastic syndrome; MOI = mode of inheritance; XL = X-linked
Eleven additional ribosomal proteins have been associated with autosomal dominant Diamond-Blackfan anemia, though each at lower frequencies than the genes included in
## Management: To Inform (When Possible) Medical Management of Monosomy 7 Based on Genetic Cause
Measures include urgent referral to a hematologist for evaluation of cytopenias and bone marrow abnormalities that appear prior to the development of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and urgent referral to a hematopoietic stem cell transplantation (HSCT) specialist to identify potential donors and determine a transplant strategy. Consultation with a clinical geneticist and/or genetic counselor is recommended.
Laboratory studies for hematologic status should include the following.
CBC, differential, reticulocyte count, and peripheral blood smear review monitored weekly to monthly based on stability
Serum lactate dehydrogenase, uric acid, BUN, and creatinine
Liver function studies including transaminases, alkaline phosphatase, total and conjugated bilirubin, total protein, albumin, and liver-dependent clotting factors
Immunologic evaluation including quantitative immunoglobulins and quantitative lymphocyte subsets
HLA typing of the affected individual, full sibs, and biological parents to identify suitable donors for HSCT (See
Unilateral or bilateral bone marrow aspirate and biopsy
Morphologic assessments including bone marrow cellularity and assessment for dysplasia
Assessment for bone marrow blasts by flow cytometry or immunostains
Reticulin stain to assess for fibrosis
Iron stain to assess for ringed sideroblasts
Karyotype analysis on metaphase cells
FISH to assess for copy number changes or translocations involving chromosome 7 and changes in other chromosomes including 1, 3, 5, 8, 17, and 20
Molecular testing for somatic pathogenic variants in
Individuals with a monosomy 7 predisposition syndrome who develop monosomy 7 clones require treatment by hematologists, oncologists, and HSCT specialists with expertise in the management of MDS and AML. In the majority of individuals with monosomy 7, the key to successful treatment is early diagnosis so that definitive therapy with HSCT can be initiated prior to the emergence of a leukemic clone. Once transformation into AML occurs, the probability that HSCT will fail to cure the disease increases significantly [
Any child or young adult with monosomy 7 in combination with cytopenias and multilineage marrow dysplasia should, therefore, proceed to HSCT as soon as possible, unless rising blast count warrants cytoreductive chemotherapy prior to transplant. The optimal pre-transplant therapy for individuals with MDS and a monosomy 7 predisposition syndrome has yet to be defined [
Since HSCT is the only effective treatment for the management of hematologic disease and the familial status of the disorder may not be known, rigorous evaluation of related donors is strongly suggested.
In individuals with a known germline pathogenic variant associated with monosomy 7 predisposition, potential related donors should have site-specific testing for the known variant.
In individuals without an identified germline pathogenic variant, the matched related donor should undergo CBC and consider bone marrow analysis for hematopoietic abnormalities. A matched related donor with a normal CBC and bone marrow analysis may not be an ideal candidate for individuals with monosomy 7 in whom a germline predisposition is unidentified; a fully matched unrelated donor may be more suitable.
In individuals with bone marrow failure syndromes (e.g., Fanconi anemia) and monosomy 7 associated AML, transplant conditioning may need to be started during the aplastic phase after a chemotherapy cycle is administered, as these individuals may not exhibit appropriate count recovery following an AML induction chemotherapy cycle [
Furthermore, individuals with monosomy 7 predisposition caused by
For individuals with other monosomy 7 predisposition syndromes, data remain too limited to determine whether standard protocols for myeloablation prior to HSCT should be modified.
In individuals with childhood-onset monosomy 7 detected in the absence of other clonal genetic abnormalities, multilineage dysplasia, or increased blasts in bone marrow or peripheral blood, close serial surveillance of bone marrow aspirates and biopsies that includes blast quantitation, karyotype, FISH, and molecular analysis for somatic pathogenic variants commonly acquired in MDS/AML may be considered as an alternative to HSCT. In some individuals, the monosomy 7 clone may show regression (e.g.,
Initially, bone marrow examination may need to be performed every one to two months to assess for chromosome abnormalities and/or acquisition of somatic pathogenic variants in MDS-related genes, until monosomy 7 clone size stability and absence of further clonal progression has been established.
Thereafter, bone marrow examination may be decreased to twice yearly as long as the monosomy 7 clone persists. Worsening blood cytopenias, growth in monosomy 7 clone size, acquisition of additional chromosome abnormalities or somatic pathogenic variants in MDS-related genes, progression toward multilineage dysplasia, or excess blasts indicate need for curative HSCT.
If HSCT is not pursued due to the presence of severe medical comorbidities that would impair successful transplant outcome (e.g., severe pulmonary disease), annual bone marrow examination is recommended to provide prognostic information regarding anticipated timing of hematologic disease progression.
• CBC, differential, reticulocyte count, and peripheral blood smear review monitored weekly to monthly based on stability
• Serum lactate dehydrogenase, uric acid, BUN, and creatinine
• Liver function studies including transaminases, alkaline phosphatase, total and conjugated bilirubin, total protein, albumin, and liver-dependent clotting factors
• Immunologic evaluation including quantitative immunoglobulins and quantitative lymphocyte subsets
• HLA typing of the affected individual, full sibs, and biological parents to identify suitable donors for HSCT (See
• Unilateral or bilateral bone marrow aspirate and biopsy
• Morphologic assessments including bone marrow cellularity and assessment for dysplasia
• Assessment for bone marrow blasts by flow cytometry or immunostains
• Reticulin stain to assess for fibrosis
• Iron stain to assess for ringed sideroblasts
• Karyotype analysis on metaphase cells
• FISH to assess for copy number changes or translocations involving chromosome 7 and changes in other chromosomes including 1, 3, 5, 8, 17, and 20
• Molecular testing for somatic pathogenic variants in
• In individuals with a known germline pathogenic variant associated with monosomy 7 predisposition, potential related donors should have site-specific testing for the known variant.
• In individuals without an identified germline pathogenic variant, the matched related donor should undergo CBC and consider bone marrow analysis for hematopoietic abnormalities. A matched related donor with a normal CBC and bone marrow analysis may not be an ideal candidate for individuals with monosomy 7 in whom a germline predisposition is unidentified; a fully matched unrelated donor may be more suitable.
• In individuals with bone marrow failure syndromes (e.g., Fanconi anemia) and monosomy 7 associated AML, transplant conditioning may need to be started during the aplastic phase after a chemotherapy cycle is administered, as these individuals may not exhibit appropriate count recovery following an AML induction chemotherapy cycle [
• Furthermore, individuals with monosomy 7 predisposition caused by
• For individuals with other monosomy 7 predisposition syndromes, data remain too limited to determine whether standard protocols for myeloablation prior to HSCT should be modified.
• Initially, bone marrow examination may need to be performed every one to two months to assess for chromosome abnormalities and/or acquisition of somatic pathogenic variants in MDS-related genes, until monosomy 7 clone size stability and absence of further clonal progression has been established.
• Thereafter, bone marrow examination may be decreased to twice yearly as long as the monosomy 7 clone persists. Worsening blood cytopenias, growth in monosomy 7 clone size, acquisition of additional chromosome abnormalities or somatic pathogenic variants in MDS-related genes, progression toward multilineage dysplasia, or excess blasts indicate need for curative HSCT.
## Evaluations Following Initial Diagnosis
Measures include urgent referral to a hematologist for evaluation of cytopenias and bone marrow abnormalities that appear prior to the development of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and urgent referral to a hematopoietic stem cell transplantation (HSCT) specialist to identify potential donors and determine a transplant strategy. Consultation with a clinical geneticist and/or genetic counselor is recommended.
Laboratory studies for hematologic status should include the following.
CBC, differential, reticulocyte count, and peripheral blood smear review monitored weekly to monthly based on stability
Serum lactate dehydrogenase, uric acid, BUN, and creatinine
Liver function studies including transaminases, alkaline phosphatase, total and conjugated bilirubin, total protein, albumin, and liver-dependent clotting factors
Immunologic evaluation including quantitative immunoglobulins and quantitative lymphocyte subsets
HLA typing of the affected individual, full sibs, and biological parents to identify suitable donors for HSCT (See
Unilateral or bilateral bone marrow aspirate and biopsy
Morphologic assessments including bone marrow cellularity and assessment for dysplasia
Assessment for bone marrow blasts by flow cytometry or immunostains
Reticulin stain to assess for fibrosis
Iron stain to assess for ringed sideroblasts
Karyotype analysis on metaphase cells
FISH to assess for copy number changes or translocations involving chromosome 7 and changes in other chromosomes including 1, 3, 5, 8, 17, and 20
Molecular testing for somatic pathogenic variants in
• CBC, differential, reticulocyte count, and peripheral blood smear review monitored weekly to monthly based on stability
• Serum lactate dehydrogenase, uric acid, BUN, and creatinine
• Liver function studies including transaminases, alkaline phosphatase, total and conjugated bilirubin, total protein, albumin, and liver-dependent clotting factors
• Immunologic evaluation including quantitative immunoglobulins and quantitative lymphocyte subsets
• HLA typing of the affected individual, full sibs, and biological parents to identify suitable donors for HSCT (See
• Unilateral or bilateral bone marrow aspirate and biopsy
• Morphologic assessments including bone marrow cellularity and assessment for dysplasia
• Assessment for bone marrow blasts by flow cytometry or immunostains
• Reticulin stain to assess for fibrosis
• Iron stain to assess for ringed sideroblasts
• Karyotype analysis on metaphase cells
• FISH to assess for copy number changes or translocations involving chromosome 7 and changes in other chromosomes including 1, 3, 5, 8, 17, and 20
• Molecular testing for somatic pathogenic variants in
## Treatment of Manifestations
Individuals with a monosomy 7 predisposition syndrome who develop monosomy 7 clones require treatment by hematologists, oncologists, and HSCT specialists with expertise in the management of MDS and AML. In the majority of individuals with monosomy 7, the key to successful treatment is early diagnosis so that definitive therapy with HSCT can be initiated prior to the emergence of a leukemic clone. Once transformation into AML occurs, the probability that HSCT will fail to cure the disease increases significantly [
Any child or young adult with monosomy 7 in combination with cytopenias and multilineage marrow dysplasia should, therefore, proceed to HSCT as soon as possible, unless rising blast count warrants cytoreductive chemotherapy prior to transplant. The optimal pre-transplant therapy for individuals with MDS and a monosomy 7 predisposition syndrome has yet to be defined [
Since HSCT is the only effective treatment for the management of hematologic disease and the familial status of the disorder may not be known, rigorous evaluation of related donors is strongly suggested.
In individuals with a known germline pathogenic variant associated with monosomy 7 predisposition, potential related donors should have site-specific testing for the known variant.
In individuals without an identified germline pathogenic variant, the matched related donor should undergo CBC and consider bone marrow analysis for hematopoietic abnormalities. A matched related donor with a normal CBC and bone marrow analysis may not be an ideal candidate for individuals with monosomy 7 in whom a germline predisposition is unidentified; a fully matched unrelated donor may be more suitable.
In individuals with bone marrow failure syndromes (e.g., Fanconi anemia) and monosomy 7 associated AML, transplant conditioning may need to be started during the aplastic phase after a chemotherapy cycle is administered, as these individuals may not exhibit appropriate count recovery following an AML induction chemotherapy cycle [
Furthermore, individuals with monosomy 7 predisposition caused by
For individuals with other monosomy 7 predisposition syndromes, data remain too limited to determine whether standard protocols for myeloablation prior to HSCT should be modified.
• In individuals with a known germline pathogenic variant associated with monosomy 7 predisposition, potential related donors should have site-specific testing for the known variant.
• In individuals without an identified germline pathogenic variant, the matched related donor should undergo CBC and consider bone marrow analysis for hematopoietic abnormalities. A matched related donor with a normal CBC and bone marrow analysis may not be an ideal candidate for individuals with monosomy 7 in whom a germline predisposition is unidentified; a fully matched unrelated donor may be more suitable.
• In individuals with bone marrow failure syndromes (e.g., Fanconi anemia) and monosomy 7 associated AML, transplant conditioning may need to be started during the aplastic phase after a chemotherapy cycle is administered, as these individuals may not exhibit appropriate count recovery following an AML induction chemotherapy cycle [
• Furthermore, individuals with monosomy 7 predisposition caused by
• For individuals with other monosomy 7 predisposition syndromes, data remain too limited to determine whether standard protocols for myeloablation prior to HSCT should be modified.
## Surveillance
In individuals with childhood-onset monosomy 7 detected in the absence of other clonal genetic abnormalities, multilineage dysplasia, or increased blasts in bone marrow or peripheral blood, close serial surveillance of bone marrow aspirates and biopsies that includes blast quantitation, karyotype, FISH, and molecular analysis for somatic pathogenic variants commonly acquired in MDS/AML may be considered as an alternative to HSCT. In some individuals, the monosomy 7 clone may show regression (e.g.,
Initially, bone marrow examination may need to be performed every one to two months to assess for chromosome abnormalities and/or acquisition of somatic pathogenic variants in MDS-related genes, until monosomy 7 clone size stability and absence of further clonal progression has been established.
Thereafter, bone marrow examination may be decreased to twice yearly as long as the monosomy 7 clone persists. Worsening blood cytopenias, growth in monosomy 7 clone size, acquisition of additional chromosome abnormalities or somatic pathogenic variants in MDS-related genes, progression toward multilineage dysplasia, or excess blasts indicate need for curative HSCT.
If HSCT is not pursued due to the presence of severe medical comorbidities that would impair successful transplant outcome (e.g., severe pulmonary disease), annual bone marrow examination is recommended to provide prognostic information regarding anticipated timing of hematologic disease progression.
• Initially, bone marrow examination may need to be performed every one to two months to assess for chromosome abnormalities and/or acquisition of somatic pathogenic variants in MDS-related genes, until monosomy 7 clone size stability and absence of further clonal progression has been established.
• Thereafter, bone marrow examination may be decreased to twice yearly as long as the monosomy 7 clone persists. Worsening blood cytopenias, growth in monosomy 7 clone size, acquisition of additional chromosome abnormalities or somatic pathogenic variants in MDS-related genes, progression toward multilineage dysplasia, or excess blasts indicate need for curative HSCT.
## Risk Assessment and Surveillance of At-Risk Relatives for Early Detection and Treatment of Monosomy 7 Predisposition Syndromes
Monosomy 7 predisposition syndromes can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
In individuals with a suspected monosomy 7 predisposition syndrome in whom no germline molecular diagnosis is found, the mode of inheritance that is most likely may be elucidated by taking a detailed, three-generation family history with attention to relatives with manifestations of monosomy 7 predisposition syndromes and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing.
The family history may suggest autosomal dominant inheritance (e.g., affected males and females in multiple generations), autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity), or X-linked inheritance (e.g., no male-to-male transmission) or the proband may appear to be the only affected family member (in which case he or she may have monosomy 7 predisposition syndrome as the result of a
Note
Modes of Inheritance of Hereditary Disorders Known to be Associated with Monosomy 7 Predisposition Syndrome
AD = autosomal dominant; AML = acute myeloid leukemia; AR = autosomal recessive; DD = developmental delay; MDS = myelodysplastic syndrome; MOI = mode of inheritance; XL = X-linked
Listed genes represent the most common genetic causes of Fanconi anemia (FA). For other genes associated with this phenotype (>20 genes have been identified), see
Some individuals with an autosomal dominant monosomy 7 predisposition syndrome may have inherited a predisposing germline pathogenic variant from a parent. A heterozygous parent may or may not have hematologic abnormalities and/or other related manifestations.
Alternatively, an individual diagnosed with a monosomy 7 predisposition syndrome may have a
Molecular genetic testing is recommended for the parents of the proband (if feasible, use of DNA derived from nonhematopoietic tissue [e.g., skin fibroblasts, hair roots] may be considered, as germline pathogenic variants may not be detectable in leukocytes in some individuals). If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline mosaicism.
The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the predisposing pathogenic variant. This somatic change (e.g., due to monosomy 7 or uniparental disomy 7) often occurs in hematopoietic tissue and results in a decreased fraction of cells with the variant, and may cause a false negative molecular result when testing leukocyte DNA.
Although rarely reported, the clinical family history of some individuals diagnosed with monosomy 7 predisposition syndromes may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or phenotypic modification resulting from a natural protective second genetic event. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing (optimally using DNA derived from nonhematopoietic tissue) has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband has the predisposing pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. The likelihood that a sib who inherits a pathogenic variant will have abnormal hematologic findings and/or other related manifestations depends on penetrance of the familial disorder and the possibility of phenotypic modification.
If the proband has a known predisposing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism and the possibility of a false negative result in a parent due to preferential loss of the chromosome with the pathogenic variant.
If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for the monosomy 7 predisposition syndrome because of the possibility that a parent either: (1) has germline mosaicism; or (2) is heterozygous but does not have apparent manifestations of the disorder because of reduced penetrance or phenotypic modification resulting from a natural protective second genetic event.
The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing (preferably using DNA from nonhematopoietic tissue) for the germline pathogenic variant identified in the proband (see Management,
The parents of a child with an autosomal recessive monosomy 7 predisposition syndrome are obligate heterozygotes (i.e., presumed to be carriers of one predisposing pathogenic variant based on family history).
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a predisposing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Individuals who are heterozygous for a pathogenic variant in a gene associated with autosomal recessive monosomy 7 predisposition have no known increased risk of developing monosomy 7-associated myeloid malignancies. However, individuals who are heterozygous for a pathogenic variant in a subset of these genes — including genes associated with
If both parents are known to be heterozygous for a predisposing pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting two causative pathogenic variants, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
Individuals who are heterozygous for a pathogenic variant in a gene associated with autosomal recessive monosomy 7 predisposition have no known increased risk of developing monosomy 7-associated myeloid malignancies. However, individuals who are heterozygous for a pathogenic variant in a subset of these genes — including genes associated with
The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing for the germline pathogenic variants identified in the proband (see Management,
The father of a male with an X-linked monosomy 7 predisposition syndrome will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the variant will be heterozygotes and will usually not be affected.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.
The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing for the germline pathogenic variant identified in the proband (see Management,
Note: Molecular genetic testing may be able to identify the family member in whom a
It is appropriate to evaluate apparently asymptomatic at-risk relatives of individuals with a history of a monosomy 7 predisposition syndrome as early as possible in order to allow initiation of HSCT prior to the emergence of a leukemic clone.
In families with an autosomal dominant monosomy 7 predisposing syndrome, those identified as heterozygous for the pathogenic variant present in the affected family member and thus at high risk for developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) should seek consultation with a hematologist, oncologist, or HSCT specialist with expertise in monosomy 7 predisposition syndromes in order to develop an individualized treatment and surveillance plan.
In families with an autosomal recessive predisposing syndrome, those identified as having biallelic predisposing pathogenic variants and thus being at high risk for developing MDS or AML should seek consultation with a hematologist, oncologist, or HSCT specialist as recommended above.
In families with an X-linked monosomy 7 predisposing syndrome, males identified as hemizygous for the pathogenic variant present in the affected family member and thus at high risk for developing MDS or AML should seek consultation with a hematologist, oncologist, or HSCT specialist as recommended above.
Provided that genetic testing was performed using a germline, nonhematologic DNA sample, those without the monosomy 7-related pathogenic variant(s) defined as causal in the proband are no longer considered to be at increased risk for MDS or AML and thus may be discharged from hematologic surveillance.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being affected or carriers.
Once the germline pathogenic variant(s) known to be associated with a monosomy 7 predisposition syndrome have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Note: Monosomy 7 is not expected to be present in most fetal tissues sampled prenatally.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Some individuals with an autosomal dominant monosomy 7 predisposition syndrome may have inherited a predisposing germline pathogenic variant from a parent. A heterozygous parent may or may not have hematologic abnormalities and/or other related manifestations.
• Alternatively, an individual diagnosed with a monosomy 7 predisposition syndrome may have a
• Molecular genetic testing is recommended for the parents of the proband (if feasible, use of DNA derived from nonhematopoietic tissue [e.g., skin fibroblasts, hair roots] may be considered, as germline pathogenic variants may not be detectable in leukocytes in some individuals). If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the predisposing pathogenic variant. This somatic change (e.g., due to monosomy 7 or uniparental disomy 7) often occurs in hematopoietic tissue and results in a decreased fraction of cells with the variant, and may cause a false negative molecular result when testing leukocyte DNA.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the predisposing pathogenic variant. This somatic change (e.g., due to monosomy 7 or uniparental disomy 7) often occurs in hematopoietic tissue and results in a decreased fraction of cells with the variant, and may cause a false negative molecular result when testing leukocyte DNA.
• Although rarely reported, the clinical family history of some individuals diagnosed with monosomy 7 predisposition syndromes may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or phenotypic modification resulting from a natural protective second genetic event. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing (optimally using DNA derived from nonhematopoietic tissue) has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the predisposing pathogenic variant. This somatic change (e.g., due to monosomy 7 or uniparental disomy 7) often occurs in hematopoietic tissue and results in a decreased fraction of cells with the variant, and may cause a false negative molecular result when testing leukocyte DNA.
• If a parent of the proband has the predisposing pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. The likelihood that a sib who inherits a pathogenic variant will have abnormal hematologic findings and/or other related manifestations depends on penetrance of the familial disorder and the possibility of phenotypic modification.
• If the proband has a known predisposing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism and the possibility of a false negative result in a parent due to preferential loss of the chromosome with the pathogenic variant.
• If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for the monosomy 7 predisposition syndrome because of the possibility that a parent either: (1) has germline mosaicism; or (2) is heterozygous but does not have apparent manifestations of the disorder because of reduced penetrance or phenotypic modification resulting from a natural protective second genetic event.
• The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing (preferably using DNA from nonhematopoietic tissue) for the germline pathogenic variant identified in the proband (see Management,
• The parents of a child with an autosomal recessive monosomy 7 predisposition syndrome are obligate heterozygotes (i.e., presumed to be carriers of one predisposing pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a predisposing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for a pathogenic variant in a gene associated with autosomal recessive monosomy 7 predisposition have no known increased risk of developing monosomy 7-associated myeloid malignancies. However, individuals who are heterozygous for a pathogenic variant in a subset of these genes — including genes associated with
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a predisposing pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting two causative pathogenic variants, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Individuals who are heterozygous for a pathogenic variant in a gene associated with autosomal recessive monosomy 7 predisposition have no known increased risk of developing monosomy 7-associated myeloid malignancies. However, individuals who are heterozygous for a pathogenic variant in a subset of these genes — including genes associated with
• The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing for the germline pathogenic variants identified in the proband (see Management,
• The father of a male with an X-linked monosomy 7 predisposition syndrome will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the variant will be heterozygotes and will usually not be affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.
• The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing for the germline pathogenic variant identified in the proband (see Management,
• In families with an autosomal dominant monosomy 7 predisposing syndrome, those identified as heterozygous for the pathogenic variant present in the affected family member and thus at high risk for developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) should seek consultation with a hematologist, oncologist, or HSCT specialist with expertise in monosomy 7 predisposition syndromes in order to develop an individualized treatment and surveillance plan.
• In families with an autosomal recessive predisposing syndrome, those identified as having biallelic predisposing pathogenic variants and thus being at high risk for developing MDS or AML should seek consultation with a hematologist, oncologist, or HSCT specialist as recommended above.
• In families with an X-linked monosomy 7 predisposing syndrome, males identified as hemizygous for the pathogenic variant present in the affected family member and thus at high risk for developing MDS or AML should seek consultation with a hematologist, oncologist, or HSCT specialist as recommended above.
• Provided that genetic testing was performed using a germline, nonhematologic DNA sample, those without the monosomy 7-related pathogenic variant(s) defined as causal in the proband are no longer considered to be at increased risk for MDS or AML and thus may be discharged from hematologic surveillance.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being affected or carriers.
## Genetic Risk Assessment
Monosomy 7 predisposition syndromes can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
In individuals with a suspected monosomy 7 predisposition syndrome in whom no germline molecular diagnosis is found, the mode of inheritance that is most likely may be elucidated by taking a detailed, three-generation family history with attention to relatives with manifestations of monosomy 7 predisposition syndromes and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing.
The family history may suggest autosomal dominant inheritance (e.g., affected males and females in multiple generations), autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity), or X-linked inheritance (e.g., no male-to-male transmission) or the proband may appear to be the only affected family member (in which case he or she may have monosomy 7 predisposition syndrome as the result of a
Note
Modes of Inheritance of Hereditary Disorders Known to be Associated with Monosomy 7 Predisposition Syndrome
AD = autosomal dominant; AML = acute myeloid leukemia; AR = autosomal recessive; DD = developmental delay; MDS = myelodysplastic syndrome; MOI = mode of inheritance; XL = X-linked
Listed genes represent the most common genetic causes of Fanconi anemia (FA). For other genes associated with this phenotype (>20 genes have been identified), see
## Autosomal Dominant Inheritance – Risk to Family Members in Families with a Known Predisposing Germline Pathogenic Variant
Some individuals with an autosomal dominant monosomy 7 predisposition syndrome may have inherited a predisposing germline pathogenic variant from a parent. A heterozygous parent may or may not have hematologic abnormalities and/or other related manifestations.
Alternatively, an individual diagnosed with a monosomy 7 predisposition syndrome may have a
Molecular genetic testing is recommended for the parents of the proband (if feasible, use of DNA derived from nonhematopoietic tissue [e.g., skin fibroblasts, hair roots] may be considered, as germline pathogenic variants may not be detectable in leukocytes in some individuals). If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline mosaicism.
The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the predisposing pathogenic variant. This somatic change (e.g., due to monosomy 7 or uniparental disomy 7) often occurs in hematopoietic tissue and results in a decreased fraction of cells with the variant, and may cause a false negative molecular result when testing leukocyte DNA.
Although rarely reported, the clinical family history of some individuals diagnosed with monosomy 7 predisposition syndromes may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or phenotypic modification resulting from a natural protective second genetic event. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing (optimally using DNA derived from nonhematopoietic tissue) has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband has the predisposing pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. The likelihood that a sib who inherits a pathogenic variant will have abnormal hematologic findings and/or other related manifestations depends on penetrance of the familial disorder and the possibility of phenotypic modification.
If the proband has a known predisposing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism and the possibility of a false negative result in a parent due to preferential loss of the chromosome with the pathogenic variant.
If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for the monosomy 7 predisposition syndrome because of the possibility that a parent either: (1) has germline mosaicism; or (2) is heterozygous but does not have apparent manifestations of the disorder because of reduced penetrance or phenotypic modification resulting from a natural protective second genetic event.
The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing (preferably using DNA from nonhematopoietic tissue) for the germline pathogenic variant identified in the proband (see Management,
• Some individuals with an autosomal dominant monosomy 7 predisposition syndrome may have inherited a predisposing germline pathogenic variant from a parent. A heterozygous parent may or may not have hematologic abnormalities and/or other related manifestations.
• Alternatively, an individual diagnosed with a monosomy 7 predisposition syndrome may have a
• Molecular genetic testing is recommended for the parents of the proband (if feasible, use of DNA derived from nonhematopoietic tissue [e.g., skin fibroblasts, hair roots] may be considered, as germline pathogenic variants may not be detectable in leukocytes in some individuals). If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the predisposing pathogenic variant. This somatic change (e.g., due to monosomy 7 or uniparental disomy 7) often occurs in hematopoietic tissue and results in a decreased fraction of cells with the variant, and may cause a false negative molecular result when testing leukocyte DNA.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the predisposing pathogenic variant. This somatic change (e.g., due to monosomy 7 or uniparental disomy 7) often occurs in hematopoietic tissue and results in a decreased fraction of cells with the variant, and may cause a false negative molecular result when testing leukocyte DNA.
• Although rarely reported, the clinical family history of some individuals diagnosed with monosomy 7 predisposition syndromes may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or phenotypic modification resulting from a natural protective second genetic event. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing (optimally using DNA derived from nonhematopoietic tissue) has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the predisposing pathogenic variant. This somatic change (e.g., due to monosomy 7 or uniparental disomy 7) often occurs in hematopoietic tissue and results in a decreased fraction of cells with the variant, and may cause a false negative molecular result when testing leukocyte DNA.
• If a parent of the proband has the predisposing pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. The likelihood that a sib who inherits a pathogenic variant will have abnormal hematologic findings and/or other related manifestations depends on penetrance of the familial disorder and the possibility of phenotypic modification.
• If the proband has a known predisposing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism and the possibility of a false negative result in a parent due to preferential loss of the chromosome with the pathogenic variant.
• If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for the monosomy 7 predisposition syndrome because of the possibility that a parent either: (1) has germline mosaicism; or (2) is heterozygous but does not have apparent manifestations of the disorder because of reduced penetrance or phenotypic modification resulting from a natural protective second genetic event.
• The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing (preferably using DNA from nonhematopoietic tissue) for the germline pathogenic variant identified in the proband (see Management,
## Autosomal Recessive Inheritance – Risk to Family Members in Families with Known Predisposing Germline Pathogenic Variants
The parents of a child with an autosomal recessive monosomy 7 predisposition syndrome are obligate heterozygotes (i.e., presumed to be carriers of one predisposing pathogenic variant based on family history).
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a predisposing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Individuals who are heterozygous for a pathogenic variant in a gene associated with autosomal recessive monosomy 7 predisposition have no known increased risk of developing monosomy 7-associated myeloid malignancies. However, individuals who are heterozygous for a pathogenic variant in a subset of these genes — including genes associated with
If both parents are known to be heterozygous for a predisposing pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting two causative pathogenic variants, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
Individuals who are heterozygous for a pathogenic variant in a gene associated with autosomal recessive monosomy 7 predisposition have no known increased risk of developing monosomy 7-associated myeloid malignancies. However, individuals who are heterozygous for a pathogenic variant in a subset of these genes — including genes associated with
The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing for the germline pathogenic variants identified in the proband (see Management,
• The parents of a child with an autosomal recessive monosomy 7 predisposition syndrome are obligate heterozygotes (i.e., presumed to be carriers of one predisposing pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a predisposing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for a pathogenic variant in a gene associated with autosomal recessive monosomy 7 predisposition have no known increased risk of developing monosomy 7-associated myeloid malignancies. However, individuals who are heterozygous for a pathogenic variant in a subset of these genes — including genes associated with
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a predisposing pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting two causative pathogenic variants, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Individuals who are heterozygous for a pathogenic variant in a gene associated with autosomal recessive monosomy 7 predisposition have no known increased risk of developing monosomy 7-associated myeloid malignancies. However, individuals who are heterozygous for a pathogenic variant in a subset of these genes — including genes associated with
• The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing for the germline pathogenic variants identified in the proband (see Management,
## X-Linked Inheritance – Risk to Family Members in Families with a Known Predisposing Germline Pathogenic Variant
The father of a male with an X-linked monosomy 7 predisposition syndrome will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the variant will be heterozygotes and will usually not be affected.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.
The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing for the germline pathogenic variant identified in the proband (see Management,
Note: Molecular genetic testing may be able to identify the family member in whom a
• The father of a male with an X-linked monosomy 7 predisposition syndrome will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the variant will be heterozygotes and will usually not be affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.
• The suitability of sibs who are potential bone marrow donors may be evaluated with molecular genetic testing for the germline pathogenic variant identified in the proband (see Management,
## Surveillance
It is appropriate to evaluate apparently asymptomatic at-risk relatives of individuals with a history of a monosomy 7 predisposition syndrome as early as possible in order to allow initiation of HSCT prior to the emergence of a leukemic clone.
In families with an autosomal dominant monosomy 7 predisposing syndrome, those identified as heterozygous for the pathogenic variant present in the affected family member and thus at high risk for developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) should seek consultation with a hematologist, oncologist, or HSCT specialist with expertise in monosomy 7 predisposition syndromes in order to develop an individualized treatment and surveillance plan.
In families with an autosomal recessive predisposing syndrome, those identified as having biallelic predisposing pathogenic variants and thus being at high risk for developing MDS or AML should seek consultation with a hematologist, oncologist, or HSCT specialist as recommended above.
In families with an X-linked monosomy 7 predisposing syndrome, males identified as hemizygous for the pathogenic variant present in the affected family member and thus at high risk for developing MDS or AML should seek consultation with a hematologist, oncologist, or HSCT specialist as recommended above.
Provided that genetic testing was performed using a germline, nonhematologic DNA sample, those without the monosomy 7-related pathogenic variant(s) defined as causal in the proband are no longer considered to be at increased risk for MDS or AML and thus may be discharged from hematologic surveillance.
• In families with an autosomal dominant monosomy 7 predisposing syndrome, those identified as heterozygous for the pathogenic variant present in the affected family member and thus at high risk for developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) should seek consultation with a hematologist, oncologist, or HSCT specialist with expertise in monosomy 7 predisposition syndromes in order to develop an individualized treatment and surveillance plan.
• In families with an autosomal recessive predisposing syndrome, those identified as having biallelic predisposing pathogenic variants and thus being at high risk for developing MDS or AML should seek consultation with a hematologist, oncologist, or HSCT specialist as recommended above.
• In families with an X-linked monosomy 7 predisposing syndrome, males identified as hemizygous for the pathogenic variant present in the affected family member and thus at high risk for developing MDS or AML should seek consultation with a hematologist, oncologist, or HSCT specialist as recommended above.
• Provided that genetic testing was performed using a germline, nonhematologic DNA sample, those without the monosomy 7-related pathogenic variant(s) defined as causal in the proband are no longer considered to be at increased risk for MDS or AML and thus may be discharged from hematologic surveillance.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being affected or carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being affected or carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the germline pathogenic variant(s) known to be associated with a monosomy 7 predisposition syndrome have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Note: Monosomy 7 is not expected to be present in most fetal tissues sampled prenatally.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Chapter Notes
10 June 2021 (sw) Review posted live
26 February 2021 (to) Original submission
• 10 June 2021 (sw) Review posted live
• 26 February 2021 (to) Original submission
## Author Notes
## Revision History
10 June 2021 (sw) Review posted live
26 February 2021 (to) Original submission
• 10 June 2021 (sw) Review posted live
• 26 February 2021 (to) Original submission
## References
## Literature Cited
|
[] |
10/6/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mopd2
|
mopd2
|
[
"Majewski Osteodysplastic Primordial Dwarfism Type II",
"MOPDII",
"PCNT-Related Microcephalic Osteodysplastic Primordial Dwarfism",
"MOPDII",
"PCNT-Related Microcephalic Osteodysplastic Primordial Dwarfism",
"Majewski Osteodysplastic Primordial Dwarfism Type II",
"Pericentrin",
"PCNT",
"Microcephalic Osteodysplastic Primordial Dwarfism Type II"
] |
Microcephalic Osteodysplastic Primordial Dwarfism Type II
|
Angela Duker, Andrew Jackson, Michael B Bober
|
Summary Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common form of microcephalic primordial dwarfism, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and that may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities. The diagnosis of MOPDII is established in a proband with suggestive findings and biallelic loss-of-function pathogenic variants in MOPDII is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for microcephalic osteodysplastic primordial dwarfism type II (MOPDII) have been published.
MOPDII
Severe pre- and postnatal growth restriction
Extreme microcephaly
Skeletal dysplasia
Distinctive facial features (see
Prominent nose with wide nasal bridge and broad root
Low-hanging columella
Ears with simple structure and attached lobes
Abnormal dentition
Microdontia
Premature tooth loss
Global vascular disease
Moyamoya vasculopathy
Aneurysms (predominantly central nervous system)
Coronary artery disease with premature myocardial infarctions
Renal artery disease
Chronic kidney disease
Insulin resistance / diabetes mellitus
Hypertension
Hematologic abnormalities
Thrombocytosis
Anemia
High-pitched nasal voice
Skeletal
Mesomelia
Slender long bones
Progressive widening of metaphyses
Epiphyseal ossification delay
Dislocation or subluxation of radial heads
Brachymesophalangy (See
Small iliac wings with flat acetabular angles
Coxa vara
Slipped capital femoral epiphysis (See
Scoliosis (See
Neuroimaging
Moyamoya
Intracranial aneurysms
The diagnosis of MOPDII
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Microcephalic Osteodysplastic Primordial Dwarfism Type II
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Severe pre- and postnatal growth restriction
• Extreme microcephaly
• Skeletal dysplasia
• Distinctive facial features (see
• Prominent nose with wide nasal bridge and broad root
• Low-hanging columella
• Ears with simple structure and attached lobes
• Prominent nose with wide nasal bridge and broad root
• Low-hanging columella
• Ears with simple structure and attached lobes
• Abnormal dentition
• Microdontia
• Premature tooth loss
• Microdontia
• Premature tooth loss
• Global vascular disease
• Moyamoya vasculopathy
• Aneurysms (predominantly central nervous system)
• Coronary artery disease with premature myocardial infarctions
• Renal artery disease
• Moyamoya vasculopathy
• Aneurysms (predominantly central nervous system)
• Coronary artery disease with premature myocardial infarctions
• Renal artery disease
• Chronic kidney disease
• Insulin resistance / diabetes mellitus
• Hypertension
• Hematologic abnormalities
• Thrombocytosis
• Anemia
• Thrombocytosis
• Anemia
• High-pitched nasal voice
• Prominent nose with wide nasal bridge and broad root
• Low-hanging columella
• Ears with simple structure and attached lobes
• Microdontia
• Premature tooth loss
• Moyamoya vasculopathy
• Aneurysms (predominantly central nervous system)
• Coronary artery disease with premature myocardial infarctions
• Renal artery disease
• Thrombocytosis
• Anemia
• Skeletal
• Mesomelia
• Slender long bones
• Progressive widening of metaphyses
• Epiphyseal ossification delay
• Dislocation or subluxation of radial heads
• Brachymesophalangy (See
• Small iliac wings with flat acetabular angles
• Coxa vara
• Slipped capital femoral epiphysis (See
• Scoliosis (See
• Mesomelia
• Slender long bones
• Progressive widening of metaphyses
• Epiphyseal ossification delay
• Dislocation or subluxation of radial heads
• Brachymesophalangy (See
• Small iliac wings with flat acetabular angles
• Coxa vara
• Slipped capital femoral epiphysis (See
• Scoliosis (See
• Neuroimaging
• Moyamoya
• Intracranial aneurysms
• Moyamoya
• Intracranial aneurysms
• Mesomelia
• Slender long bones
• Progressive widening of metaphyses
• Epiphyseal ossification delay
• Dislocation or subluxation of radial heads
• Brachymesophalangy (See
• Small iliac wings with flat acetabular angles
• Coxa vara
• Slipped capital femoral epiphysis (See
• Scoliosis (See
• Moyamoya
• Intracranial aneurysms
## Suggestive Findings
MOPDII
Severe pre- and postnatal growth restriction
Extreme microcephaly
Skeletal dysplasia
Distinctive facial features (see
Prominent nose with wide nasal bridge and broad root
Low-hanging columella
Ears with simple structure and attached lobes
Abnormal dentition
Microdontia
Premature tooth loss
Global vascular disease
Moyamoya vasculopathy
Aneurysms (predominantly central nervous system)
Coronary artery disease with premature myocardial infarctions
Renal artery disease
Chronic kidney disease
Insulin resistance / diabetes mellitus
Hypertension
Hematologic abnormalities
Thrombocytosis
Anemia
High-pitched nasal voice
Skeletal
Mesomelia
Slender long bones
Progressive widening of metaphyses
Epiphyseal ossification delay
Dislocation or subluxation of radial heads
Brachymesophalangy (See
Small iliac wings with flat acetabular angles
Coxa vara
Slipped capital femoral epiphysis (See
Scoliosis (See
Neuroimaging
Moyamoya
Intracranial aneurysms
• Severe pre- and postnatal growth restriction
• Extreme microcephaly
• Skeletal dysplasia
• Distinctive facial features (see
• Prominent nose with wide nasal bridge and broad root
• Low-hanging columella
• Ears with simple structure and attached lobes
• Prominent nose with wide nasal bridge and broad root
• Low-hanging columella
• Ears with simple structure and attached lobes
• Abnormal dentition
• Microdontia
• Premature tooth loss
• Microdontia
• Premature tooth loss
• Global vascular disease
• Moyamoya vasculopathy
• Aneurysms (predominantly central nervous system)
• Coronary artery disease with premature myocardial infarctions
• Renal artery disease
• Moyamoya vasculopathy
• Aneurysms (predominantly central nervous system)
• Coronary artery disease with premature myocardial infarctions
• Renal artery disease
• Chronic kidney disease
• Insulin resistance / diabetes mellitus
• Hypertension
• Hematologic abnormalities
• Thrombocytosis
• Anemia
• Thrombocytosis
• Anemia
• High-pitched nasal voice
• Prominent nose with wide nasal bridge and broad root
• Low-hanging columella
• Ears with simple structure and attached lobes
• Microdontia
• Premature tooth loss
• Moyamoya vasculopathy
• Aneurysms (predominantly central nervous system)
• Coronary artery disease with premature myocardial infarctions
• Renal artery disease
• Thrombocytosis
• Anemia
• Skeletal
• Mesomelia
• Slender long bones
• Progressive widening of metaphyses
• Epiphyseal ossification delay
• Dislocation or subluxation of radial heads
• Brachymesophalangy (See
• Small iliac wings with flat acetabular angles
• Coxa vara
• Slipped capital femoral epiphysis (See
• Scoliosis (See
• Mesomelia
• Slender long bones
• Progressive widening of metaphyses
• Epiphyseal ossification delay
• Dislocation or subluxation of radial heads
• Brachymesophalangy (See
• Small iliac wings with flat acetabular angles
• Coxa vara
• Slipped capital femoral epiphysis (See
• Scoliosis (See
• Neuroimaging
• Moyamoya
• Intracranial aneurysms
• Moyamoya
• Intracranial aneurysms
• Mesomelia
• Slender long bones
• Progressive widening of metaphyses
• Epiphyseal ossification delay
• Dislocation or subluxation of radial heads
• Brachymesophalangy (See
• Small iliac wings with flat acetabular angles
• Coxa vara
• Slipped capital femoral epiphysis (See
• Scoliosis (See
• Moyamoya
• Intracranial aneurysms
## Establishing the Diagnosis
The diagnosis of MOPDII
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Microcephalic Osteodysplastic Primordial Dwarfism Type II
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Microcephalic Osteodysplastic Primordial Dwarfism Type II
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common of the microcephalic primordial dwarfism syndromes, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and which may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities [
Anticipated life expectancy is shortened due to the associated comorbidities, which when untreated can lead to early death, predominately in early adulthood (age range 7-41 years) [
More than 150 individuals with a molecularly confirmed diagnosis have been identified [
The following description of the phenotypic features associated with this condition is based on the most recent review of 47 individuals with molecularly confirmed MOPDII [
Features of Microcephalic Osteodysplastic Primordial Dwarfism Type II
Based on
ADHD = attention-deficit/hyperactivity disorder; ASD = atrial septal defect; IUGR = intrauterine growth restriction; MI = myocardial infarction; PFO = patent foramen ovale; VSD = ventricular septal defect
Body habitus evolves with time. Infants and young children have decreased subcutaneous fat; truncal obesity tends to develop through puberty. In contrast to weight gain in age-related peers, the average expected daily weight gain in individuals with MOPDII is 2 g/day throughout the life span, from infancy to skeletal maturity. Appropriate weight gain expectations are paramount to avoid excessive and unnecessary nutritional interventions [
Ivory and cone-shaped phalangeal epiphyses have been described; fifth finger clinodactyly and brachymesophalangy are common.
Iliac wings are small with flat acetabular angles.
Scoliosis may occur and can rapidly progress in late childhood / puberty, leading to the need for spinal fusion [
Associated hip pathology includes coxa vara, coxa valga, developmental dysplasia, dislocation/subluxation, proximal femoral epiphysiolysis, and avascular necrosis. Eight of 12 individuals had hip pathology, some unilaterally (equaling 50% of the total hips). Developmental coxa vara was the most common finding, often beginning with a slipped capital femoral epiphysis and progressing to severe coxa vara, typically identified between ages two and five years [
Secondary teeth tend to be more affected. They are disproportionately small, dysplastic, and can have enamel hypoplasia. They are typically poorly rooted, and chewing can be affected. In many individuals, secondary teeth either prematurely shed or are extracted, and are replaced with dentures and/or implants [
In a cohort of 47 individuals, eight had myocardial infarctions as young adults (range 17-33 years; mean age 24±5.2 years; median age 24 years); multiple individuals had more than one acute coronary event.
Approximately 25% of individuals had cardiac malformations, including atrial septal defect, ventricular septal defect, and persistent patent foramen ovale. One individual had multiple cardiac rhabdomyomas [
Another individual who had renal artery stenosis in addition to a renal artery aneurysm ultimately had a partial infarct of a kidney.
Six individuals had nephrolithiasis in early adulthood; all were on anti-hypertensive medications at the time of the diagnosis of nephrolithiasis.
Congenital anomalies included accessory/duplicated renal arteries in seven males and no females [
Seventeen of 46 individuals (in a different but overlapping cohort) had insulin resistance and/or diabetes, typically detected in adolescence [
These issues can also lead to dyslipidemia and fatty liver [
Skin:
Acanthosis nigricans, repeatedly documented, is likely related to concomitant insulin resistance [
Café au lait patches have been described, with areas of hypopigmentation later in life.
"Wizened hands" with multiple creases developing in childhood have been noted (see
Neuroimaging findings can include simplified gyral patterns and hypoplasia of the corpus callosum [
Subglottic stenosis, described in some individuals, required tracheostomy in at least two affected individuals [
Craniosynostosis has been infrequently described, at times requiring surgical intervention. One child had bilateral coronal synostosis recognized in the neonatal period which required repair [
No genotype-phenotype correlations have been identified.
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is rare. More than 150 individuals with molecularly confirmed MOPDII have been identified across many populations worldwide [
Many different loss-of-function variants have been identified. Founder variants reported in specific populations include the following:
• Skin:
• Acanthosis nigricans, repeatedly documented, is likely related to concomitant insulin resistance [
• Café au lait patches have been described, with areas of hypopigmentation later in life.
• "Wizened hands" with multiple creases developing in childhood have been noted (see
• Acanthosis nigricans, repeatedly documented, is likely related to concomitant insulin resistance [
• Café au lait patches have been described, with areas of hypopigmentation later in life.
• "Wizened hands" with multiple creases developing in childhood have been noted (see
• Neuroimaging findings can include simplified gyral patterns and hypoplasia of the corpus callosum [
• Subglottic stenosis, described in some individuals, required tracheostomy in at least two affected individuals [
• Craniosynostosis has been infrequently described, at times requiring surgical intervention. One child had bilateral coronal synostosis recognized in the neonatal period which required repair [
• Acanthosis nigricans, repeatedly documented, is likely related to concomitant insulin resistance [
• Café au lait patches have been described, with areas of hypopigmentation later in life.
• "Wizened hands" with multiple creases developing in childhood have been noted (see
## Clinical Description
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common of the microcephalic primordial dwarfism syndromes, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and which may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities [
Anticipated life expectancy is shortened due to the associated comorbidities, which when untreated can lead to early death, predominately in early adulthood (age range 7-41 years) [
More than 150 individuals with a molecularly confirmed diagnosis have been identified [
The following description of the phenotypic features associated with this condition is based on the most recent review of 47 individuals with molecularly confirmed MOPDII [
Features of Microcephalic Osteodysplastic Primordial Dwarfism Type II
Based on
ADHD = attention-deficit/hyperactivity disorder; ASD = atrial septal defect; IUGR = intrauterine growth restriction; MI = myocardial infarction; PFO = patent foramen ovale; VSD = ventricular septal defect
Body habitus evolves with time. Infants and young children have decreased subcutaneous fat; truncal obesity tends to develop through puberty. In contrast to weight gain in age-related peers, the average expected daily weight gain in individuals with MOPDII is 2 g/day throughout the life span, from infancy to skeletal maturity. Appropriate weight gain expectations are paramount to avoid excessive and unnecessary nutritional interventions [
Ivory and cone-shaped phalangeal epiphyses have been described; fifth finger clinodactyly and brachymesophalangy are common.
Iliac wings are small with flat acetabular angles.
Scoliosis may occur and can rapidly progress in late childhood / puberty, leading to the need for spinal fusion [
Associated hip pathology includes coxa vara, coxa valga, developmental dysplasia, dislocation/subluxation, proximal femoral epiphysiolysis, and avascular necrosis. Eight of 12 individuals had hip pathology, some unilaterally (equaling 50% of the total hips). Developmental coxa vara was the most common finding, often beginning with a slipped capital femoral epiphysis and progressing to severe coxa vara, typically identified between ages two and five years [
Secondary teeth tend to be more affected. They are disproportionately small, dysplastic, and can have enamel hypoplasia. They are typically poorly rooted, and chewing can be affected. In many individuals, secondary teeth either prematurely shed or are extracted, and are replaced with dentures and/or implants [
In a cohort of 47 individuals, eight had myocardial infarctions as young adults (range 17-33 years; mean age 24±5.2 years; median age 24 years); multiple individuals had more than one acute coronary event.
Approximately 25% of individuals had cardiac malformations, including atrial septal defect, ventricular septal defect, and persistent patent foramen ovale. One individual had multiple cardiac rhabdomyomas [
Another individual who had renal artery stenosis in addition to a renal artery aneurysm ultimately had a partial infarct of a kidney.
Six individuals had nephrolithiasis in early adulthood; all were on anti-hypertensive medications at the time of the diagnosis of nephrolithiasis.
Congenital anomalies included accessory/duplicated renal arteries in seven males and no females [
Seventeen of 46 individuals (in a different but overlapping cohort) had insulin resistance and/or diabetes, typically detected in adolescence [
These issues can also lead to dyslipidemia and fatty liver [
Skin:
Acanthosis nigricans, repeatedly documented, is likely related to concomitant insulin resistance [
Café au lait patches have been described, with areas of hypopigmentation later in life.
"Wizened hands" with multiple creases developing in childhood have been noted (see
Neuroimaging findings can include simplified gyral patterns and hypoplasia of the corpus callosum [
Subglottic stenosis, described in some individuals, required tracheostomy in at least two affected individuals [
Craniosynostosis has been infrequently described, at times requiring surgical intervention. One child had bilateral coronal synostosis recognized in the neonatal period which required repair [
• Skin:
• Acanthosis nigricans, repeatedly documented, is likely related to concomitant insulin resistance [
• Café au lait patches have been described, with areas of hypopigmentation later in life.
• "Wizened hands" with multiple creases developing in childhood have been noted (see
• Acanthosis nigricans, repeatedly documented, is likely related to concomitant insulin resistance [
• Café au lait patches have been described, with areas of hypopigmentation later in life.
• "Wizened hands" with multiple creases developing in childhood have been noted (see
• Neuroimaging findings can include simplified gyral patterns and hypoplasia of the corpus callosum [
• Subglottic stenosis, described in some individuals, required tracheostomy in at least two affected individuals [
• Craniosynostosis has been infrequently described, at times requiring surgical intervention. One child had bilateral coronal synostosis recognized in the neonatal period which required repair [
• Acanthosis nigricans, repeatedly documented, is likely related to concomitant insulin resistance [
• Café au lait patches have been described, with areas of hypopigmentation later in life.
• "Wizened hands" with multiple creases developing in childhood have been noted (see
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is rare. More than 150 individuals with molecularly confirmed MOPDII have been identified across many populations worldwide [
Many different loss-of-function variants have been identified. Founder variants reported in specific populations include the following:
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
While heterozygous missense variants in
## Differential Diagnosis
Selected Genes of Interest in the Differential Diagnosis of Microcephalic Osteodysplastic Primordial Dwarfism Type II
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; IUGR = intrauterine growth restriction; MOI = mode of inheritance; MOPD = microcephalic osteodysplastic primordial dwarfism
Meier-Gorlin syndrome is typically inherited in an autosomal recessive manner.
Or other microdeletion
Listed genes are those in which pathogenic variants were identified in at least two persons with microcephalic dwarfism (defined as height & head circumference both greater than 4 SD below the mean at the time of exam) referred to the author's research laboratory for investigation [AJ, personal communication]. Other genes are also associated with extreme microcephalic dwarfism in some persons. (Note: Primary microcephaly genes are sometimes associated with short stature and therefore overlap with this definition of microcephalic dwarfism [
## Management
Clinical practice guidelines for microcephalic osteodysplastic primordial dwarfism type II (MOPDII) have been proposed [
To establish the extent of disease and needs in an individual diagnosed with MOPDII, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Microcephalic Osteodysplastic Primordial Dwarfism Type II
Renal ultrasound exam
Measure blood pressure.
If age ≥5 yrs, lab studies to assess renal function
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support.
Based on clinical practice guidelines proposed by
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Microcephalic Osteodysplastic Primordial Dwarfism Type II
Use MOPDII-specific growth curves
G-tube overfeeding can result in iatrogenic oral aversion.
Hip pathology has been treated with in situ pinning or osteotomy.
Scoliosis has been treated by spinal fusion.
Aneurysm treatment can be needed in childhood as well as throughout adulthood.
Aneurysm development is likely exacerbated by hypertension.
Cardiovascular disease has been treated w/stents & bypass.
Hypercholesterolemia & hypertension have been treated w/medication.
The definition of hypertension is not well understood; standard adult ranges are likely too high for adults w/MOPDII.
Consider 110/70 as cutoff for hypertension in adulthood.
Based on clinical practice guidelines proposed by
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and modified classroom equipment/furniture.
Developmental Disabilities Administration (DDA) is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Recommended Surveillance for Individuals with Microcephalic Osteodysplastic Primordial Dwarfism Type II
Serial radiographs of hips in early childhood
Evaluate for scoliosis through skeletal maturity.
Routine dental care
Prosthodontist may be required for small implants in early adulthood.
Monitor blood pressure w/appropriately sized cuff.
Consider 110/70 as cutoff for hypertension in adulthood.
Consider echocardiogram & EKG as well.
Growth hormone supplementation in the absence of growth hormone deficiency has not been helpful, and in fact can contribute to morbidity [
See
Search
• Renal ultrasound exam
• Measure blood pressure.
• If age ≥5 yrs, lab studies to assess renal function
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support.
• Use MOPDII-specific growth curves
• G-tube overfeeding can result in iatrogenic oral aversion.
• Hip pathology has been treated with in situ pinning or osteotomy.
• Scoliosis has been treated by spinal fusion.
• Aneurysm treatment can be needed in childhood as well as throughout adulthood.
• Aneurysm development is likely exacerbated by hypertension.
• Cardiovascular disease has been treated w/stents & bypass.
• Hypercholesterolemia & hypertension have been treated w/medication.
• The definition of hypertension is not well understood; standard adult ranges are likely too high for adults w/MOPDII.
• Consider 110/70 as cutoff for hypertension in adulthood.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and modified classroom equipment/furniture.
• Developmental Disabilities Administration (DDA) is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Serial radiographs of hips in early childhood
• Evaluate for scoliosis through skeletal maturity.
• Routine dental care
• Prosthodontist may be required for small implants in early adulthood.
• Monitor blood pressure w/appropriately sized cuff.
• Consider 110/70 as cutoff for hypertension in adulthood.
• Consider echocardiogram & EKG as well.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MOPDII, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Microcephalic Osteodysplastic Primordial Dwarfism Type II
Renal ultrasound exam
Measure blood pressure.
If age ≥5 yrs, lab studies to assess renal function
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support.
Based on clinical practice guidelines proposed by
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Renal ultrasound exam
• Measure blood pressure.
• If age ≥5 yrs, lab studies to assess renal function
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Microcephalic Osteodysplastic Primordial Dwarfism Type II
Use MOPDII-specific growth curves
G-tube overfeeding can result in iatrogenic oral aversion.
Hip pathology has been treated with in situ pinning or osteotomy.
Scoliosis has been treated by spinal fusion.
Aneurysm treatment can be needed in childhood as well as throughout adulthood.
Aneurysm development is likely exacerbated by hypertension.
Cardiovascular disease has been treated w/stents & bypass.
Hypercholesterolemia & hypertension have been treated w/medication.
The definition of hypertension is not well understood; standard adult ranges are likely too high for adults w/MOPDII.
Consider 110/70 as cutoff for hypertension in adulthood.
Based on clinical practice guidelines proposed by
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and modified classroom equipment/furniture.
Developmental Disabilities Administration (DDA) is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Use MOPDII-specific growth curves
• G-tube overfeeding can result in iatrogenic oral aversion.
• Hip pathology has been treated with in situ pinning or osteotomy.
• Scoliosis has been treated by spinal fusion.
• Aneurysm treatment can be needed in childhood as well as throughout adulthood.
• Aneurysm development is likely exacerbated by hypertension.
• Cardiovascular disease has been treated w/stents & bypass.
• Hypercholesterolemia & hypertension have been treated w/medication.
• The definition of hypertension is not well understood; standard adult ranges are likely too high for adults w/MOPDII.
• Consider 110/70 as cutoff for hypertension in adulthood.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and modified classroom equipment/furniture.
• Developmental Disabilities Administration (DDA) is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and modified classroom equipment/furniture.
Developmental Disabilities Administration (DDA) is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and modified classroom equipment/furniture.
• Developmental Disabilities Administration (DDA) is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Physical accommodations for short stature and small hands associated with MOPDII should be a part of the plan.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Surveillance
Recommended Surveillance for Individuals with Microcephalic Osteodysplastic Primordial Dwarfism Type II
Serial radiographs of hips in early childhood
Evaluate for scoliosis through skeletal maturity.
Routine dental care
Prosthodontist may be required for small implants in early adulthood.
Monitor blood pressure w/appropriately sized cuff.
Consider 110/70 as cutoff for hypertension in adulthood.
Consider echocardiogram & EKG as well.
• Serial radiographs of hips in early childhood
• Evaluate for scoliosis through skeletal maturity.
• Routine dental care
• Prosthodontist may be required for small implants in early adulthood.
• Monitor blood pressure w/appropriately sized cuff.
• Consider 110/70 as cutoff for hypertension in adulthood.
• Consider echocardiogram & EKG as well.
## Agents/Circumstances to Avoid
Growth hormone supplementation in the absence of growth hormone deficiency has not been helpful, and in fact can contribute to morbidity [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is inherited in an autosomal recessive manner.
The parents of an affected child are usually heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing for the parents of a proband can be performed to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are usually heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing for the parents of a proband can be performed to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is inherited in an autosomal recessive manner.
The parents of an affected child are usually heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing for the parents of a proband can be performed to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic.
• The parents of an affected child are usually heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing for the parents of a proband can be performed to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
Nemours Children’s Health
1600 Rockland Road
Wilmington DE 19803
•
•
•
• United Kingdom
•
•
•
•
• Nemours Children’s Health
• 1600 Rockland Road
• Wilmington DE 19803
•
•
•
## Molecular Genetics
Microcephalic Osteodysplastic Primordial Dwarfism Type II: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Microcephalic Osteodysplastic Primordial Dwarfism Type II (
Biallelic loss-of-function
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Biallelic loss-of-function
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
The authors wish to wholeheartedly thank the Potentials Foundation and the Walking with Giants Foundation for their support of families worldwide with MOPDII, as well as for their support of research into this condition. Work in the Jackson lab has been supported by the European Union's Horizon 2020 research and innovation program ERC Advanced Grant (grant agreement 788093), and by a UK Medical Research Council (MRC) Human Genetics Unit core grant (MRC, U127580972).
30 March 2023 (sw) Revision: Nosology of Genetic Skeletal Disorders: 2023 Revision [
30 December 2021 (bp) Review posted live
12 October 2021 (mb) Original submission
• 30 March 2023 (sw) Revision: Nosology of Genetic Skeletal Disorders: 2023 Revision [
• 30 December 2021 (bp) Review posted live
• 12 October 2021 (mb) Original submission
## Acknowledgments
The authors wish to wholeheartedly thank the Potentials Foundation and the Walking with Giants Foundation for their support of families worldwide with MOPDII, as well as for their support of research into this condition. Work in the Jackson lab has been supported by the European Union's Horizon 2020 research and innovation program ERC Advanced Grant (grant agreement 788093), and by a UK Medical Research Council (MRC) Human Genetics Unit core grant (MRC, U127580972).
## Revision History
30 March 2023 (sw) Revision: Nosology of Genetic Skeletal Disorders: 2023 Revision [
30 December 2021 (bp) Review posted live
12 October 2021 (mb) Original submission
• 30 March 2023 (sw) Revision: Nosology of Genetic Skeletal Disorders: 2023 Revision [
• 30 December 2021 (bp) Review posted live
• 12 October 2021 (mb) Original submission
## References
## Literature Cited
A-C. Same young man with MOPDII at ages 1 year, 5 years 7 months, and 16 years 6 months
D. Secondary teeth are small and dysplastic with enamel hypoplasia.
E. Brachymesophalangy and wizening noted in the hands of a 16 year old
A. Right slipped capital femoral epiphysis in a female age 26 months, subsequently treated with in situ pinning
B. 110-degree thoracolumbar scoliosis in a male age 13 years, subsequently treated with posterior spinal fusion with instrumentation
|
[] |
30/12/2021
|
30/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mota
|
mota
|
[
"Manitoba Oculotrichoanal (MOTA) Syndrome",
"Bifid Nose With or Without Anorectal and Renal Anomalies (BNAR) Syndrome",
"FREM1-Related Congenital Anomalies of Kidney and Urinary Tract (CAKUT)",
"FRAS1-related extracellular matrix protein 1",
"FREM1",
"FREM1 Autosomal Recessive Disorders"
] |
Chumei Li, Anne Slavotinek
|
Summary MOTA syndrome is characterized by an aberrant hairline (unilateral or bilateral wedge-shaped extension of the anterior hairline from the temple region to the ipsilateral eye) and anomalies of the eyes (widely spaced eyes, anophthalmia/microphthalmia and/or cryptophthalmos, colobomas of the upper eyelid, and corneopalpebral synechiae), nose (bifid or broad nasal tip), abdominal wall (omphalocele or umbilical hernia), and anus (stenosis and/or anterior displacement of the anal opening). The manifestations and degree of severity vary even among affected members of the same family. Growth and psychomotor development are normal. BNAR syndrome is characterized by a bifid or wide nasal tip, anorectal anomalies, and kidney malformations (e.g., renal agenesis, renal dysplasia). Typically, the eye manifestations of MOTA syndrome are absent. The diagnosis of a Phenotypes caused by biallelic
|
Manitoba oculotrichoanal (MOTA) syndrome
Bifid nose with or without anorectal and renal anomalies (BNAR) syndrome
Nonsyndromic metopic craniosynostosis (OMIM
• Manitoba oculotrichoanal (MOTA) syndrome
• Bifid nose with or without anorectal and renal anomalies (BNAR) syndrome
## Diagnosis
No consensus clinical diagnostic criteria for
A
Widely spaced eyes
Aberrant anterior hairline extending to the ipsilateral eye (unilateral or bilateral); often wedge-shaped, but may also resemble a thin stripe or appear tongue-shaped
Ocular abnormalities including ipsilateral colobomas of the upper eyelid (sometimes referred to as a Tessier number 10 cleft by surgeons), corneopalpebral synechiae (i.e., adhesions between the eyelids and the cornea), and microphthalmia/anophthalmia and/or cryptophthalmos. Corneal clouding was described in one individual. The upper eyelid colobomas and cryptophthalmos are part of a spectrum of anomalies ranging from colobomas of the lid to eyelid coloboma plus corneopalpebral synechiae (also known as abortive cryptophthalmos) to complete cryptophthalmos [
Absent or interrupted eyebrow ipsilateral to the eye defect
Bifid nose, notch at the nasal tip, or broad nose
Anal stenosis and/or anteriorly placed anus
Omphalocele or umbilical hernia
Ethnic origin of aboriginal Oji-Cree
Median nose cleft or notch, or wide bulbous nasal tip
Anorectal anomalies (e.g., anal stenosis, anteriorly placed anus)
Kidney malformations (e.g., renal agenesis, renal dysplasia)
Eye manifestations of MOTA syndrome typically absent
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic findings suggest the diagnosis of a
Note: In individuals with
For an introduction to multigene panels click
When the diagnosis of a
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
A deletion of exons 8 to 23 (
• Widely spaced eyes
• Aberrant anterior hairline extending to the ipsilateral eye (unilateral or bilateral); often wedge-shaped, but may also resemble a thin stripe or appear tongue-shaped
• Ocular abnormalities including ipsilateral colobomas of the upper eyelid (sometimes referred to as a Tessier number 10 cleft by surgeons), corneopalpebral synechiae (i.e., adhesions between the eyelids and the cornea), and microphthalmia/anophthalmia and/or cryptophthalmos. Corneal clouding was described in one individual. The upper eyelid colobomas and cryptophthalmos are part of a spectrum of anomalies ranging from colobomas of the lid to eyelid coloboma plus corneopalpebral synechiae (also known as abortive cryptophthalmos) to complete cryptophthalmos [
• Absent or interrupted eyebrow ipsilateral to the eye defect
• Bifid nose, notch at the nasal tip, or broad nose
• Anal stenosis and/or anteriorly placed anus
• Omphalocele or umbilical hernia
• Ethnic origin of aboriginal Oji-Cree
• Median nose cleft or notch, or wide bulbous nasal tip
• Anorectal anomalies (e.g., anal stenosis, anteriorly placed anus)
• Kidney malformations (e.g., renal agenesis, renal dysplasia)
• Eye manifestations of MOTA syndrome typically absent
• Note: In individuals with
• For an introduction to multigene panels click
## Suggestive Findings
A
Widely spaced eyes
Aberrant anterior hairline extending to the ipsilateral eye (unilateral or bilateral); often wedge-shaped, but may also resemble a thin stripe or appear tongue-shaped
Ocular abnormalities including ipsilateral colobomas of the upper eyelid (sometimes referred to as a Tessier number 10 cleft by surgeons), corneopalpebral synechiae (i.e., adhesions between the eyelids and the cornea), and microphthalmia/anophthalmia and/or cryptophthalmos. Corneal clouding was described in one individual. The upper eyelid colobomas and cryptophthalmos are part of a spectrum of anomalies ranging from colobomas of the lid to eyelid coloboma plus corneopalpebral synechiae (also known as abortive cryptophthalmos) to complete cryptophthalmos [
Absent or interrupted eyebrow ipsilateral to the eye defect
Bifid nose, notch at the nasal tip, or broad nose
Anal stenosis and/or anteriorly placed anus
Omphalocele or umbilical hernia
Ethnic origin of aboriginal Oji-Cree
Median nose cleft or notch, or wide bulbous nasal tip
Anorectal anomalies (e.g., anal stenosis, anteriorly placed anus)
Kidney malformations (e.g., renal agenesis, renal dysplasia)
Eye manifestations of MOTA syndrome typically absent
• Widely spaced eyes
• Aberrant anterior hairline extending to the ipsilateral eye (unilateral or bilateral); often wedge-shaped, but may also resemble a thin stripe or appear tongue-shaped
• Ocular abnormalities including ipsilateral colobomas of the upper eyelid (sometimes referred to as a Tessier number 10 cleft by surgeons), corneopalpebral synechiae (i.e., adhesions between the eyelids and the cornea), and microphthalmia/anophthalmia and/or cryptophthalmos. Corneal clouding was described in one individual. The upper eyelid colobomas and cryptophthalmos are part of a spectrum of anomalies ranging from colobomas of the lid to eyelid coloboma plus corneopalpebral synechiae (also known as abortive cryptophthalmos) to complete cryptophthalmos [
• Absent or interrupted eyebrow ipsilateral to the eye defect
• Bifid nose, notch at the nasal tip, or broad nose
• Anal stenosis and/or anteriorly placed anus
• Omphalocele or umbilical hernia
• Ethnic origin of aboriginal Oji-Cree
• Median nose cleft or notch, or wide bulbous nasal tip
• Anorectal anomalies (e.g., anal stenosis, anteriorly placed anus)
• Kidney malformations (e.g., renal agenesis, renal dysplasia)
• Eye manifestations of MOTA syndrome typically absent
## Establishing the Diagnosis
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic findings suggest the diagnosis of a
Note: In individuals with
For an introduction to multigene panels click
When the diagnosis of a
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
A deletion of exons 8 to 23 (
• Note: In individuals with
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of a
Note: In individuals with
For an introduction to multigene panels click
• Note: In individuals with
• For an introduction to multigene panels click
## Option 2
When the diagnosis of a
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
A deletion of exons 8 to 23 (
## Clinical Characteristics
Visual impairment may result directly from the ocular malformations or indirectly from exposure keratopathy. The long-term visual outcome depends on the severity of the ocular malformations and is poor for individuals with bilateral complete cryptophthalmos. In those with milder ocular malformations, such as upper eyelid colobomas, vision is typically intact.
Corneal clouding was described in one individual.
The manifestations and degree of severity vary even among affected members of the same family.
BNAR syndrome was described in ten individuals from three consanguineous families of Egyptian, Afghani, and Pakistani origin [
The following additional phenotypes have been reported in individuals with biallelic
One individual was reported with isolated congenital diaphragmatic hernia [
One fetus had severe hydrocephalus and shortened limbs associated with novel
One individual with bifid nose, facial cleft-like dysmorphism, aberrant hairline, and blepharon-coloboma was reported. [
One individual with homozygous 9p22.3 deletion (encompassing
One individual with VACTERL had biallelic
Genotype-phenotype correlations have not been possible to date given the rarity of the condition and limited number of pathogenic variants described.
The prevalence of
To date, the authors are aware of 30 published individuals with MOTA syndrome.
Based on the number of individuals identified to date in the aboriginal Oji-Cree community of the Island Lake region of northern Manitoba, Canada, which had a population of 4,685 in 1996 and 2,020 in 2001 [First Nation
• One individual was reported with isolated congenital diaphragmatic hernia [
• One fetus had severe hydrocephalus and shortened limbs associated with novel
• One individual with bifid nose, facial cleft-like dysmorphism, aberrant hairline, and blepharon-coloboma was reported. [
• One individual with homozygous 9p22.3 deletion (encompassing
• One individual with VACTERL had biallelic
## Clinical Description
Visual impairment may result directly from the ocular malformations or indirectly from exposure keratopathy. The long-term visual outcome depends on the severity of the ocular malformations and is poor for individuals with bilateral complete cryptophthalmos. In those with milder ocular malformations, such as upper eyelid colobomas, vision is typically intact.
Corneal clouding was described in one individual.
The manifestations and degree of severity vary even among affected members of the same family.
BNAR syndrome was described in ten individuals from three consanguineous families of Egyptian, Afghani, and Pakistani origin [
The following additional phenotypes have been reported in individuals with biallelic
One individual was reported with isolated congenital diaphragmatic hernia [
One fetus had severe hydrocephalus and shortened limbs associated with novel
One individual with bifid nose, facial cleft-like dysmorphism, aberrant hairline, and blepharon-coloboma was reported. [
One individual with homozygous 9p22.3 deletion (encompassing
One individual with VACTERL had biallelic
• One individual was reported with isolated congenital diaphragmatic hernia [
• One fetus had severe hydrocephalus and shortened limbs associated with novel
• One individual with bifid nose, facial cleft-like dysmorphism, aberrant hairline, and blepharon-coloboma was reported. [
• One individual with homozygous 9p22.3 deletion (encompassing
• One individual with VACTERL had biallelic
## Manitoba Oculotrichoanal (MOTA) Syndrome
Visual impairment may result directly from the ocular malformations or indirectly from exposure keratopathy. The long-term visual outcome depends on the severity of the ocular malformations and is poor for individuals with bilateral complete cryptophthalmos. In those with milder ocular malformations, such as upper eyelid colobomas, vision is typically intact.
Corneal clouding was described in one individual.
The manifestations and degree of severity vary even among affected members of the same family.
## Bifid Nose with or without Anorectal and Renal Anomalies (BNAR) Syndrome
BNAR syndrome was described in ten individuals from three consanguineous families of Egyptian, Afghani, and Pakistani origin [
## Other Phenotypes
The following additional phenotypes have been reported in individuals with biallelic
One individual was reported with isolated congenital diaphragmatic hernia [
One fetus had severe hydrocephalus and shortened limbs associated with novel
One individual with bifid nose, facial cleft-like dysmorphism, aberrant hairline, and blepharon-coloboma was reported. [
One individual with homozygous 9p22.3 deletion (encompassing
One individual with VACTERL had biallelic
• One individual was reported with isolated congenital diaphragmatic hernia [
• One fetus had severe hydrocephalus and shortened limbs associated with novel
• One individual with bifid nose, facial cleft-like dysmorphism, aberrant hairline, and blepharon-coloboma was reported. [
• One individual with homozygous 9p22.3 deletion (encompassing
• One individual with VACTERL had biallelic
## Genotype-Phenotype Correlations
Genotype-phenotype correlations have not been possible to date given the rarity of the condition and limited number of pathogenic variants described.
## Prevalence
The prevalence of
To date, the authors are aware of 30 published individuals with MOTA syndrome.
Based on the number of individuals identified to date in the aboriginal Oji-Cree community of the Island Lake region of northern Manitoba, Canada, which had a population of 4,685 in 1996 and 2,020 in 2001 [First Nation
## Genetically Related (Allelic) Disorders
Heterozygous
In a cohort of 18 probands with developmental delay and heterozygous intragenic deletions in
Variable findings in persons from two families with
• In a cohort of 18 probands with developmental delay and heterozygous intragenic deletions in
• Variable findings in persons from two families with
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of MOTA Syndrome and BNAR Syndrome
Widely spaced eyes
Broad forehead
Widow's peak
Broad nasal root; absence of nasal tip formation; unilateral/bilateral cleft ala nasi
Absence of cryptophthalmos
Cranium bifidum
Absence of omphalocele & anorectal abnormalities
Widely spaced eyes
Broad nasal bridge, bifid nasal tip
Absence of cryptophthalmos
Craniosynostosis
Cranium bifidum
Absence of omphalocele & anorectal abnormalities
Anophthalmia/microphthalmia, cryptophthalmos, eyelid colobomas, widely spaced eyes
Wedge-shaped lateral anterior hairline
Bifid nasal tip / notched ala nasi
Anal stenosis or imperforate anus
Cognitive impairment
Often early mortality
Widely spaced eyes
Omphalocele
Agenesis of corpus callosum
Sensorineural hearing loss
Diaphragmatic hernia
Widely spaced eyes
Anteriorly placed anus, anal stenosis
Thumb anomalies
Vertebral abnormalities
AD = autosomal dominant; AR = autosomal recessive; BNAR = bifid nose with or without anorectal and renal anomalies; MOI = mode of inheritance; MOTA = Manitoba oculotrichoanal; XL = X-linked
Cranium bifidum is a midline defect of the frontal bone detected on skull radiographs.
Craniofrontonasal dysplasia shows greater severity in heterozygous females than in hemizygous males. Typically, females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, a bifid nasal tip, and grooved nails; they may also have skeletal abnormalities. In contrast, males typically show only widely spaced eyes (see OMIM
• Widely spaced eyes
• Broad forehead
• Widow's peak
• Broad nasal root; absence of nasal tip formation; unilateral/bilateral cleft ala nasi
• Absence of cryptophthalmos
• Cranium bifidum
• Absence of omphalocele & anorectal abnormalities
• Widely spaced eyes
• Broad nasal bridge, bifid nasal tip
• Absence of cryptophthalmos
• Craniosynostosis
• Cranium bifidum
• Absence of omphalocele & anorectal abnormalities
• Anophthalmia/microphthalmia, cryptophthalmos, eyelid colobomas, widely spaced eyes
• Wedge-shaped lateral anterior hairline
• Bifid nasal tip / notched ala nasi
• Anal stenosis or imperforate anus
• Cognitive impairment
• Often early mortality
• Widely spaced eyes
• Omphalocele
• Agenesis of corpus callosum
• Sensorineural hearing loss
• Diaphragmatic hernia
• Widely spaced eyes
• Anteriorly placed anus, anal stenosis
• Thumb anomalies
• Vertebral abnormalities
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with a
MOTA Syndrome: Recommended Evaluations Following Initial Diagnosis
MOI = mode of inheritance; MOTA = Manitoba oculotrichoanal
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
BNAR Syndrome: Recommended Evaluations Following Initial Diagnosis
Eval for bifid or notched nose
Eval of airway
BNAR = bifid nose with or without anorectal and renal anomalies; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
CAKUT = congenital anomalies of kidney and urinary tract; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Treatment of
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Supportive treatment to preserve kidney function & electrolyte balance
Surgical correction when indicated
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
AR = autosomal recessive; OT = occupational therapy
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
See
Search
• Eval for bifid or notched nose
• Eval of airway
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Supportive treatment to preserve kidney function & electrolyte balance
• Surgical correction when indicated
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
MOTA Syndrome: Recommended Evaluations Following Initial Diagnosis
MOI = mode of inheritance; MOTA = Manitoba oculotrichoanal
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
BNAR Syndrome: Recommended Evaluations Following Initial Diagnosis
Eval for bifid or notched nose
Eval of airway
BNAR = bifid nose with or without anorectal and renal anomalies; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
CAKUT = congenital anomalies of kidney and urinary tract; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Eval for bifid or notched nose
• Eval of airway
## Treatment of Manifestations
Treatment of
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Supportive treatment to preserve kidney function & electrolyte balance
Surgical correction when indicated
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
AR = autosomal recessive; OT = occupational therapy
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Supportive treatment to preserve kidney function & electrolyte balance
• Surgical correction when indicated
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Phenotypes caused by biallelic
The parents of a child with a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) do not have MOTA syndrome, BNAR syndrome, or
If both parents are known to be heterozygous for a
Heterozygotes (carriers) do not have MOTA syndrome, BNAR syndrome, or
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of a child with a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) do not have MOTA syndrome, BNAR syndrome, or
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) do not have MOTA syndrome, BNAR syndrome, or
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with a
## Mode of Inheritance
Phenotypes caused by biallelic
## Risk to Family Members
The parents of a child with a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) do not have MOTA syndrome, BNAR syndrome, or
If both parents are known to be heterozygous for a
Heterozygotes (carriers) do not have MOTA syndrome, BNAR syndrome, or
• The parents of a child with a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) do not have MOTA syndrome, BNAR syndrome, or
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) do not have MOTA syndrome, BNAR syndrome, or
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with a
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with a
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
FREM1 Autosomal Recessive Disorders : Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FREM1 Autosomal Recessive Disorders (
MOTA = Manitoba oculotrichoanal
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
MOTA = Manitoba oculotrichoanal
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Chapter Notes
Chumei Li (
Anne Slavotinek (
Albert E Chudley, MD, FRCPC, FCCMG; University of Manitoba (2011-2019)Chumei Li, MD, PhD, FRCPC, FCCMG (2008-present)Anne Slavotinek, MBBS, PhD (2011-present)
1 May 2025 (sw) Comprehensive update posted live
9 May 2019 (sw) Comprehensive update posted live
13 October 2011 (me) Comprehensive update posted live
9 July 2008 (me) Review posted live
16 May 2008 (cl) Original submission
• 1 May 2025 (sw) Comprehensive update posted live
• 9 May 2019 (sw) Comprehensive update posted live
• 13 October 2011 (me) Comprehensive update posted live
• 9 July 2008 (me) Review posted live
• 16 May 2008 (cl) Original submission
## Author Notes
Chumei Li (
Anne Slavotinek (
## Author History
Albert E Chudley, MD, FRCPC, FCCMG; University of Manitoba (2011-2019)Chumei Li, MD, PhD, FRCPC, FCCMG (2008-present)Anne Slavotinek, MBBS, PhD (2011-present)
## Revision History
1 May 2025 (sw) Comprehensive update posted live
9 May 2019 (sw) Comprehensive update posted live
13 October 2011 (me) Comprehensive update posted live
9 July 2008 (me) Review posted live
16 May 2008 (cl) Original submission
• 1 May 2025 (sw) Comprehensive update posted live
• 9 May 2019 (sw) Comprehensive update posted live
• 13 October 2011 (me) Comprehensive update posted live
• 9 July 2008 (me) Review posted live
• 16 May 2008 (cl) Original submission
## References
## Literature Cited
|
[] |
9/7/2008
|
1/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mpd1
|
mpd1
|
[
"Laing Early-Onset Distal Myopathy",
"Laing Early-Onset Distal Myopathy",
"Myosin-7",
"MYH7",
"Laing Distal Myopathy"
] |
Laing Distal Myopathy
|
Phillipa Lamont, Nigel G Laing
|
Summary Laing distal myopathy is characterized by early-onset weakness (usually before age 5 years) that initially involves the dorsiflexors of the ankles and great toes and then the finger extensors, especially those of the third and fourth fingers. Weakness of the neck flexors is seen in most affected individuals and mild facial weakness is often present. After distal weakness has been present for more than ten years, mild proximal weakness may be observed. Life expectancy is normal. The diagnosis of Laing distal myopathy is established in a proband with suggestive findings and a heterozygous pathogenic variant in Laing distal myopathy is an autosomal dominant disorder. Approximately 65%-70% of affected individuals have an affected parent;
|
## Diagnosis
No consensus clinical diagnostic criteria for Laing distal myopathy have been published.
Laing distal myopathy
The diagnosis of Laing distal myopathy
Note: Identification of a heterozygous
Because the phenotype of Laing distal myopathy can be indistinguishable from many other inherited disorders with muscle weakness, recommended molecular genetic testing approaches include use of a
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Laing Distal Myopathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Laing distal myopathy
## Establishing the Diagnosis
The diagnosis of Laing distal myopathy
Note: Identification of a heterozygous
Because the phenotype of Laing distal myopathy can be indistinguishable from many other inherited disorders with muscle weakness, recommended molecular genetic testing approaches include use of a
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Laing Distal Myopathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Laing distal myopathy is characterized by muscle weakness and atrophy beginning in the lower legs [
More than 200 individuals have been identified with a pathogenic variant in
Laing Distal Myopathy: Frequency of Select Features
The most common myopathic feature is excessive variation in fiber size, with either type 1 or type 2 fibers involved.
Fiber type predominance is common. In one large family, ten of 14 muscle biopsies showed abnormally small type 1 fibers with type 1 predominance, fulfilling criteria for congenital fiber-type disproportion [
Another common finding is core pathology of either central cores or multiminicores, with or without subsarcolemmal hyaline bodies [
Other reported findings:
Excessive central nucleation and mild necrosis and regeneration
Fatty replacement in "end-stage" muscles
Cytoplasmic bodies and myofibrillar-like myopathy features [
Spheroid cytoplasmic body-like inclusions with a moth-eaten appearance [
Inflammatory myopathy with rimmed vacuoles resembling inclusion body myositis [
Immunohistochemical staining for slow and fast myosin demonstrating co-expression of both isoforms in some muscle fibers, possibly indicating a switch from fiber type 1 to fiber type 2 [
Laing distal myopathy may be caused by different types of variants in the distal myosin tail. These include missense changes that insert proline, or cause charge changes or deletion or insertion of amino acids [
Penetrance appears to be at least 85%.
In one apparent instance of a
The following alternate terms for Laing distal myopathy are no longer in use or are too nonspecific to be useful:
Early-onset chromosome 14-linked distal myopathy (Laing)
Autosomal dominant distal muscular dystrophy
Infantile autosomal dominant distal myopathy
Autosomal dominant distal myopathy (a nonspecific term that could apply to other distal myopathies such as
Gowers myopathy
The prevalence of Laing distal myopathy is unknown. It is thought to be the most common distal myopathy worldwide [B Udd, personal communication], accounting for approximately 50% of early-onset distal myopathy [Author, personal observation]. The frequency of
Laing distal myopathy has been reported in most populations [
• The most common myopathic feature is excessive variation in fiber size, with either type 1 or type 2 fibers involved.
• Fiber type predominance is common. In one large family, ten of 14 muscle biopsies showed abnormally small type 1 fibers with type 1 predominance, fulfilling criteria for congenital fiber-type disproportion [
• Another common finding is core pathology of either central cores or multiminicores, with or without subsarcolemmal hyaline bodies [
• Other reported findings:
• Excessive central nucleation and mild necrosis and regeneration
• Fatty replacement in "end-stage" muscles
• Cytoplasmic bodies and myofibrillar-like myopathy features [
• Spheroid cytoplasmic body-like inclusions with a moth-eaten appearance [
• Inflammatory myopathy with rimmed vacuoles resembling inclusion body myositis [
• Immunohistochemical staining for slow and fast myosin demonstrating co-expression of both isoforms in some muscle fibers, possibly indicating a switch from fiber type 1 to fiber type 2 [
• Excessive central nucleation and mild necrosis and regeneration
• Fatty replacement in "end-stage" muscles
• Cytoplasmic bodies and myofibrillar-like myopathy features [
• Spheroid cytoplasmic body-like inclusions with a moth-eaten appearance [
• Inflammatory myopathy with rimmed vacuoles resembling inclusion body myositis [
• Immunohistochemical staining for slow and fast myosin demonstrating co-expression of both isoforms in some muscle fibers, possibly indicating a switch from fiber type 1 to fiber type 2 [
• Excessive central nucleation and mild necrosis and regeneration
• Fatty replacement in "end-stage" muscles
• Cytoplasmic bodies and myofibrillar-like myopathy features [
• Spheroid cytoplasmic body-like inclusions with a moth-eaten appearance [
• Inflammatory myopathy with rimmed vacuoles resembling inclusion body myositis [
• Immunohistochemical staining for slow and fast myosin demonstrating co-expression of both isoforms in some muscle fibers, possibly indicating a switch from fiber type 1 to fiber type 2 [
• Early-onset chromosome 14-linked distal myopathy (Laing)
• Autosomal dominant distal muscular dystrophy
• Infantile autosomal dominant distal myopathy
• Autosomal dominant distal myopathy (a nonspecific term that could apply to other distal myopathies such as
• Gowers myopathy
## Clinical Description
Laing distal myopathy is characterized by muscle weakness and atrophy beginning in the lower legs [
More than 200 individuals have been identified with a pathogenic variant in
Laing Distal Myopathy: Frequency of Select Features
The most common myopathic feature is excessive variation in fiber size, with either type 1 or type 2 fibers involved.
Fiber type predominance is common. In one large family, ten of 14 muscle biopsies showed abnormally small type 1 fibers with type 1 predominance, fulfilling criteria for congenital fiber-type disproportion [
Another common finding is core pathology of either central cores or multiminicores, with or without subsarcolemmal hyaline bodies [
Other reported findings:
Excessive central nucleation and mild necrosis and regeneration
Fatty replacement in "end-stage" muscles
Cytoplasmic bodies and myofibrillar-like myopathy features [
Spheroid cytoplasmic body-like inclusions with a moth-eaten appearance [
Inflammatory myopathy with rimmed vacuoles resembling inclusion body myositis [
Immunohistochemical staining for slow and fast myosin demonstrating co-expression of both isoforms in some muscle fibers, possibly indicating a switch from fiber type 1 to fiber type 2 [
• The most common myopathic feature is excessive variation in fiber size, with either type 1 or type 2 fibers involved.
• Fiber type predominance is common. In one large family, ten of 14 muscle biopsies showed abnormally small type 1 fibers with type 1 predominance, fulfilling criteria for congenital fiber-type disproportion [
• Another common finding is core pathology of either central cores or multiminicores, with or without subsarcolemmal hyaline bodies [
• Other reported findings:
• Excessive central nucleation and mild necrosis and regeneration
• Fatty replacement in "end-stage" muscles
• Cytoplasmic bodies and myofibrillar-like myopathy features [
• Spheroid cytoplasmic body-like inclusions with a moth-eaten appearance [
• Inflammatory myopathy with rimmed vacuoles resembling inclusion body myositis [
• Immunohistochemical staining for slow and fast myosin demonstrating co-expression of both isoforms in some muscle fibers, possibly indicating a switch from fiber type 1 to fiber type 2 [
• Excessive central nucleation and mild necrosis and regeneration
• Fatty replacement in "end-stage" muscles
• Cytoplasmic bodies and myofibrillar-like myopathy features [
• Spheroid cytoplasmic body-like inclusions with a moth-eaten appearance [
• Inflammatory myopathy with rimmed vacuoles resembling inclusion body myositis [
• Immunohistochemical staining for slow and fast myosin demonstrating co-expression of both isoforms in some muscle fibers, possibly indicating a switch from fiber type 1 to fiber type 2 [
• Excessive central nucleation and mild necrosis and regeneration
• Fatty replacement in "end-stage" muscles
• Cytoplasmic bodies and myofibrillar-like myopathy features [
• Spheroid cytoplasmic body-like inclusions with a moth-eaten appearance [
• Inflammatory myopathy with rimmed vacuoles resembling inclusion body myositis [
• Immunohistochemical staining for slow and fast myosin demonstrating co-expression of both isoforms in some muscle fibers, possibly indicating a switch from fiber type 1 to fiber type 2 [
## Genotype-Phenotype Correlations
Laing distal myopathy may be caused by different types of variants in the distal myosin tail. These include missense changes that insert proline, or cause charge changes or deletion or insertion of amino acids [
## Penetrance
Penetrance appears to be at least 85%.
In one apparent instance of a
## Nomenclature
The following alternate terms for Laing distal myopathy are no longer in use or are too nonspecific to be useful:
Early-onset chromosome 14-linked distal myopathy (Laing)
Autosomal dominant distal muscular dystrophy
Infantile autosomal dominant distal myopathy
Autosomal dominant distal myopathy (a nonspecific term that could apply to other distal myopathies such as
Gowers myopathy
• Early-onset chromosome 14-linked distal myopathy (Laing)
• Autosomal dominant distal muscular dystrophy
• Infantile autosomal dominant distal myopathy
• Autosomal dominant distal myopathy (a nonspecific term that could apply to other distal myopathies such as
• Gowers myopathy
## Prevalence
The prevalence of Laing distal myopathy is unknown. It is thought to be the most common distal myopathy worldwide [B Udd, personal communication], accounting for approximately 50% of early-onset distal myopathy [Author, personal observation]. The frequency of
Laing distal myopathy has been reported in most populations [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
AD = autosomal dominant; AR = autosomal recessive; LDM = Laing distal myopathy; MOI = mode of inheritance; MSM = myosin storage myopathy; SNV = single-nucleotide variant
## Differential Diagnosis
Other disorders to consider in the differential diagnosis of Laing distal myopathy are indicated in this section.
The early onset of Laing distal myopathy means that any of the milder congenital myopathies may be a differential diagnosis (see
Congenital Myopathies of Interest in the Differential Diagnosis of Laing Distal Myopathy
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
The other major group in the differential diagnosis of Laing distal myopathy is distal myopathies (see
Distal Myopathies of Interest in the Differential Diagnosis of Laing Distal Myopathy
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Listed from most similar to Laing distal myopathy to least similar
Typically characterized by onset of proximal weakness, but all myofibrillar myopathies can have onset of distal weakness, most often in the legs. Common finding is disintegration of the sarcomeric Z-discs and the myofibrils leading to abnormal ectopic accumulation of multiple proteins involved in the structure of the Z-disc (e.g., desmin, dystrophin, and myotilin).
Usually begins in the hand and finger extensors but may begin in the anterior compartment muscles of the lower legs [
Muscle weakness in CMT is often associated with mild-to-moderate distal sensory loss. Although usually described as "painless," the neuropathy can be painful. Sensory loss can most easily be demonstrated by a decreased appreciation of vibration, but can also include impaired sensation of pain/pinprick, temperature, and joint position. More than 80 genes are associated with CMT.
One aid to differential diagnosis between Laing distal myopathy and CMT: unlike in CMT, in Laing distal myopathy the extensor digitorum brevis muscles are preserved [
• Muscle weakness in CMT is often associated with mild-to-moderate distal sensory loss. Although usually described as "painless," the neuropathy can be painful. Sensory loss can most easily be demonstrated by a decreased appreciation of vibration, but can also include impaired sensation of pain/pinprick, temperature, and joint position. More than 80 genes are associated with CMT.
• One aid to differential diagnosis between Laing distal myopathy and CMT: unlike in CMT, in Laing distal myopathy the extensor digitorum brevis muscles are preserved [
## Congenital Myopathy
The early onset of Laing distal myopathy means that any of the milder congenital myopathies may be a differential diagnosis (see
Congenital Myopathies of Interest in the Differential Diagnosis of Laing Distal Myopathy
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
## Distal Myopathies
The other major group in the differential diagnosis of Laing distal myopathy is distal myopathies (see
Distal Myopathies of Interest in the Differential Diagnosis of Laing Distal Myopathy
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Listed from most similar to Laing distal myopathy to least similar
Typically characterized by onset of proximal weakness, but all myofibrillar myopathies can have onset of distal weakness, most often in the legs. Common finding is disintegration of the sarcomeric Z-discs and the myofibrils leading to abnormal ectopic accumulation of multiple proteins involved in the structure of the Z-disc (e.g., desmin, dystrophin, and myotilin).
Usually begins in the hand and finger extensors but may begin in the anterior compartment muscles of the lower legs [
Muscle weakness in CMT is often associated with mild-to-moderate distal sensory loss. Although usually described as "painless," the neuropathy can be painful. Sensory loss can most easily be demonstrated by a decreased appreciation of vibration, but can also include impaired sensation of pain/pinprick, temperature, and joint position. More than 80 genes are associated with CMT.
One aid to differential diagnosis between Laing distal myopathy and CMT: unlike in CMT, in Laing distal myopathy the extensor digitorum brevis muscles are preserved [
• Muscle weakness in CMT is often associated with mild-to-moderate distal sensory loss. Although usually described as "painless," the neuropathy can be painful. Sensory loss can most easily be demonstrated by a decreased appreciation of vibration, but can also include impaired sensation of pain/pinprick, temperature, and joint position. More than 80 genes are associated with CMT.
• One aid to differential diagnosis between Laing distal myopathy and CMT: unlike in CMT, in Laing distal myopathy the extensor digitorum brevis muscles are preserved [
## Management
No clinical practice guidelines for Laing distal myopathy have been published.
To establish the extent of disease and needs in an individual diagnosed with Laing distal myopathy, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Laing Distal Myopathy
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations in Individuals with Laing Distal Myopathy
Recommended Surveillance for Individuals with Laing Distal Myopathy
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from physiotherapy and surveillance for cardiomyopathy. Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known;
Evaluations for muscle weakness and secondary contractures if the pathogenic variant in the family is not known.
See
Search
• Molecular genetic testing if the pathogenic variant in the family is known;
• Evaluations for muscle weakness and secondary contractures if the pathogenic variant in the family is not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Laing distal myopathy, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Laing Distal Myopathy
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Laing Distal Myopathy
## Surveillance
Recommended Surveillance for Individuals with Laing Distal Myopathy
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from physiotherapy and surveillance for cardiomyopathy. Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known;
Evaluations for muscle weakness and secondary contractures if the pathogenic variant in the family is not known.
See
• Molecular genetic testing if the pathogenic variant in the family is known;
• Evaluations for muscle weakness and secondary contractures if the pathogenic variant in the family is not known.
## Therapies Under Investigation
Search
## Genetic Counseling
Laing distal myopathy is an autosomal dominant disorder.
Approximately 65%-70% of individuals diagnosed with Laing distal myopathy have an affected parent.
Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include full history, examination looking for weakness and secondary contractures, and molecular genetic testing for the
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with Laing distal myopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance of Laing distal myopathy is approximately 85%; it is therefore 85% likely that a sib who inherits a familial pathogenic variant will have clinical manifestations of the disorder. Considerable intrafamilial variation in severity has been described in Laing distal myopathy; in one family, some heterozygous individuals were asymptomatic while others required a wheelchair for mobility [
If the proband has a known
If the parents have not been tested for the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Approximately 65%-70% of individuals diagnosed with Laing distal myopathy have an affected parent.
• Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include full history, examination looking for weakness and secondary contractures, and molecular genetic testing for the
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• The family history of some individuals diagnosed with Laing distal myopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance of Laing distal myopathy is approximately 85%; it is therefore 85% likely that a sib who inherits a familial pathogenic variant will have clinical manifestations of the disorder. Considerable intrafamilial variation in severity has been described in Laing distal myopathy; in one family, some heterozygous individuals were asymptomatic while others required a wheelchair for mobility [
• If the proband has a known
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Laing distal myopathy is an autosomal dominant disorder.
## Risk to Family Members
Approximately 65%-70% of individuals diagnosed with Laing distal myopathy have an affected parent.
Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include full history, examination looking for weakness and secondary contractures, and molecular genetic testing for the
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with Laing distal myopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance of Laing distal myopathy is approximately 85%; it is therefore 85% likely that a sib who inherits a familial pathogenic variant will have clinical manifestations of the disorder. Considerable intrafamilial variation in severity has been described in Laing distal myopathy; in one family, some heterozygous individuals were asymptomatic while others required a wheelchair for mobility [
If the proband has a known
If the parents have not been tested for the
• Approximately 65%-70% of individuals diagnosed with Laing distal myopathy have an affected parent.
• Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include full history, examination looking for weakness and secondary contractures, and molecular genetic testing for the
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• The family history of some individuals diagnosed with Laing distal myopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• * A parent with somatic and germline mosaicism for an
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance of Laing distal myopathy is approximately 85%; it is therefore 85% likely that a sib who inherits a familial pathogenic variant will have clinical manifestations of the disorder. Considerable intrafamilial variation in severity has been described in Laing distal myopathy; in one family, some heterozygous individuals were asymptomatic while others required a wheelchair for mobility [
• If the proband has a known
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
United Kingdom
•
•
•
• Canada
•
•
• United Kingdom
•
## Molecular Genetics
Laing Distal Myopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Laing Distal Myopathy (
The
The tail of a myosin molecule forms an alpha-helical coiled coil with the tail of another myosin molecule and through this process forms a dimer [
Similarly, proline residues are not compatible with a coiled coil since they introduce a kink in protein structure [
Thus, most of the
The missense variants causing large charge changes are different. There is a pattern of charge changes along the length of the myosin rod, which plays a role in the formation of the thick filament [
The pathogenic mechanism by which these effects on coiled coil or thick filament formation ultimately have the effects on specific muscles seen in Laing distal myopathy, such as early and severe involvement of the tibialis anterior, remains a complete mystery. As MYH7 protein is present in every slow muscle fiber in every muscle in the human body and in the heart, why then is the pattern of weakness restricted? It may not be possible to model the effect of Laing distal myopathy myosin variants in any animal other than human beings.
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The
The tail of a myosin molecule forms an alpha-helical coiled coil with the tail of another myosin molecule and through this process forms a dimer [
Similarly, proline residues are not compatible with a coiled coil since they introduce a kink in protein structure [
Thus, most of the
The missense variants causing large charge changes are different. There is a pattern of charge changes along the length of the myosin rod, which plays a role in the formation of the thick filament [
The pathogenic mechanism by which these effects on coiled coil or thick filament formation ultimately have the effects on specific muscles seen in Laing distal myopathy, such as early and severe involvement of the tibialis anterior, remains a complete mystery. As MYH7 protein is present in every slow muscle fiber in every muscle in the human body and in the heart, why then is the pattern of weakness restricted? It may not be possible to model the effect of Laing distal myopathy myosin variants in any animal other than human beings.
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Nigel Laing's work focuses on disease gene discovery, development and implementation of improved molecular diagnostics, preclinical investigation of potential treatments for selected genetic muscle diseases, and reproductive genetic carrier screening. He has a research professorship in the Centre for Medical Research, University of Western Australia, located in the Harry Perkins Institute of Medical Research, and a senior medical scientist position within the Neurogenetic Unit, Department of Diagnostic Genomics, PathWest Laboratory Medicine, Health Department of Western Australia. Websites:
Phillipa Lamont's work focuses on clinical investigation and research of neuromuscular disorders, disease gene discovery, and clinical trials. Professor Lamont heads the Neurogenetic Clinic at Royal Perth Hospital in Perth, Western Australia, which provides a statewide service for genetic neurologic conditions.
NGL is supported by Australian National Health and Medical Research Council Fellowship APP1117510.
Nigel G Laing, PhD (2006-present)Phillipa Lamont, MBBS, PhD (2006-present)William Wallefeld, BSc (Hons); University of Western Australia (2010-2015)
4 February 2021 (ha) Comprehensive update posted live
12 March 2015 (me) Comprehensive update posted live
17 June 2010 (me) Comprehensive update posted live
17 October 2006 (me) Review posted live
6 September 2006 (nl) Original submission
• 4 February 2021 (ha) Comprehensive update posted live
• 12 March 2015 (me) Comprehensive update posted live
• 17 June 2010 (me) Comprehensive update posted live
• 17 October 2006 (me) Review posted live
• 6 September 2006 (nl) Original submission
## Author Notes
Nigel Laing's work focuses on disease gene discovery, development and implementation of improved molecular diagnostics, preclinical investigation of potential treatments for selected genetic muscle diseases, and reproductive genetic carrier screening. He has a research professorship in the Centre for Medical Research, University of Western Australia, located in the Harry Perkins Institute of Medical Research, and a senior medical scientist position within the Neurogenetic Unit, Department of Diagnostic Genomics, PathWest Laboratory Medicine, Health Department of Western Australia. Websites:
Phillipa Lamont's work focuses on clinical investigation and research of neuromuscular disorders, disease gene discovery, and clinical trials. Professor Lamont heads the Neurogenetic Clinic at Royal Perth Hospital in Perth, Western Australia, which provides a statewide service for genetic neurologic conditions.
## Acknowledgments
NGL is supported by Australian National Health and Medical Research Council Fellowship APP1117510.
## Author History
Nigel G Laing, PhD (2006-present)Phillipa Lamont, MBBS, PhD (2006-present)William Wallefeld, BSc (Hons); University of Western Australia (2010-2015)
## Revision History
4 February 2021 (ha) Comprehensive update posted live
12 March 2015 (me) Comprehensive update posted live
17 June 2010 (me) Comprehensive update posted live
17 October 2006 (me) Review posted live
6 September 2006 (nl) Original submission
• 4 February 2021 (ha) Comprehensive update posted live
• 12 March 2015 (me) Comprehensive update posted live
• 17 June 2010 (me) Comprehensive update posted live
• 17 October 2006 (me) Review posted live
• 6 September 2006 (nl) Original submission
## References
## Literature Cited
Early development of anterior compartment weakness has led to marked tightening of the Achilles tendon bilaterally, with the affected individual unable to place his heels on the ground.
Individual with Laing distal myopathy attempting to extend her second to fifth fingers. Note marked weakness of third- and fourth-finger extension.
Mild scapular winging and weakness develops later.
|
[
"M Achal, AS Trujillo, GC Melkani, GP Farman, K Ocorr, MC Viswanathan, G Kaushik, CS Newhard, BM Glasheen, A Melkani, JA Suggs, JR Moore, DM Swank, R Bodmer, A Cammarato, SI Bernstein. A restrictive cardiomyopathy mutation in an invariant proline at the myosin head/rod junction enhances head flexibility and function, yielding muscle defects in drosophila.. J Mol Biol. 2016;428:2446-61",
"SJ Beecroft, JM van der Locht, CA Ottenheim, CA Sewry, S Mohammed, MM Ryan, IR Woodcock, L Sanders, R Gooding, MR Davis, EC Oates, NG Laing, G Ravenscroft, CA McLean, H Jungbluth. Recessive MYH7-related myopathy in 2 families.. Neuromuscul Disord. 2019;29:456-67",
"SJ Beecroft, KS Yau, RJN Allcock, K Mina, R Gooding, F Faiz, VJ Atkinson, C Wise, P Sivadorai, D Trajanoski, N Kresoje, R Ong, RM Duff, M Cabrera-Serrano, KJ Nowak, N Pachter, G Ravenscroft, PJ Lamont, MR Davis, NG Laing. Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience.. Ann Clin Transl Neurol. 2020;7:353-62",
"M Buvoli, A Buvoli, LA Leinwand. Effects of pathogenic proline mutations on myosin assembly.. J Mol Biol. 2012;415:807-18",
"P Carbonell-Corvillo, E Tristán-Clavijo, M Cabrera-Serrano, E Servián-Morilla, G García-Martín, L Villarreal-Pérez, E Rivas-Infante, E Area-Gómez, MI Chamorro-Muñoz, A Gil-Gálvez, A Miranda-Vizuete, A Martinez-Mir, N Laing, C Paradas. A novel MYH7 founder mutation causing Laing distal myopathy in Southern Spain.. Neuromuscul Disord. 2018;28:828-36",
"FHC Crick. The packing of a-helices: simple coiled coils.. Acta Crystallographica. 1953;6:689-97",
"T Cullup, PJ Lamont, S Cirak, MS Damian, W Wallefeld, R Gooding, SV Tan, J Sheehan, F Muntoni, S Abbs, CA Sewry, V Dubowitz, NG Laing, H Jungbluth. Mutations in MYH7 cause multi-minicore disease with variable cardiac involvement.. Neuromuscul Disord. 2012;22:1096-104",
"I Dabaj, RY Carlier, D Gómez-Andrés, OA Neto, E Bertini, A D'amico, F Fattori. PéRéon Y, Castiglioni C, Rodillo E, Catteruccia M, Guimarães JB, Oliveira ASB, Reed UC, Mesrob L, Lechner D, Boland A, Deleuze JF, Malfatti E, Bonnemann C, Laporte J, Romero N, Felter A, Quijano-Roy S, Moreno CAM, Zanoteli E. Clinical and imaging hallmarks of the MYH7-related myopathy with severe axial involvement.. Muscle Nerve. 2018;58:224-34",
"M Feinstein-Linial, M Buvoli, A Buvoli, M Sadeh, R Dabby, R Straussberg, I Shelef, D Dayan, LA Leinwand, OS Birk. Two novel MYH7 proline substitutions cause Laing distal myopathy-like phenotypes with variable expressivity and neck extensor contracture.. BMC Med Genet. 2016;17:57",
"J Finsterer, O Brandau, C Stollberger, W Wallefeld, NG Laing, F Laccone. Distal myosin heavy chain-7 myopathy due to the novel transition c.5566G>A (p.E1856K) with high interfamilial cardiac variability and putative anticipation.. Neuromuscul Disord. 2014a;24:721-5",
"J Finsterer, C Stollberger, O Brandau, F Laccone, K Bichler, NG Laing. 2014b. Novel MYH7 mutation associated with mild myopathy but life-threatening ventricular arrhythmias and noncompaction.. Int J Cardiol. 2014b;173:532-5",
"C Fiorillo, G Astrea, M Savarese, D Cassandrini, G Brisca, F Trucco, M Pedemonte, R Trovato, L Ruggiero, L Vercelli, A D'Amico, G Tasca, M Pane, M Fanin, L Bello, P Broda, O Musumeci, C Rodolico, S Messina, GL Vita, M Sframeli, S Gibertini, L Morandi, M Mora, L Maggi, A Petrucci, R Massa, M Grandis, A Toscano, E Pegoraro, E Mercuri, E Bertini, T Mongini, L Santoro, V Nigro, C Minetti, FM Santorelli, C Bruno. MYH7-related myopathies: clinical, histopathological and imaging findings in a cohort of Italian patients.. Orphanet J Rare Dis. 2016;11:91",
"P Hackman, J Sarparanta, S Lehtinen, A Vihola, A Evilä, PH Jonson, H Luque, J Kere, M Screen, PF Chinnery, G Åhlberg, L Edström, B Udd. Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1.. Ann Neurol. 2013;73:500-9",
"K Hara, H Miyata, I. Nishino. Rinsho Shinkeigaku. 2019;59:823-8",
"P Hedera, EM Petty, MR Bui, M Blaivas, JK Fink. The second kindred with autosomal dominant distal myopathy linked to chromosome 14q: genetic and clinical analysis.. Arch Neurol. 2003;60:1321-5",
"PJ Lamont, B Udd, FL Mastaglia, M de Visser, P Hedera, T Voit, LR Bridges, V Fabian, A Rozemuller, NG Laing. Laing early onset distal myopathy: slow myosin defect with variable abnormalities on muscle biopsy.. J Neurol Neurosurg Psychiatry. 2006;77:208-15",
"PJ Lamont, W Wallefeld, D Hilton-Jones, B Udd, Z Argov, AC Barboi, C Bonneman, KM Boycott, K Bushby, AM Connolly, N Davies, AH Beggs, GF Cox, J Dastgir, ET DeChene, R Gooding, H Jungbluth, N Muelas, J Palmio, S Penttilä, E Schmedding, T Suominen, V Straub, C Staples, PY Van den Bergh, JJ Vilchez, KR Wagner, PG Wheeler, E Wraige, NG Laing. Novel mutations widen the phenotypic spectrum of slow skeletal/β-cardiac myosin (MYH7) distal myopathy.. Hum Mutat. 2014;35:868-79",
"S Lefter, R Hardiman, RL McLaughlin, SM Murphy, M Farrell, AM Ryan. A novel MYH7 Leu1453pro mutation resulting in Laing distal myopathy in an Irish family.. Neuromuscul Disord. 2015;25:155-60",
"AD McLachlan, J Karn. Periodic charge distributions in the myosin rod amino acid sequence match cross-bridge spacings in muscle.. Nature. 1982;299:226-31",
"C Meredith, R Herrmann, C Parry, K Liyanage, DE Dye, HJ Durling, RM Duff, K Beckman, M de Visser, MM van der Graaff, P Hedera, JK Fink, EM Petty, P Lamont, V Fabian, L Bridges, T Voit, FL Mastaglia, NG Laing. Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause Laing early-onset distal myopathy (MPD1).. Am J Hum Genet. 2004;75:703-8",
"N Muelas, P Hackman, H Luque, M Garcés-Sánchez, I Azorín, T Suominen, T Sevilla, F Mayordomo, L Gómez, P Martí, J María Millán, B Udd, JJ Vílchez. MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy.. Neurology. 2010;75:732-41",
"N Muelas, P Hackman, H Luque, T Suominen, C Espinos, M Garces-Sanchez, T Sevilla, I Azorin, J Millan, B Udd, J. Vilchez. Spanish MYH7 founder mutation of Italian ancestry causing a large cluster of Laing myopathy patients.. Clin Genet. 2012;81:491-4",
"L Negrão, R Machado, M Lourenco, A Fernandez-Marmiesse, O Rebelo. Laing distal myopathy with subsarcolemmal hyaline bodies caused by a novel variant in the MYH7 gene.. Acta Myologica. 2020;39:24-8",
"KT O'Neil, WF DeGrado. A thermodynamic scale for the helix-forming tendencies of the commonly occurring amino acids.. Science. 1990;250:646-51",
"S Pajusalu, I Talvik, K Noormets, T Talvik, H Poder, K Joost, S Puusepp, A Piirsoo, W Stenzel, HH Goebel, T Nikopensius, T Annilo, M Noukas, A Metspalu, K Ounap, T Reimand. De novo exonic mutation in MYH7 gene leading to exon skipping in a patient with early onset muscular weakness and fiber-type disproportion.. Neuromuscul Disord. 2016;26:236-9",
"JM Park, YJ Kim, JH Yoo, YB Hong, JH Park, H Koo, KW Chung, BO Choi. A novel MYH7 mutation with prominent paraspinal and proximal muscle involvement.. Neuromuscul Disord. 2013;23:580-6",
"E Pegoraro, BF Gavassini, C Borsato, P Melacini, A Vianello, R Stramare, G Cenacchi, C Angelini. MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy.. Neuromuscul Disord. 2007;17:321-9",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"RH Roda, AB Schindler, C Blackstone, AL Mammen, AM Corse, TE Lloyd. Laing distal myopathy pathologically resembling inclusion body myositis.. Ann Clin Transl Neurol. 2014;1:1053-8",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"H Tajsharghi, A. Oldfors. Myosinopathies: pathology and mechanisms.. Acta Neuropathologica. 2013;125:3-18",
"G Tasca, E Ricci, S Pentilla, M Monforte, V Giglio, P Ottavani, G Camstra, G Silvestri, B Udd. New phenotype and pathology features in MYH7-related distal myopathy.. Neuromuscul Disord. 2012;22:640-7",
"B. Udd. 165th ENMC International Workshop: distal myopathies 6-8th February 2009, Naarden, the Netherlands.. Neuromuscul Disord. 2009;19:429-38",
"D von Tell, H Somer, B Udd, L Edstrom, K Borg, G Ahlberg. Welander distal myopathy outside the Swedish population: phenotype and genotype.. Neuromuscul Disord. 2002;12:544-7",
"M Yu, Y Zhu, Y Lu, H Lv, W Zhang, Y Yuan, Z. Wang. Clinical features and genotypes of Laing distal myopathy in a group of Chinese patients, with in-frame deletions of MYH7 as common mutations.. Orphanet J Rare Dis. 2020;15:344",
"F Zimprich, A Djamshidian, JA Hainfellner, H Budka, J Zeitlhofer. An autosomal dominant early adult-onset distal muscular dystrophy.. Muscle Nerve. 2000;23:1876-9"
] |
17/10/2006
|
4/2/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mpgn
|
mpgn
|
[
"C3G",
"Glomerulonephritis with Dominant C3",
"Glomerulonephritis with Dominant C3",
"C3G",
"Complement C3",
"Complement factor B",
"Complement factor H",
"Complement factor H-related protein 1",
"Complement factor H-related protein 5",
"Complement factor I",
"Diacylglycerol kinase epsilon",
"Membrane cofactor protein",
"C3",
"CD46",
"CFB",
"CFH",
"CFHR1",
"CFHR5",
"CFI",
"DGKE",
"C3 Glomerulopathy"
] |
C3 Glomerulopathy
|
Bertha Martín, Richard JH Smith
|
Summary C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal disease caused by uncontrolled activation of the complement alternative pathway (AP) in the fluid phase (as opposed to cell surface) that is rarely inherited in a simple mendelian fashion. C3G affects individuals of all ages, with a median age at diagnosis of 23 years. Individuals with C3G typically present with hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome, and low levels of the complement component C3. Spontaneous remission of C3G is uncommon, and about half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis, occasionally developing the late comorbidity of impaired visual acuity. The definitive diagnosis of C3G requires a renal biopsy with specialized immunofluorescence and electron microscopy studies both for diagnosis and to distinguish between the two major subtypes of C3G: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes that have been implicated in the pathogenesis of C3G (i.e., C3G is a complex genetic disorder that is rarely inherited in a simple mendelian fashion. Multiple affected persons within a single nuclear family are reported only occasionally, with both dominant and recessive inheritance being described.
|
## Diagnosis
C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal disease caused by uncontrolled activation of the complement alternative pathway (AP) in the fluid phase (as opposed to cell surface); it is rarely inherited in a simple mendelian fashion.
C3G
Hematuria
Proteinuria
Hematuria and proteinuria
Acute nephritic syndrome
Nephrotic syndrome
Persistent hypocomplementemia (low serum levels of complement component C3)
The diagnosis of C3G
Note: Identification of a pathogenic variant may help to direct treatment of the individual.
Immunofluorescence (IF). The diagnosis of C3G can only be made with IF studies of a renal biopsy.
The predominant staining of C3 is key in delivering a C3G diagnosis.
IF should be predominantly positive for C3 with C3 intensity at least two orders of magnitude greater than any other immune reactant (i.e., IgA, IgG, IgM, and C1q) (
Electron microscopy (EM) is used to distinguish between C3GN and DDD, a clinically relevant distinction (
In C3GN there are light, hump-like and clustered deposits, which are found in the mesangium or in the subendothelial and/or subepithelial spaces.
In DDD, the deposits are darker, denser, segmental, discontinuous, ribbon-like, or diffuse and are most frequently located in the lamina densa of the glomerular basement membrane (GBM) (
Light microscopy (LM) is necessary to quantitate changes associated with chronic kidney disease and risk for progression of ESRD.
LM most commonly demonstrates mild mesangial cell hypercellularity (45% of cases), although membranoproliferative (25%), crescentic (18%), and acute proliferative and exudative (12%) patterns are also seen (
Note: Timing of the biopsy is important. If the presentation suggests post-infectious glomerulonephritis (PIGN; see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in C3G
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Four individuals of non-Cypriot origin; however, hundreds of affected individuals with a duplication of exons 2 and 3, presumably due to a founder effect, have been identified in Cyprus [
Three patients of non-Cypriot origin have been reported with variants detectable by sequencing [
See
• Hematuria
• Proteinuria
• Hematuria and proteinuria
• Acute nephritic syndrome
• Nephrotic syndrome
• Persistent hypocomplementemia (low serum levels of complement component C3)
• Immunofluorescence (IF). The diagnosis of C3G can only be made with IF studies of a renal biopsy.
• The predominant staining of C3 is key in delivering a C3G diagnosis.
• IF should be predominantly positive for C3 with C3 intensity at least two orders of magnitude greater than any other immune reactant (i.e., IgA, IgG, IgM, and C1q) (
• The predominant staining of C3 is key in delivering a C3G diagnosis.
• IF should be predominantly positive for C3 with C3 intensity at least two orders of magnitude greater than any other immune reactant (i.e., IgA, IgG, IgM, and C1q) (
• Electron microscopy (EM) is used to distinguish between C3GN and DDD, a clinically relevant distinction (
• In C3GN there are light, hump-like and clustered deposits, which are found in the mesangium or in the subendothelial and/or subepithelial spaces.
• In DDD, the deposits are darker, denser, segmental, discontinuous, ribbon-like, or diffuse and are most frequently located in the lamina densa of the glomerular basement membrane (GBM) (
• In C3GN there are light, hump-like and clustered deposits, which are found in the mesangium or in the subendothelial and/or subepithelial spaces.
• In DDD, the deposits are darker, denser, segmental, discontinuous, ribbon-like, or diffuse and are most frequently located in the lamina densa of the glomerular basement membrane (GBM) (
• Light microscopy (LM) is necessary to quantitate changes associated with chronic kidney disease and risk for progression of ESRD.
• LM most commonly demonstrates mild mesangial cell hypercellularity (45% of cases), although membranoproliferative (25%), crescentic (18%), and acute proliferative and exudative (12%) patterns are also seen (
• The predominant staining of C3 is key in delivering a C3G diagnosis.
• IF should be predominantly positive for C3 with C3 intensity at least two orders of magnitude greater than any other immune reactant (i.e., IgA, IgG, IgM, and C1q) (
• In C3GN there are light, hump-like and clustered deposits, which are found in the mesangium or in the subendothelial and/or subepithelial spaces.
• In DDD, the deposits are darker, denser, segmental, discontinuous, ribbon-like, or diffuse and are most frequently located in the lamina densa of the glomerular basement membrane (GBM) (
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
C3G
Hematuria
Proteinuria
Hematuria and proteinuria
Acute nephritic syndrome
Nephrotic syndrome
Persistent hypocomplementemia (low serum levels of complement component C3)
• Hematuria
• Proteinuria
• Hematuria and proteinuria
• Acute nephritic syndrome
• Nephrotic syndrome
• Persistent hypocomplementemia (low serum levels of complement component C3)
## Establishing the Diagnosis
The diagnosis of C3G
Note: Identification of a pathogenic variant may help to direct treatment of the individual.
Immunofluorescence (IF). The diagnosis of C3G can only be made with IF studies of a renal biopsy.
The predominant staining of C3 is key in delivering a C3G diagnosis.
IF should be predominantly positive for C3 with C3 intensity at least two orders of magnitude greater than any other immune reactant (i.e., IgA, IgG, IgM, and C1q) (
Electron microscopy (EM) is used to distinguish between C3GN and DDD, a clinically relevant distinction (
In C3GN there are light, hump-like and clustered deposits, which are found in the mesangium or in the subendothelial and/or subepithelial spaces.
In DDD, the deposits are darker, denser, segmental, discontinuous, ribbon-like, or diffuse and are most frequently located in the lamina densa of the glomerular basement membrane (GBM) (
Light microscopy (LM) is necessary to quantitate changes associated with chronic kidney disease and risk for progression of ESRD.
LM most commonly demonstrates mild mesangial cell hypercellularity (45% of cases), although membranoproliferative (25%), crescentic (18%), and acute proliferative and exudative (12%) patterns are also seen (
Note: Timing of the biopsy is important. If the presentation suggests post-infectious glomerulonephritis (PIGN; see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in C3G
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Four individuals of non-Cypriot origin; however, hundreds of affected individuals with a duplication of exons 2 and 3, presumably due to a founder effect, have been identified in Cyprus [
Three patients of non-Cypriot origin have been reported with variants detectable by sequencing [
See
• Immunofluorescence (IF). The diagnosis of C3G can only be made with IF studies of a renal biopsy.
• The predominant staining of C3 is key in delivering a C3G diagnosis.
• IF should be predominantly positive for C3 with C3 intensity at least two orders of magnitude greater than any other immune reactant (i.e., IgA, IgG, IgM, and C1q) (
• The predominant staining of C3 is key in delivering a C3G diagnosis.
• IF should be predominantly positive for C3 with C3 intensity at least two orders of magnitude greater than any other immune reactant (i.e., IgA, IgG, IgM, and C1q) (
• Electron microscopy (EM) is used to distinguish between C3GN and DDD, a clinically relevant distinction (
• In C3GN there are light, hump-like and clustered deposits, which are found in the mesangium or in the subendothelial and/or subepithelial spaces.
• In DDD, the deposits are darker, denser, segmental, discontinuous, ribbon-like, or diffuse and are most frequently located in the lamina densa of the glomerular basement membrane (GBM) (
• In C3GN there are light, hump-like and clustered deposits, which are found in the mesangium or in the subendothelial and/or subepithelial spaces.
• In DDD, the deposits are darker, denser, segmental, discontinuous, ribbon-like, or diffuse and are most frequently located in the lamina densa of the glomerular basement membrane (GBM) (
• Light microscopy (LM) is necessary to quantitate changes associated with chronic kidney disease and risk for progression of ESRD.
• LM most commonly demonstrates mild mesangial cell hypercellularity (45% of cases), although membranoproliferative (25%), crescentic (18%), and acute proliferative and exudative (12%) patterns are also seen (
• The predominant staining of C3 is key in delivering a C3G diagnosis.
• IF should be predominantly positive for C3 with C3 intensity at least two orders of magnitude greater than any other immune reactant (i.e., IgA, IgG, IgM, and C1q) (
• In C3GN there are light, hump-like and clustered deposits, which are found in the mesangium or in the subendothelial and/or subepithelial spaces.
• In DDD, the deposits are darker, denser, segmental, discontinuous, ribbon-like, or diffuse and are most frequently located in the lamina densa of the glomerular basement membrane (GBM) (
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
In comparing the two major subtypes, the median age at time of diagnosis in C3 glomerulonephritis (C3GN) is higher than in dense deposit disease (DDD). In childhood, DDD is more frequently diagnosed than C3GN [
Hematuria
Proteinuria
Hematuria and proteinuria
Acute nephritic syndrome
Nephrotic syndrome
Autoantibodies that may be detected in individuals with C3G:
Serum C3 nephritic factor (C3NeFs). C3NeFs are present in up to ~50% of individuals with C3GN and ~80% of individuals with DDD [
Factor H autoantibodies (FHAAs).
Factor B autoantibodies (FBAAs). FBAAs have been linked to C3G; their role in disease remains unclear [
Spontaneous remission of C3G is uncommon [
About half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis [
Progression to ESRD can be rapid [
Age and sex of an individual are not significant predictors of disease course.
Native kidney survival is comparable in C3GN and DDD [
Recent investigations convey the importance of the complications that result from drusen [
The long-term risk for visual problems in individuals with C3G is approximately 10%. No correlation exists between disease severity in the kidney and in the eye.
See
During disease progression, activation of downstream complement proteins in the solid phase, in particular cleavage of C5 to C5a and C5b, can contribute to tissue injury in the micro-environment of the renal glomerulus [
Acquired drivers of disease include autoantibodies such as C3 nephritic factors (C3NeFs), C4 nephritic factors (C4NeFs), C5 nephritic factors (C5NeFs), factor H autoantibodies (FHAA), and factor B autoantibodies (FBAA).
C3NeFs and C5NeFs are most commonly detected and are autoantibodies that recognize neoantigenic epitopes on C3bBb, the C3 convertase of the AP, and on C3bBbC3b, the C5 convertase of the terminal pathway, respectively (see
Nephritic factors may persist in serum throughout the disease course [
The consequence of AP dysregulation in C3G is kidney damage. As the degree of chronic damage increases, renal outcome ultimately becomes independent of the degree of complement dysregulation. With sufficient chronic damage, even if complement normalcy is restored, the likelihood of improving or stabilizing renal function becomes remote and ESRD ensues.
Factor H autoantibodies (FHAA) have been reported in individuals with C3G; epitope mapping shows that these autoantibodies bind the N-terminus of fH [
Factor B autoantibodies (FBAA) have been linked to C3G; however, their role in disease remains unclear [
As a general rule, C3Nefs, FHAAs, and FBAAs extend the half-life and stabilize C3 convertase, which leads to persistent AP activation in the fluid phase [
To date, the most striking genotype-phenotype correlation has been with
The rarity of C3G makes it difficult to estimate prevalence, although from epidemiologic studies, its prevalence in the USA is estimated at 2-3 per 1,000,000 [
• Hematuria
• Proteinuria
• Hematuria and proteinuria
• Acute nephritic syndrome
• Nephrotic syndrome
• Serum C3 nephritic factor (C3NeFs). C3NeFs are present in up to ~50% of individuals with C3GN and ~80% of individuals with DDD [
• Factor H autoantibodies (FHAAs).
• Factor B autoantibodies (FBAAs). FBAAs have been linked to C3G; their role in disease remains unclear [
• Spontaneous remission of C3G is uncommon [
• About half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis [
• Progression to ESRD can be rapid [
• Age and sex of an individual are not significant predictors of disease course.
• Native kidney survival is comparable in C3GN and DDD [
• Progression to ESRD can be rapid [
• Age and sex of an individual are not significant predictors of disease course.
• Native kidney survival is comparable in C3GN and DDD [
• Progression to ESRD can be rapid [
• Age and sex of an individual are not significant predictors of disease course.
• Native kidney survival is comparable in C3GN and DDD [
## Clinical Description
In comparing the two major subtypes, the median age at time of diagnosis in C3 glomerulonephritis (C3GN) is higher than in dense deposit disease (DDD). In childhood, DDD is more frequently diagnosed than C3GN [
Hematuria
Proteinuria
Hematuria and proteinuria
Acute nephritic syndrome
Nephrotic syndrome
Autoantibodies that may be detected in individuals with C3G:
Serum C3 nephritic factor (C3NeFs). C3NeFs are present in up to ~50% of individuals with C3GN and ~80% of individuals with DDD [
Factor H autoantibodies (FHAAs).
Factor B autoantibodies (FBAAs). FBAAs have been linked to C3G; their role in disease remains unclear [
Spontaneous remission of C3G is uncommon [
About half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis [
Progression to ESRD can be rapid [
Age and sex of an individual are not significant predictors of disease course.
Native kidney survival is comparable in C3GN and DDD [
Recent investigations convey the importance of the complications that result from drusen [
The long-term risk for visual problems in individuals with C3G is approximately 10%. No correlation exists between disease severity in the kidney and in the eye.
See
During disease progression, activation of downstream complement proteins in the solid phase, in particular cleavage of C5 to C5a and C5b, can contribute to tissue injury in the micro-environment of the renal glomerulus [
Acquired drivers of disease include autoantibodies such as C3 nephritic factors (C3NeFs), C4 nephritic factors (C4NeFs), C5 nephritic factors (C5NeFs), factor H autoantibodies (FHAA), and factor B autoantibodies (FBAA).
C3NeFs and C5NeFs are most commonly detected and are autoantibodies that recognize neoantigenic epitopes on C3bBb, the C3 convertase of the AP, and on C3bBbC3b, the C5 convertase of the terminal pathway, respectively (see
Nephritic factors may persist in serum throughout the disease course [
The consequence of AP dysregulation in C3G is kidney damage. As the degree of chronic damage increases, renal outcome ultimately becomes independent of the degree of complement dysregulation. With sufficient chronic damage, even if complement normalcy is restored, the likelihood of improving or stabilizing renal function becomes remote and ESRD ensues.
Factor H autoantibodies (FHAA) have been reported in individuals with C3G; epitope mapping shows that these autoantibodies bind the N-terminus of fH [
Factor B autoantibodies (FBAA) have been linked to C3G; however, their role in disease remains unclear [
As a general rule, C3Nefs, FHAAs, and FBAAs extend the half-life and stabilize C3 convertase, which leads to persistent AP activation in the fluid phase [
• Hematuria
• Proteinuria
• Hematuria and proteinuria
• Acute nephritic syndrome
• Nephrotic syndrome
• Serum C3 nephritic factor (C3NeFs). C3NeFs are present in up to ~50% of individuals with C3GN and ~80% of individuals with DDD [
• Factor H autoantibodies (FHAAs).
• Factor B autoantibodies (FBAAs). FBAAs have been linked to C3G; their role in disease remains unclear [
• Spontaneous remission of C3G is uncommon [
• About half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis [
• Progression to ESRD can be rapid [
• Age and sex of an individual are not significant predictors of disease course.
• Native kidney survival is comparable in C3GN and DDD [
• Progression to ESRD can be rapid [
• Age and sex of an individual are not significant predictors of disease course.
• Native kidney survival is comparable in C3GN and DDD [
• Progression to ESRD can be rapid [
• Age and sex of an individual are not significant predictors of disease course.
• Native kidney survival is comparable in C3GN and DDD [
## Pathophysiology
See
During disease progression, activation of downstream complement proteins in the solid phase, in particular cleavage of C5 to C5a and C5b, can contribute to tissue injury in the micro-environment of the renal glomerulus [
Acquired drivers of disease include autoantibodies such as C3 nephritic factors (C3NeFs), C4 nephritic factors (C4NeFs), C5 nephritic factors (C5NeFs), factor H autoantibodies (FHAA), and factor B autoantibodies (FBAA).
C3NeFs and C5NeFs are most commonly detected and are autoantibodies that recognize neoantigenic epitopes on C3bBb, the C3 convertase of the AP, and on C3bBbC3b, the C5 convertase of the terminal pathway, respectively (see
Nephritic factors may persist in serum throughout the disease course [
The consequence of AP dysregulation in C3G is kidney damage. As the degree of chronic damage increases, renal outcome ultimately becomes independent of the degree of complement dysregulation. With sufficient chronic damage, even if complement normalcy is restored, the likelihood of improving or stabilizing renal function becomes remote and ESRD ensues.
Factor H autoantibodies (FHAA) have been reported in individuals with C3G; epitope mapping shows that these autoantibodies bind the N-terminus of fH [
Factor B autoantibodies (FBAA) have been linked to C3G; however, their role in disease remains unclear [
As a general rule, C3Nefs, FHAAs, and FBAAs extend the half-life and stabilize C3 convertase, which leads to persistent AP activation in the fluid phase [
## Genotype-Phenotype Correlations
To date, the most striking genotype-phenotype correlation has been with
## Nomenclature
## Prevalence
The rarity of C3G makes it difficult to estimate prevalence, although from epidemiologic studies, its prevalence in the USA is estimated at 2-3 per 1,000,000 [
## Genetically Related (Allelic) Disorders
Allelic Disorders
See hyperlinked
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of C3G
abnl = abnormal; AD = autosomal dominant; AR = autosomal recessive; EM = electron microscopy; IF = immunofluorescence; MOI = mode of inheritance; MPGN = membranoproliferative glomerulonephritis; nl = normal
## Management
To establish the extent of disease and needs in an individual diagnosed with C3G, the following evaluations are recommended if they have not already been completed:
Evaluate the complement system by measuring serum/plasma concentrations of C3, C3c, C3d, C4, C5, fB, Ba, Bb, fH, fI, properdin, and s(C5b-9).
Quantitate the degree of complement function by measuring CH50 and APH50.
Measure autoantibodies including C3NeFs, C4NeFs, C5NeFs, FHAA, and FBAA.
Establish the extent of renal disease by measuring serum creatinine concentration, and monitor creatinine clearance, proteinuria, and hematuria.
Quantitate the degree of chronic renal damage by renal biopsy.
Obtain a baseline ophthalmologic examination.
Consult with a clinical geneticist and/or genetic counselor.
Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G. Nonspecific therapies are most commonly used.
Individuals with C3G treated with eculizumab have not produced a uniform response [
Early administration of eculizumab prior to sclerotic tissue formation provides better results, reduces proteinuria, and improves kidney health [
Most treatments for C3G are ineffective; however, plasma replacement therapy in individuals with pathogenic variants in
The following are appropriate:
Close monitoring of renal function by a nephrologist with familiarity with the C3G disease spectrum
Note: Frequency of follow up and testing required is determined by the degree of renal dysfunction.
Complete biannual assessment of the complement pathway
Periodic eye examinations to evaluate the fundus
There are very few familial cases of C3G. However, if the family history is positive for renal disease, it is appropriate to evaluate apparently asymptomatic sibs of a proband and at-risk relatives to identify those who would benefit from periodic observation and continued follow up for management of renal disease.
Evaluations can include:
Molecular genetic testing if the pathogenic variants in the family are known. Penetrance rates, however, are not known.
Urinalysis
Comprehensive analysis of the complement system if the pathogenic variants in the family are not known.
See
Chronic kidney disease does not preclude pregnancy, but any pregnancy in a woman with C3G should be followed by a nephrologist and obstetrician with expertise in caring for pregnant women with chronic kidney disease [
See
Numerous anti-complement therapies are entering clinical trials for individuals with C3G. These trials are registered under
Search
• Evaluate the complement system by measuring serum/plasma concentrations of C3, C3c, C3d, C4, C5, fB, Ba, Bb, fH, fI, properdin, and s(C5b-9).
• Quantitate the degree of complement function by measuring CH50 and APH50.
• Measure autoantibodies including C3NeFs, C4NeFs, C5NeFs, FHAA, and FBAA.
• Establish the extent of renal disease by measuring serum creatinine concentration, and monitor creatinine clearance, proteinuria, and hematuria.
• Quantitate the degree of chronic renal damage by renal biopsy.
• Obtain a baseline ophthalmologic examination.
• Consult with a clinical geneticist and/or genetic counselor.
• Individuals with C3G treated with eculizumab have not produced a uniform response [
• Early administration of eculizumab prior to sclerotic tissue formation provides better results, reduces proteinuria, and improves kidney health [
• Individuals with C3G treated with eculizumab have not produced a uniform response [
• Early administration of eculizumab prior to sclerotic tissue formation provides better results, reduces proteinuria, and improves kidney health [
• Individuals with C3G treated with eculizumab have not produced a uniform response [
• Early administration of eculizumab prior to sclerotic tissue formation provides better results, reduces proteinuria, and improves kidney health [
• Close monitoring of renal function by a nephrologist with familiarity with the C3G disease spectrum
• Note: Frequency of follow up and testing required is determined by the degree of renal dysfunction.
• Complete biannual assessment of the complement pathway
• Periodic eye examinations to evaluate the fundus
• Molecular genetic testing if the pathogenic variants in the family are known. Penetrance rates, however, are not known.
• Urinalysis
• Comprehensive analysis of the complement system if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with C3G, the following evaluations are recommended if they have not already been completed:
Evaluate the complement system by measuring serum/plasma concentrations of C3, C3c, C3d, C4, C5, fB, Ba, Bb, fH, fI, properdin, and s(C5b-9).
Quantitate the degree of complement function by measuring CH50 and APH50.
Measure autoantibodies including C3NeFs, C4NeFs, C5NeFs, FHAA, and FBAA.
Establish the extent of renal disease by measuring serum creatinine concentration, and monitor creatinine clearance, proteinuria, and hematuria.
Quantitate the degree of chronic renal damage by renal biopsy.
Obtain a baseline ophthalmologic examination.
Consult with a clinical geneticist and/or genetic counselor.
• Evaluate the complement system by measuring serum/plasma concentrations of C3, C3c, C3d, C4, C5, fB, Ba, Bb, fH, fI, properdin, and s(C5b-9).
• Quantitate the degree of complement function by measuring CH50 and APH50.
• Measure autoantibodies including C3NeFs, C4NeFs, C5NeFs, FHAA, and FBAA.
• Establish the extent of renal disease by measuring serum creatinine concentration, and monitor creatinine clearance, proteinuria, and hematuria.
• Quantitate the degree of chronic renal damage by renal biopsy.
• Obtain a baseline ophthalmologic examination.
• Consult with a clinical geneticist and/or genetic counselor.
## Treatment of Manifestations
Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G. Nonspecific therapies are most commonly used.
Individuals with C3G treated with eculizumab have not produced a uniform response [
Early administration of eculizumab prior to sclerotic tissue formation provides better results, reduces proteinuria, and improves kidney health [
• Individuals with C3G treated with eculizumab have not produced a uniform response [
• Early administration of eculizumab prior to sclerotic tissue formation provides better results, reduces proteinuria, and improves kidney health [
• Individuals with C3G treated with eculizumab have not produced a uniform response [
• Early administration of eculizumab prior to sclerotic tissue formation provides better results, reduces proteinuria, and improves kidney health [
• Individuals with C3G treated with eculizumab have not produced a uniform response [
• Early administration of eculizumab prior to sclerotic tissue formation provides better results, reduces proteinuria, and improves kidney health [
## Prevention of Primary Manifestations
Most treatments for C3G are ineffective; however, plasma replacement therapy in individuals with pathogenic variants in
## Surveillance
The following are appropriate:
Close monitoring of renal function by a nephrologist with familiarity with the C3G disease spectrum
Note: Frequency of follow up and testing required is determined by the degree of renal dysfunction.
Complete biannual assessment of the complement pathway
Periodic eye examinations to evaluate the fundus
• Close monitoring of renal function by a nephrologist with familiarity with the C3G disease spectrum
• Note: Frequency of follow up and testing required is determined by the degree of renal dysfunction.
• Complete biannual assessment of the complement pathway
• Periodic eye examinations to evaluate the fundus
## Evaluation of Relatives at Risk
There are very few familial cases of C3G. However, if the family history is positive for renal disease, it is appropriate to evaluate apparently asymptomatic sibs of a proband and at-risk relatives to identify those who would benefit from periodic observation and continued follow up for management of renal disease.
Evaluations can include:
Molecular genetic testing if the pathogenic variants in the family are known. Penetrance rates, however, are not known.
Urinalysis
Comprehensive analysis of the complement system if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variants in the family are known. Penetrance rates, however, are not known.
• Urinalysis
• Comprehensive analysis of the complement system if the pathogenic variants in the family are not known.
## Pregnancy Management
Chronic kidney disease does not preclude pregnancy, but any pregnancy in a woman with C3G should be followed by a nephrologist and obstetrician with expertise in caring for pregnant women with chronic kidney disease [
See
## Therapies Under Investigation
Numerous anti-complement therapies are entering clinical trials for individuals with C3G. These trials are registered under
Search
## Genetic Counseling
C3G is a complex genetic disorder that is rarely inherited in a simple mendelian fashion. In most persons with C3G, inheritance is complex and incompletely understood. For these reasons, recurrence risk to family members is not known but likely very low.
In persons with C3G in whom two pathogenic variants can be identified
Multiple affected persons within a single nuclear family are only reported occasionally; in these instances, parental consanguinity is common [
Autosomal dominant cases of C3G are reported in association with CFHR hybrid fusion proteins (see
The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
Few individuals (<1%) diagnosed with C3G have an affected parent.
Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the pathogenic variant occurred
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with C3G may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs of inheriting the genetic variant is 50%. However, there is reduced penetrance in families [
If the parents have been tested for the pathogenic variant identified in the proband and:
A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.
If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband is extremely low. The sibs of a proband with clinically unaffected parents are still at increased risk for C3G because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
See Management,
Other autoimmune diseases, in particular diabetes mellitus type 1 and
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• In persons with C3G in whom two pathogenic variants can be identified
• Multiple affected persons within a single nuclear family are only reported occasionally; in these instances, parental consanguinity is common [
• Autosomal dominant cases of C3G are reported in association with CFHR hybrid fusion proteins (see
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Few individuals (<1%) diagnosed with C3G have an affected parent.
• Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the pathogenic variant occurred
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with C3G may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs of inheriting the genetic variant is 50%. However, there is reduced penetrance in families [
• If the parents have been tested for the pathogenic variant identified in the proband and:
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband is extremely low. The sibs of a proband with clinically unaffected parents are still at increased risk for C3G because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
C3G is a complex genetic disorder that is rarely inherited in a simple mendelian fashion. In most persons with C3G, inheritance is complex and incompletely understood. For these reasons, recurrence risk to family members is not known but likely very low.
In persons with C3G in whom two pathogenic variants can be identified
Multiple affected persons within a single nuclear family are only reported occasionally; in these instances, parental consanguinity is common [
Autosomal dominant cases of C3G are reported in association with CFHR hybrid fusion proteins (see
• In persons with C3G in whom two pathogenic variants can be identified
• Multiple affected persons within a single nuclear family are only reported occasionally; in these instances, parental consanguinity is common [
• Autosomal dominant cases of C3G are reported in association with CFHR hybrid fusion proteins (see
## Autosomal Recessive C3G – Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
## Autosomal Dominant C3G – Risk to Family Members
Few individuals (<1%) diagnosed with C3G have an affected parent.
Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the pathogenic variant occurred
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with C3G may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs of inheriting the genetic variant is 50%. However, there is reduced penetrance in families [
If the parents have been tested for the pathogenic variant identified in the proband and:
A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.
If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband is extremely low. The sibs of a proband with clinically unaffected parents are still at increased risk for C3G because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
• Few individuals (<1%) diagnosed with C3G have an affected parent.
• Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the pathogenic variant occurred
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with C3G may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs of inheriting the genetic variant is 50%. However, there is reduced penetrance in families [
• If the parents have been tested for the pathogenic variant identified in the proband and:
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband is extremely low. The sibs of a proband with clinically unaffected parents are still at increased risk for C3G because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.
## Other Etiologies – Risk to Family Members
## Related Genetic Counseling Issues
See Management,
Other autoimmune diseases, in particular diabetes mellitus type 1 and
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Cedar Rapids IA
Canada
•
•
• Cedar Rapids IA
•
•
• Canada
•
•
•
•
•
## Molecular Genetics
C3 Glomerulopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for C3 Glomerulopathy (
The complement system, composed of the classic pathway and the alternate pathway, is a component of the immune system that enhances the function of antibodies and phagocytes. C3 glomerulopathy (C3G) is caused by uncontrolled activation of the complement alternative pathway.
With the exception of
Familial cases of C3G are uncommon and when identified are most often highly penetrant heterozygous copy number variants involving the
Since C3G is rarely inherited in a simple mendelian fashion, the study of rare variants and haplotypes associated with disease is important.
Several studies have shown that some common variants in complement genes are also associated with C3G and increase the odds ratio of developing disease [
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
A report of two sisters with DDD who were homozygous for the
Studies of skin fibroblasts from a child with fH deficiency and chronic hypocomplementemic renal disease and abnormal fH localization. One copy of a
Two brothers with MPGN were reportedly homozygous for a
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Variants listed in the table have been provided by the authors.
The presence of
c-4C>T – in the Kozac sequence. This noncoding variant is associated with DDD [
p.Gly57Asp – in FIMAC domain, a region for fI-C3b degradation [
c.Ala240Gly – in LDL receptor class A 1 and associated with C3G, aHUS, and AMD. The variant results in partial reduction in secretion [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
p.Gln43Ter [
p.Lys101Ter [
c.610delA [
p.Trp322Ter [
p.Trp350Ter [
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
In the kidney, DGKE is ubiquitously expressed in podocytes and endothelial cells. Although
• A report of two sisters with DDD who were homozygous for the
• Studies of skin fibroblasts from a child with fH deficiency and chronic hypocomplementemic renal disease and abnormal fH localization. One copy of a
• Two brothers with MPGN were reportedly homozygous for a
• c-4C>T – in the Kozac sequence. This noncoding variant is associated with DDD [
• p.Gly57Asp – in FIMAC domain, a region for fI-C3b degradation [
• c.Ala240Gly – in LDL receptor class A 1 and associated with C3G, aHUS, and AMD. The variant results in partial reduction in secretion [
• p.Gln43Ter [
• p.Lys101Ter [
• c.610delA [
• p.Trp322Ter [
• p.Trp350Ter [
## Molecular Pathogenesis
The complement system, composed of the classic pathway and the alternate pathway, is a component of the immune system that enhances the function of antibodies and phagocytes. C3 glomerulopathy (C3G) is caused by uncontrolled activation of the complement alternative pathway.
With the exception of
Familial cases of C3G are uncommon and when identified are most often highly penetrant heterozygous copy number variants involving the
Since C3G is rarely inherited in a simple mendelian fashion, the study of rare variants and haplotypes associated with disease is important.
Several studies have shown that some common variants in complement genes are also associated with C3G and increase the odds ratio of developing disease [
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
A report of two sisters with DDD who were homozygous for the
Studies of skin fibroblasts from a child with fH deficiency and chronic hypocomplementemic renal disease and abnormal fH localization. One copy of a
Two brothers with MPGN were reportedly homozygous for a
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Variants listed in the table have been provided by the authors.
The presence of
c-4C>T – in the Kozac sequence. This noncoding variant is associated with DDD [
p.Gly57Asp – in FIMAC domain, a region for fI-C3b degradation [
c.Ala240Gly – in LDL receptor class A 1 and associated with C3G, aHUS, and AMD. The variant results in partial reduction in secretion [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
p.Gln43Ter [
p.Lys101Ter [
c.610delA [
p.Trp322Ter [
p.Trp350Ter [
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
In the kidney, DGKE is ubiquitously expressed in podocytes and endothelial cells. Although
• A report of two sisters with DDD who were homozygous for the
• Studies of skin fibroblasts from a child with fH deficiency and chronic hypocomplementemic renal disease and abnormal fH localization. One copy of a
• Two brothers with MPGN were reportedly homozygous for a
• c-4C>T – in the Kozac sequence. This noncoding variant is associated with DDD [
• p.Gly57Asp – in FIMAC domain, a region for fI-C3b degradation [
• c.Ala240Gly – in LDL receptor class A 1 and associated with C3G, aHUS, and AMD. The variant results in partial reduction in secretion [
• p.Gln43Ter [
• p.Lys101Ter [
• c.610delA [
• p.Trp322Ter [
• p.Trp350Ter [
##
Variants listed in the table have been provided by the authors.
##
##
Variants listed in the table have been provided by the authors.
##
A report of two sisters with DDD who were homozygous for the
Studies of skin fibroblasts from a child with fH deficiency and chronic hypocomplementemic renal disease and abnormal fH localization. One copy of a
Two brothers with MPGN were reportedly homozygous for a
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• A report of two sisters with DDD who were homozygous for the
• Studies of skin fibroblasts from a child with fH deficiency and chronic hypocomplementemic renal disease and abnormal fH localization. One copy of a
• Two brothers with MPGN were reportedly homozygous for a
##
Variants listed in the table have been provided by the authors.
##
The presence of
##
c-4C>T – in the Kozac sequence. This noncoding variant is associated with DDD [
p.Gly57Asp – in FIMAC domain, a region for fI-C3b degradation [
c.Ala240Gly – in LDL receptor class A 1 and associated with C3G, aHUS, and AMD. The variant results in partial reduction in secretion [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• c-4C>T – in the Kozac sequence. This noncoding variant is associated with DDD [
• p.Gly57Asp – in FIMAC domain, a region for fI-C3b degradation [
• c.Ala240Gly – in LDL receptor class A 1 and associated with C3G, aHUS, and AMD. The variant results in partial reduction in secretion [
##
p.Gln43Ter [
p.Lys101Ter [
c.610delA [
p.Trp322Ter [
p.Trp350Ter [
Note on variant classification: Variants listed in the table have been provided by the authors.
Note on nomenclature:
In the kidney, DGKE is ubiquitously expressed in podocytes and endothelial cells. Although
• p.Gln43Ter [
• p.Lys101Ter [
• c.610delA [
• p.Trp322Ter [
• p.Trp350Ter [
## References
## Literature Cited
## Chapter Notes
Richard JH Smith Division of Nephrology University of Iowa 200 Hawkins Drive Iowa City, IA 52242 Telephone: 319-356-3612 Fax: 319-356-4108 Email: [email protected]
Supported in part by grant RO1-DK110023 from the NIDDK (RJHS)
Johnny Cruz Corchado; University of Iowa (2011-2018)Bertha Martín, PhD (2018-present)Sanjeev Sethi, MD, PhD; Mayo Clinic (2007-2011)Richard JH Smith, MD (2007-present)Peter F Zipfel, PhD habil Prof; Hans Knöll Institute (2007-2011)
5 April 2018 (ha) Comprehensive update posted live
19 May 2011 (me) Comprehensive update posted live
2 January 2008 (rjhs/cd) Revision: clinical testing (sequence analysis) for
20 July 2007 (me) Review posted live
17 August 2005 (rjhs) Original submission
• 5 April 2018 (ha) Comprehensive update posted live
• 19 May 2011 (me) Comprehensive update posted live
• 2 January 2008 (rjhs/cd) Revision: clinical testing (sequence analysis) for
• 20 July 2007 (me) Review posted live
• 17 August 2005 (rjhs) Original submission
## Author Notes
Richard JH Smith Division of Nephrology University of Iowa 200 Hawkins Drive Iowa City, IA 52242 Telephone: 319-356-3612 Fax: 319-356-4108 Email: [email protected]
## Acknowledgments
Supported in part by grant RO1-DK110023 from the NIDDK (RJHS)
## Author History
Johnny Cruz Corchado; University of Iowa (2011-2018)Bertha Martín, PhD (2018-present)Sanjeev Sethi, MD, PhD; Mayo Clinic (2007-2011)Richard JH Smith, MD (2007-present)Peter F Zipfel, PhD habil Prof; Hans Knöll Institute (2007-2011)
## Revision History
5 April 2018 (ha) Comprehensive update posted live
19 May 2011 (me) Comprehensive update posted live
2 January 2008 (rjhs/cd) Revision: clinical testing (sequence analysis) for
20 July 2007 (me) Review posted live
17 August 2005 (rjhs) Original submission
• 5 April 2018 (ha) Comprehensive update posted live
• 19 May 2011 (me) Comprehensive update posted live
• 2 January 2008 (rjhs/cd) Revision: clinical testing (sequence analysis) for
• 20 July 2007 (me) Review posted live
• 17 August 2005 (rjhs) Original submission
Disease-specific characteristic IF, EM, and LM biopsy images in C3 glomerulopathy (C3G)
A. Immunofluoresence (IF) shows bright staining for C3, which must be at least two orders of magnitude greater than any other immune reactant. Note the diffuse glomerular capillary C3 IF in this case.
B. EM of a glomerulus with C3GN (black arrows) showing light, hump-like, and clustered deposits in the mesangium and in the subendothelial and/or subepithelial spaces
C. EM of a glomerulus with DDD (white arrows). Note that the DDD deposits appear denser and more ribbon-like than the C3GN deposits.
D. LM showing mesangial proliferation with obliteration of glomerular capillaries and a robust inflammatory infiltrate
Schematic representation of disease types
Post-infectious glomerulonephritis (PIGN), C3 glomerulopathy (C3G), and other disease types fall under the classification "glomerular diseases with dominant C3" immunofluorescence (IF) staining, with the term "dominant" denoting an IF C3 intensity at least two orders of magnitude greater than any other immune reactant. C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) are subtypes of C3G.
Complement factor H-related hybrid proteins and C3G
Adapted from
Complement alternative pathway (AP)
Left. Three phases of complement activity are illustrated:
Phase 1. Initiation of a "tick-over," or the spontaneous activation of the AP, occurs through the hydrolysis of C3 to C3(H
Phase 2. Amplification of cleavage of C3 into C3a and C3b provides a source of C3b, from which additional C3 convertase is generated in a robust amplification process. Complement factor H (fH) and complement factor I (fI) are important regulators of complement activity, while properdin (fP) potentiates complement activity. Persistent amplification ultimately leads to generation of C5 convertase and triggering of the terminal pathway of complement.
Phase 3. Effector in further pathway continues unchecked; C5 convertase is formed. This serine protease cleaves C5 into C5a and C5b. C5b associates with C6, C7, C8, and C9 to generate the membrane attack complex (MAC). Multiple different levels of investigation are required to evaluate the complement system. Simply measuring C3 and C4 serum levels is not adequate. Obtaining detailed data on complement is comparable to adding pieces to a puzzle, and allows for a more complete picture of complement activity in the individual with C3G.
Right. A comprehensive analysis includes the following:
A. Genetic testing
B. Screening for autoantibodies (acquired drivers of disease)
C. Measuring complement biomarkers (complement proteins and their breakdown products)
D. Quantitating complement pathway activity
Schematic representation of complement component C3
The structural organization of C3 contains eight macroglobulins, anaphylatoxin (ANA), αNT, CUB (C1r/C1s, Uegf, Bmp1), C345C, linker, and thioester (TED) domains.
Schematic representation of factor H
The 20 bead-like homologous short consensus repeats (SCRs) each have 60 amino acids. The first four SCRs (1-4) (red beads) regulate activation in the fluid phase, binding to C3b, decay acceleration activity, and fI cofactor activity. The last two SCRs (19-20) (green beads) bind to cell surfaces and regulate complement activity on cells.
|
[
"MA Abrera-Abeleda, C Nishimura, K Frees, M Jones, T Maga, LM Katz, Y Zhang, RJH Smith. Allele variants of complement genes associated with dense deposit disease.. J Am Soc Nephrol. 2011;22:1551-9",
"MA Abrera-Abeleda, C Nishimura, JL Smith, S Sethi, JL McRae, BF Murphy, G Silvestri, C Skerka, M Józsi, PF Zipfel, GS Hageman, RJ Smith. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).. J Med Genet. 2006;43:582-9",
"JR Angelo, CS Bell, MC Braun. Allograft failure in kidney transplant recipients with membranoproliferative glomerulonephritis.. Am J Kidney Dis. 2011;57:291-9",
"GB Appel, HT Cook, G Hageman, JC Jennette, M Kashgarian, M Kirschfink, JD Lambris, L Lanning, HU Lutz, S Meri, NR Rose, DJ Salant, S Sethi, RJ Smith, W Smoyer, HF Tully, SP Tully, P Walker, M Welsh, R Wurzner, PF Zipfel. Membranoproliferative glomerulonephritis type II (dense deposit disease): an update.. J Am Soc Nephrol 2005;16:1392-403",
"Y Athanasiou, K Voskarides, DP Gale, L Damianou, C Patsias, M Zavros, PH Maxwell, HT Cook, P Demosthenous, A Hadjisavvas, K Kyriacou, I Zouvani, A Pierides, C Deltas. Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.. Clin J Am Soc Nephrol 2011;6:1436-46",
"BH Ault, BZ Schmidt, NL Fowler, CE Kashtan, AE Ahmed, BA Vogt, HR Colten. Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism.. J Biol Chem 1997;272:25168-75",
"K Azukaitis, E Simkova, MA Majid, M Galiano, K Benz, K Amann, C Bockmeyer, R Gajjar, KE Meyers, HI Cheong, B Lange-Sperandio, T Jungraithmayr, V Fremeaux-Bacchi, C Bergmann, C Bereczki, M Miklaszewska, D Csuka, Z Prohászka, P Gipson, MG Sampson, M Lemaire, F Schaefer. The phenotypic spectrum of nephropathies associated with mutations in diacylglycerol kinase ε.. J Am Soc Nephrol. 2017;28:3066-75",
"TD Barbour, MC Pickering, HT Cook. Recent insights into C3 glomerulopathy.. Nephrol Dial Transplant. 2013a;28:1685-93",
"TD Barbour, MC Pickering, H Terence Cook. Dense deposit disease and C3 glomerulopathy.. Semin Nephrol. 2013b;33:493-507",
"N Besbas, B Gulhan, S Gucer, E Korkmaz, F. Ozaltin. A novel CFHR5 mutation associated with C3 glomerulonephritis in a Turkish girl.. J Nephrol. 2014;27:457-60",
"C Blanc, SK Togarsimalemath, S Chauvet, M Le Quintrec, B Moulin, M Buchler, TS Jokiranta, LT Roumenina, V Fremeaux-Bacchi, MA Dragon-Durey. Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target, two diseases.. J Immunol 2015;194:5129-38",
"AS Bomback, RJ Smith, GR Barile, Y Zhang, EC Heher, L Herlitz, MB Stokes, GS Markowitz, VD D'Agati, PA Canetta, J Radhakrishnan, GB Appel. Eculizumab for dense deposit disease and C3 glomerulonephritis.. Clin J Am Soc Nephrol. 2012;7:748-56",
"F Bu, NG Borsa, MB Jones, E Takanami, C Nishimura, JJ Hauer, H Azaiez, EA Black-Ziegelbein, NC Meyer, DL Kolbe, Y Li, K Frees, MJ Schnieders, C Thomas, C Nester, RJ Smith. High-throughput genetic testing for thrombotic microangiopathies and C3 glomerulopathies.. J Am Soc Nephrol. 2016;27:1245-53",
"JS Cameron, DR Turner, J Heaton, DG Williams, CS Ogg, C Chantler, GB Haycock, J Hicks. Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis.. Am J Med 1983;74:175-92",
"Z Cebeci, S Bayraktar, M Oray, N Kir. Multimodal imaging of membranoproliferative glomerulonephritis type II.. Saudi J Ophthalmol. 2016;30:260-3",
"S Chauvet, V Fremeaux-Bacchi, F Petitprez, A Karras, L Daniel, S Burtey, G Choukroun, Y Delmas, D Guerrot, A François, M Le Quintrec, V Javaugue, D Ribes, L Vrigneaud, B Arnulf, JM Goujon, P Ronco, G Touchard, F Bridoux. Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy.. Blood. 2017;129:1437-47",
"Q Chen, D Muller, B Rudolph, A Hartmann, E Kuwertz-Broking, K Wu, M Kirschfink, C Skerka, PF Zipfel. Combined C3b and factor B autoantibodies and MPGN type II.. N Engl J Med 2011;365:2340-2",
"Q Chen, M Wiesener, HU Eberhardt, A Hartmann, B Uzonyi, M Kirschfink, K Amann, M Buettner, T Goodship, C Hugo, C Skerka, PF Zipfel. Complement factor H-related hybrid protein deregulates complement in dense deposit disease.. J Clin Invest. 2014;124:145-55",
"HT Cook. C3 glomerulopathy.. F1000Res. 2017;6:248",
"VD D'Agati, AS Bomback. C3 glomerulopathy: what's in a name?. Kidney Int. 2012;82:379-81",
"E Daina, M Noris, G Remuzzi. Eculizumab in a patient with dense-deposit disease.. N Engl J Med. 2012;366:1161-3",
"LA Dalvin, FC Fervenza, S Sethi, JS Pulido. Shedding light on fundus drusen associated with membranoproliferative glomerulonephritis: breaking stereotypes of types I, II, and III.. Retin Cases Brief Rep. 2016;10:72-8",
"C Deltas, D Gale, T Cook, K Voskarides, Y Athanasiou, A. Pierides. C3 glomerulonephritis/CFHR5 nephropathy is an endemic disease in Cyprus: clinical and molecular findings in 21 families.. Adv Exp Med Biol. 2013;735:189-96",
"MA Dragon-Durey, V Fremeaux-Bacchi, C Loirat, J Blouin, P Niaudet, G Deschenes, P Coppo, W Herman Fridman, L Weiss. Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases.. J Am Soc Nephrol 2004;15:787-95",
"YB D'Souza, CJ Jones, CD Short, IS Roberts, RE Bonshek. Oligosaccharide composition is similar in drusen and dense deposits in membranoproliferative glomerulonephritis type II.. Kidney Int. 2009;75:824-7",
"AJ Eisinger, JR Shortland, PJ Moorhead. Renal disease in partial lipodystrophy.. Q J Med. 1972;41:343-54",
"CJ Fang, V Fremeaux-Bacchi, MK Liszewski, G Pianetti, M Noris, TH Goodship, JP Atkinson. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome.. Blood. 2008;111:624-32",
"V Fremeaux-Bacchi, F Fakhouri, A Garnier, F Bienaimé, MA Dragon-Durey, S Ngo, B Moulin, A Servais, F Provot, L Rostaing, S Burtey, P Niaudet, G Deschênes, Y Lebranchu, J Zuber, C Loirat. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.. Clin J Am Soc Nephrol. 2013;8:554-62",
"V Fremeaux-Bacchi, F Fakhouri, C. Loirat. Hemolytic-uremic syndrome: what is the mechanism?. Rev Prat. 2008;58:2093-6",
"V Fremeaux-Bacchi, L Weiss, P Brun, MD Kazatchkine. Selective disappearance of C3NeF IgG autoantibody in the plasma of a patient with membranoproliferative glomerulonephritis following renal transplantation.. Nephrol Dial Transplant. 1994;9:811-4",
"T Fujita, K Nozu, K Iijima, I Kamioka, H Kaito, R Tanaka, K Nakanishi, M Matsuo, N Yoshikawa. Long-term follow-up of juvenile acute nonproliferative glomerulitis (JANG).. Pediatr Nephrol. 2007;22:1957-61",
"DP Gale, EG de Jorge, HT Cook, R Martínez-Barricarte, A Hadjisavvas, AG McLean, CD Pusey, A Pierides, K Kyriacou, Y Athanasiou, K Voskarides, C Deltas, A Palmer, V Fremeaux-Bacchi, SR de Cordoba, PH Maxwell, MC Pickering. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.. Lancet. 2010;376:794-801",
"E Goicoechea de Jorge, DP Gale, HT Cook, A Martínez-Barricate, A Hadjisavvas, CD Pusey, A Palmer, V Fremeaux-Bacchi, S Rodriguez de Cordoba, PH Maxwell, MC Pickering. A mutant complement factor H-related 5 protein is associated with familial C3 glomerulonephritis.. Mol Immunol. 2009;46:2822",
"B Gold, JE Merriam, J Zernant, LS Hancox, AJ Taiber, K Gehrs, K Cramer, J Neel, J Bergeron, GR Barile, RT Smith, GS Hageman, M Dean, R Allikmets. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.. Nat Genet. 2006;38:458-62",
"TH Goodship, HT Cook, F Fakhouri, FC Fervenza, V Fremeaux-Bacchi, D Kavanagh, CM Nester, M Noris, MC Pickering, S Rodríguez de Córdoba, LT Roumenina, S Sethi, RJ Smith. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a \"Kidney Disease: Improving Global Outcomes\" (KDIGO) Controversies Conference.. Kidney Int. 2017;91:539-51",
"R Habib, MC Gubler, C Loirat, HB Maiz, M Levy. Dense deposit disease: a variant of membranoproliferative glomerulonephritis.. Kidney Int 1975;7:204-15",
"GS Hageman, DH Anderson, LV Johnson, LS Hancox, AJ Taiber, LI Hardisty, JL Hageman, HA Stockman, JD Borchardt, KM Gehrs, RJ Smith, G Silvestri, SR Russell, CC Klaver, I Barbazetto, S Chang, LA Yannuzzi, GR Barile, JC Merriam, RT Smith, AK Olsh, J Bergeron, J Zernant, JE Merriam, B Gold, M Dean, R Allikmets. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.. Proc Natl Acad Sci U S A 2005;102:7227-32",
"JD Hulleman. Malattia Leventinese/Doyne honeycomb retinal dystrophy: similarities to age-related macular degeneration and potential therapies.. Adv Exp Med Biol. 2016;854:153-8",
"P Iatropoulos, M Noris, C Mele, R Piras, E Valoti, E Bresin, M Curreri, E Mondo, A Zito, S Gamba, S Bettoni, L Murer, V Fremeaux-Bacchi, M Vivarelli, F Emma, E Daina, G Remuzzi. Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome.. Mol Immunol. 2016;71:131-42",
"H Imamura, T Konomoto, E Tanaka, S Hisano, Y Yoshida, Y Fujimura, T Miyata, H. Nunoi. Familial C3 glomerulonephritis associated with mutations in the gene for complement factor B.. Nephrol Dial Transplant. 2015;30:862-4",
"SA Johnson, EK Wong, CM Taylor. Making sense of the spectrum of glomerular disease associated with complement dysregulation.. Pediatr Nephrol. 2014;29:1883-94",
"N. Kambham. Postinfectious glomerulonephritis.. Adv Anat Pathol. 2012;19:338-47",
"MA Khalighi, S Wang, KJ Henriksen, M Bock, M Keswani, SM Meehan, A Chang. Revisiting post-infectious glomerulonephritis in the emerging era of C3 glomerulopathy.. Clin Kidney J. 2016;9:397-402",
"Y Kobayashi, S Yang, K Nykamp, J Garcia, SE Lincoln, SE Topper. Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.. Genome Med 2017;9:13",
"KA Kurtz, AJ Schlueter. Management of membranoproliferative glomerulonephritis type II with plasmapheresis.. J Clin Apher 2002;17:135-7",
"M Lemaire, V Fremeaux-Bacchi, F Schaefer, M Choi, WH Tang, M Le Quintrec, F Fakhouri, S Taque, F Nobili, F Martínez, W Ji, JD Overton, SM Mane, G Nürnberg, J Altmüller, H Thiele, D Morin, G Deschenes, V Baudouin, B Llanas, L Collard, MA Majid, E Simkova, P Nürnberg, N Rioux-Leclerc, GW Moeckel, MC Gubler, J Hwa, C Loirat, RP Lifton. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.. Nat Genet. 2013;45:531-6",
"C Licht, V Fremeaux-Bacchi. Hereditary and acquired complement dysregulation in membranoproliferative glomerulonephritis.. Thromb Haemost. 2009;101:271-8",
"C Licht, S Heinen, M Jozsi, I Loschmann, RE Saunders, SJ Perkins, C Skerka, M Kirschfink, B Hoppe, PF Zipfel. Deletion of Lys224 in regulatory domain 4 of factor H reveals a novel pathomechanism for dense deposit disease (MPGNII).. Kidney Int 2006;70:42-50",
"MK Liszewski, JP Atkinson. Complement regulator CD46: genetic variants and disease associations.. Hum Genomics. 2015;9:7",
"DF Lu, AM McCarthy, LD Lanning, C Delaney, C Porter. A descriptive study of individuals with membranoproliferative glomerulonephritis.. Nephrol Nurs J. 2007;34:295-302",
"DF Lu, M Moon, LD Lanning, AM McCarthy, RJ Smith. Clinical features and outcomes of 98 children and adults with dense deposit disease.. Pediatr Nephrol. 2012;27:773-81",
"TH Malik, PJ Lavin, E Goicoechea de Jorge, KA Vernon, KL Rose, MP Patel, M de Leeuw, JJ Neary, PJ Conlon, MP Winn, MC Pickering. A hybrid CFHR3-1 gene causes familial C3 glomerulopathy.. J Am Soc Nephrol. 2012;23:1155-60",
"SD Marks, L Rees. Spontaneous clinical improvement in dense deposit disease.. Pediatr Nephrol 2000;14:322-4",
"R Martínez-Barricarte, M Heurich, F Valdes-Cañedo, E Vazquez-Martul, E Torreira, T Montes, A Tortajada, S Pinto, M Lopez-Trascasa, BP Morgan, O Llorca, CL Harris, S Rodríguez de Córdoba. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation.. J Clin Invest. 2010;120:3702-12",
"PW Mathieson, DK Peters. Lipodystrophy in MCGN type II: the clue to links between the adipocyte and the complement system.. Nephrol Dial Transplant. 1997;12:1804-6",
"JA McCaughan, DM O'Rourke, AE Courtney. Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies.. Am J Transplant. 2012;12:1046-51",
"JL McRae, PJ Cowan, DA Power, KI Mitchelhill, BE Kemp, BP Morgan, BF Murphy. Human factor H-related protein 5 (FHR-5). A new complement-associated protein.. J Biol Chem 2001;276:6747-54",
"JL McRae, TG Duthy, KM Griggs, RJ Ormsby, PJ Cowan, BA Cromer, WJ McKinstry, MW Parker, BF Murphy, DL Gordon. Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein.. J Immunol 2005;174:6250-6",
"N Medjeral-Thomas, TH Malik, MP Patel, T Toth, HT Cook, C Tomson, MC Pickering. A novel CFHR5 fusion protein causes C3 glomerulopathy in a family without Cypriot ancestry.. Kidney Int. 2014;85:933-7",
"HM Merinero, SP García, J García-Fernández, E Arjona, A Tortajada, S Rodríguez de Córdoba. Complete functional characterization of disease-associated genetic variants in the complement factor H gene.. Kidney Int. 2018;93:470-81",
"RF Mullins, N Aptsiauri, GS Hageman. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis.. Eye (Lond) 2001;15:390-5",
"B Murphy, T Georgiou, D Machet, P Hill, J McRae. Factor H-related protein-5: a novel component of human glomerular immune deposits.. Am J Kidney Dis 2002;39:24-7",
"SH Nasr, AM Valeri, GB Appel, J Sherwinter, MB Stokes, SM Said, GS Markowitz, VD D'Agati. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.. Clin J Am Soc Nephrol. 2009;4:22-32",
"J Nava, S Moran, V Figueroa, A Salinas, M Lopez, R Urbina, A Gutierrez, JL Lujan, A Orozco, R Montufar, GB Piccoli. Successful pregnancy in a CKD patient on a low-protein, supplemented diet: an opportunity to reflect on CKD and pregnancy in Mexico, an emerging country.. J Nephrol. 2017;30:877-82",
"CM Nester, RJ Smith. Complement inhibition in C3 glomerulopathy.. Semin Immunol. 2016;28:241-9",
"CM Nester, RJ Smith. Diagnosis and treatment of C3 glomerulopathy.. Clin Nephrol. 2013a;80:395-403",
"CM Nester, RJ Smith. Treatment options for C3 glomerulopathy.. Curr Opin Nephrol Hypertens. 2013b;22:231-7",
"C Nicolas, V Vuiblet, V Baudouin, MA Macher, I Vrillon, N Biebuyck-Gouge, M Dehennault, S Gié, D Morin, H Nivet, F Nobili, T Ulinski, B Ranchin, MC Marinozzi, S Ngo, V Fremeaux-Bacchi, C Pietrement. C3 nephritic factor associated with C3 glomerulopathy in children.. Pediatr Nephrol. 2014;29:85-94",
"SC Nilsson, N Kalchishkova, LA Trouw, V Fremeaux-Bacchi, BO Villoutreix, AM Blom. Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I.. Eur J Immunol. 2010;40:172-85",
"M Noris, G Remuzzi. Genetics of immune-mediated glomerular diseases: focus on complement.. Semin Nephrol 2017;37:447-63",
"M Noris, G Remuzzi. Glomerular diseases dependent on complement activation, including atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, and C3 glomerulopathy: core curriculum 2015.. Am J Kidney Dis. 2015;66:359-75",
"H Ohi, S Watanabe, T Fujita, T Yasugi. Significance of C3 nephritic factor (C3NeF) in non-hypocomplementaemic serum with membranoproliferative glomerulonephritis (MPGN).. Clin Exp Immunol 1992;89:479-84",
"AJ Osborne, M Breno, NG Borsa, F Bu, V Fremeaux-Bacchi, DP Gale, LP van den Heuvel, D Kavanagh, M Noris, S Pinto, PM Rallapalli, G Remuzzi, S Rodríguez de Cordoba, A Ruiz, RJH Smith, P Vieira-Martins, E Volokhina, V Wilson, THJ Goodship, SJ Perkins. Statistical validation of rare complement variants provides insights into the molecular basis of atypical hemolytic uremic syndrome and C3 glomerulopathy.. J Immunol 2018;200:2464-78",
"A Ossoli, F Lucca, G Boscutti, AT Remaley, L Calabresi. Familial LCAT deficiency: from pathology to enzyme replacement therapy.. Clinical Lipidology. 2015;10:405-13",
"F Ozaltin, B Li, A Rauhauser, SW An, O Soylemezoglu, II Gonul, EZ Taskiran, T Ibsirlioglu, E Korkmaz, Y Bilginer, A Duzova, S Ozen, R Topaloglu, N Besbas, S Ashraf, Y Du, C Liang, P Chen, D Lu, K Vadnagara, S Arbuckle, D Lewis, B Wakeland, RJ Quigg, RF Ransom, EK Wakeland, MK Topham, NG Bazan, C Mohan, F Hildebrandt, A Bakkaloglu, CL Huang, M Attanasio. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN.. J Am Soc Nephrol. 2013;24:377-84",
"D Paixão-Cavalcante, M López-Trascasa, L Skattum, PC Giclas, TH Goodship, SR de Córdoba, L Truedsson, BP Morgan, CL Harris. Sensitive and specific assays for C3 nephritic factors clarify mechanisms underlying complement dysregulation.. Kidney Int. 2012;82:1084-92",
"GB Piccoli, M Alrukhaimi, ZH Liu, E Zakharova, A Levin. What we do and do not know about women and kidney diseases; questions unanswered and answers unquestioned: reflection on World Kidney Day and International Woman's Day.. BMC Nephrol. 2018;19:66",
"MC Pickering, VD D'Agati, CM Nester, RJ Smith, M Haas, GB Appel, CE Alpers, IM Bajema, C Bedrosian, M Braun, M Doyle, F Fakhouri, FC Fervenza, AB Fogo, V Fremeaux-Bacchi, DP Gale, E Goicoechea de Jorge, G Griffin, CL Harris, VM Holers, S Johnson, PJ Lavin, N Medjeral-Thomas, B Paul Morgan, CC Nast, LH Noel, DK Peters, S Rodríguez de Córdoba, A Servais, S Sethi, WC Song, P Tamburini, JM Thurman, M Zavros, HT Cook. C3 glomerulopathy: consensus report.. Kidney Int. 2013;84:1079-89",
"C Rabasco, T Cavero, E Román, J Rojas-Rivera, T Olea, M Espinosa, V Cabello, G Fernández-Juarez, F González, A Ávila, JM Baltar, M Díaz, R Alegre, S Elías, M Antón, MA Frutos, A Pobes, M Blasco, F Martín, C Bernis, M Macías, S Barroso, A de Lorenzo, G Ariceta, M López-Mendoza, B Rivas, K López-Revuelta, JM Campistol, S Mendizábal, SR de Córdoba, M Praga. Effectiveness of mycophenolate mofetil in C3 glomerulonephritis.. Kidney Int. 2015;88:1153-60",
"S Recalde, A Tortajada, M Subias, J Anter, M Blasco, R Maranta, R Coco, S Pinto, M Noris, A García-Layana, S. Rodríguez de Córdoba. Molecular basis of factor H R1210C association with ocular and renal diseases.. J Am Soc Nephrol. 2016;27:1305-11",
"M Riedl, P Thorner, C. Licht. C3 glomerulopathy.. Pediatr Nephrol. 2017;32:43-57",
"S Rodríguez de Córdoba, J Esparza-Gordillo, E Goicoechea de Jorge, M Lopez-Trascasa, P Sanchez-Corral. The human complement factor H: functional roles, genetic variations and disease associations.. Mol Immunol 2004;41:355-67",
"M Salvadori, E Bertoni. Complement related kidney diseases: recurrence after transplantation.. World J Transplant. 2016;6:632-45",
"J Savige, L Amos, F Ierino, HG Mack, RC Symons, P Hughes, K Nicholls, D Colville. Retinal disease in the C3 glomerulopathies and the risk of impaired vision.. Ophthalmic Genet. 2016;37:369-76",
"R Schwertz, U Rother, D Anders, N Gretz, K Scharer, M Kirschfink. Complement analysis in children with idiopathic membranoproliferative glomerulonephritis: a long-term follow-up.. Pediatr Allergy Immunol. 2001;12:166-72",
"A Servais, V Fremeaux-Bacchi, M Lequintrec, R Salomon, J Blouin, B Knebelmann, JP Grünfeld, P Lesavre, LH Noël, F Fakhouri. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.. J Med Genet. 2007;44:193-9",
"A Servais, LH Noël, V Fremeaux-Bacchi, P Lesavre. C3 glomerulopathy.. Contrib Nephrol. 2013;181:185-93",
"A Servais, LH Noel, LT Roumenina, M Le Quintrec, S Ngo, MA Dragon-Durey, MA Macher, J Zuber, A Karras, F Provot, B Moulin, JP Grünfeld, P Niaudet, P Lesavre, V Fremeaux-Bacchi. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.. Kidney Int. 2012;82:454-64",
"A Sessa, G Battini, M Meroni, G Daidone, I Carnera, PL Brambilla, G Vigano, F Giordano, F Pallotti, L Torri Tarelli, L Calabresi, M Rolleri, S Bertolini. Hypocomplementemic type II membranoproliferative glomerulonephritis in a male patient with familial lecithin-cholesterol acyltransferase deficiency due to two different allelic mutations.. Nephron 2001;88:268-72",
"S Sethi, FC Fervenza. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification.. Semin Nephrol. 2011;31:341-8",
"S Sethi, FC Fervenza, Y Zhang, L Zand, NC Meyer, N Borsa, SH Nasr, RJ Smith. Atypical post-infectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement.. Kidney Int. 2013;83:293-9",
"S Sethi, FC Fervenza, Y Zhang, L Zand, JA Vrana, SH Nasr, JD Theis, A Dogan, RJ Smith. C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.. Kidney Int. 2012a;82:465-73",
"S Sethi, M Haas, GS Markowitz, VD D'Agati, HG Rennke, JC Jennette, IM Bajema, CE Alpers, A Chang, LD Cornell, FG Cosio, AB Fogo, RJ Glassock, S Hariharan, N Kambham, DJ Lager, N Leung, M Mengel, KA Nath, IS Roberts, BH Rovin, SV Seshan, RJ Smith, PD Walker, CG Winearls, GB Appel, MP Alexander, DC Cattran, CA Casado, HT Cook, AS De Vriese, J Radhakrishnan, LC Racusen, P Ronco, FC Fervenza. Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN.. J Am Soc Nephrol. 2016;27:1278-87",
"S Sethi, CM Nester, RJ Smith. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.. Kidney Int. 2012b;81:434-41",
"RJ Smith, J Alexander, PN Barlow, M Botto, TL Cassavant, HT Cook, SR de Cordoba, GS Hageman, TS Jokiranta, WJ Kimberling, JD Lambris, LD Lanning, V Levidiotis, C Licht, HU Lutz, S Meri, MC Pickering, RJ Quigg, AL Rops, DJ Salant, S Sethi, JM Thurman, HF Tully, SP Tully, J van der Vlag, PD Walker, R Wurzner, PF Zipfel. New approaches to the treatment of dense deposit disease.. J Am Soc Nephrol 2007;18:2447-56",
"EH Sohn, K Wang, S Thompson, MJ Riker, JM Hoffmann, EM Stone, RF Mullins. Comparison of drusen and modifying genes in autosomal dominant radial drusen and age-related macular degeneration.. Retina. 2015;35:48-57",
"F. Sotsiou. Postinfectious glomerulonephritis.. Nephrol Dial Transplant. 2001;16:68-70",
"RE Spitzer, AE Stitzel. Loss of autoantibody activity by alteration in autoantigen.. Clin Immunol Immunopathol 1996;80:211-3",
"EM Stone, AJ Lotery, FL Munier, E Heon, B Piguet, RH Guymer, K Vandenburgh, P Cousin, D Nishimura, RE Swiderski, G Silvestri, DA Mackey, GS Hageman, AC Bird, VC Sheffield, DF Schorderet. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy.. Nat Genet 1999;22:199-202",
"S Strobel, M Zimmering, K Papp, J Prechl, M. Józsi. Anti-factor B autoantibody in dense deposit disease.. Mol Immunol. 2010;47:1476-83",
"S Thomas, D Ranganathan, L Francis, K Madhan, GT John. Current concepts in C3 glomerulopathy.. Indian J Nephrol. 2014;24:339-48",
"SK Togarsimalemath, SK Sethi, R Duggal, ML Quintrec, P Jha, R Daniel, F Gonnet, S Bansal, LT Roumenina, V Fremeaux-Bacchi, V Kher, MA Dragon-Durey. A novel CFHR1-CFHR5 hybrid leads to a familial dominant C3 glomerulopathy.. Kidney Int. 2017;92:876-87",
"A Tortajada, H Yébenes, C Abarrategui-Garrido, J Anter, JM García-Fernández, R Martínez-Barricarte, M Alba-Domínguez, TH Malik, R Bedoya, R Cabrera Pérez, M López Trascasa, MC Pickering, CL Harris, P Sánchez-Corral, O Llorca, S Rodríguez de Córdoba. C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation.. J Clin Invest. 2013;123:2434-46",
"KA Vernon, E Goicoechea de Jorge, AE Hall, V Fremeaux-Bacchi, TJ Aitman, HT Cook, R Hangartner, A Koziell, MC Pickering. Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency.. Am J Kidney Dis. 2012;60:121-5",
"M Vivarelli, F. Emma. Treatment of C3 glomerulopathy with complement blockers.. Semin Thromb Hemost. 2014;40:472-7",
"PD Walker, F Ferrario, K Joh, SM Bonsib. Dense deposit disease is not a membranoproliferative glomerulonephritis.. Mod Pathol 2007;20:605-16",
"CD West, AJ McAdams, DP Witte. Acute non-proliferative glomerulitis: a cause of renal failure unique to children.. Pediatr Nephrol 2000;14:786-93",
"R Westland, M Bodria, A Carrea, S Lata, F Scolari, V Fremeaux-Bacchi, VD D'Agati, RP Lifton, AG Gharavi, GM Ghiggeri, S Sanna-Cherchi. Phenotypic expansion of DGKE-associated diseases.. J Am Soc Nephrol. 2014;25:1408-14",
"X Xiao, C Ghossein, A Tortajada, Y Zhang, N Meyer, M Jones, NG Borsa, CM Nester, CP Thomas, SR de Córdoba, RJ Smith. Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene.. Mol Immunol. 2016;77:89-96",
"X Xiao, MC Pickering, RJH Smith. C3 glomerulopathy: the genetic and clinical findings in dense deposit disease and C3 glomerulonephritis.. Semin Thromb Hemost 2014;40:465-71",
"L Zand, EC Lorenz, FG Cosio, FC Fervenza, SH Nasr, MJ Gandhi, RJ Smith, S Sethi. Clinical findings, pathology, and outcomes of C3GN after kidney transplantation.. J Am Soc Nephrol. 2014;25:1110-7",
"Y Zhang, NC Meyer, FC Fervenza, W Lau, A Keenan, G Cara-Fuentes, D Shao, A Akber, V Fremeaux-Bacchi, S Sethi, CM Nester, RJ Smith. C4 nephritic factors in C3 glomerulopathy: a case series.. Am J Kidney Dis. 2017;70:834-43",
"Y Zhang, NC Meyer, K Wang, C Nishimura, K Frees, M Jones, LM Katz, S Sethi, RJ Smith. Causes of alternative pathway dysregulation in dense deposit disease.. Clin J Am Soc Nephrol. 2012;7:265-74",
"Y Zhang, CM Nester, DG Holanda, HC Marsh, RA Hammond, LJ Thomas, NC Meyer, LG Hunsicker, S Sethi, RJ Smith. Soluble CR1 therapy improves complement regulation in C3 glomerulopathy.. J Am Soc Nephrol. 2013;24:1820-9",
"J Zhu, M Chaki, D Lu, C Ren, SS Wang, A Rauhauser, B Li, S Zimmerman, B Jun, Y Du, K Vadnagara, H Wang, S Elhadi, RJ Quigg, MK Topham, C Mohan, F Ozaltin, XJ Zhou, DK Marciano, NG Bazan, M Attanasio. Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production.. Am J Physiol Renal Physiol. 2016;310:F895-908",
"PF Zipfel, C Skerka, Q Chen, T Wiech, T Goodship, S Johnson, V Fremeaux-Bacchi, C Nester, SR de Córdoba, M Noris, M Pickering, R Smith. The role of complement in C3 glomerulopathy.. Mol Immunol. 2015;67:21-30"
] |
20/7/2007
|
5/4/2018
|
2/1/2008
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mpph
|
mpph
|
[
"Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome",
"Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome",
"G1/S-specific cyclin-D2",
"Phosphatidylinositol 3-kinase regulatory subunit beta",
"RAC-gamma serine/threonine-protein kinase",
"AKT3",
"CCND2",
"PIK3R2",
"MPPH Syndrome"
] |
MPPH Syndrome
|
Ghayda Mirzaa
|
Summary MPPH ( The clinical diagnosis of MPPH syndrome can be established in individuals with the two core features: megalencephaly and polymicrogyria (PMG). The molecular diagnosis of MPPH syndrome is established in a proband with some of the suggestive clinical and imaging features by identification of a heterozygous pathogenic variant in one of three genes: MPPH syndrome is an autosomal dominant disorder typically caused by a
|
## Diagnosis
MPPH syndrome
Postaxial polydactyly of one or more extremities
Hypotonia
Early-onset epilepsy
Intellectual disability
Oromotor dysfunction (including speech/swallowing difficulties, excessive drooling, expressive speech delays)
Progressive ventriculomegaly leading to hydrocephalus
Cerebellar tonsillar ectopia or Chiari malformations
Thick corpus callosum (or mega corpus callosum)
The
The
Note: Failure to detect either a germline or somatic mosaic pathogenic variant in one of these three genes does not exclude a clinical diagnosis of MPPH syndrome in a proband with the two core clinical and imaging features.
Molecular genetic testing approaches used to identify germline and somatic pathogenic variants can include use of a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
If no germline pathogenic variant is found in any of the three genes, sequence analysis for
Note: Sensitivity to detect low-level mosaicism of a somatic pathogenic variant is greatest using massively parallel sequencing (i.e., next-generation sequencing) in tissues other than blood, and in particular will be of high yield when analyzing affected tissues.
Molecular Genetic Testing Used in MPPH Syndrome
See
References for the 41 individuals with a molecularly confirmed diagnosis:
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Duplications of 1q43-q44, which include
Mosaicism for a
Most individuals with a
• Postaxial polydactyly of one or more extremities
• Hypotonia
• Early-onset epilepsy
• Intellectual disability
• Oromotor dysfunction (including speech/swallowing difficulties, excessive drooling, expressive speech delays)
• Progressive ventriculomegaly leading to hydrocephalus
• Cerebellar tonsillar ectopia or Chiari malformations
• Thick corpus callosum (or mega corpus callosum)
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• Note: Sensitivity to detect low-level mosaicism of a somatic pathogenic variant is greatest using massively parallel sequencing (i.e., next-generation sequencing) in tissues other than blood, and in particular will be of high yield when analyzing affected tissues.
## Suggestive Findings
MPPH syndrome
Postaxial polydactyly of one or more extremities
Hypotonia
Early-onset epilepsy
Intellectual disability
Oromotor dysfunction (including speech/swallowing difficulties, excessive drooling, expressive speech delays)
Progressive ventriculomegaly leading to hydrocephalus
Cerebellar tonsillar ectopia or Chiari malformations
Thick corpus callosum (or mega corpus callosum)
• Postaxial polydactyly of one or more extremities
• Hypotonia
• Early-onset epilepsy
• Intellectual disability
• Oromotor dysfunction (including speech/swallowing difficulties, excessive drooling, expressive speech delays)
• Progressive ventriculomegaly leading to hydrocephalus
• Cerebellar tonsillar ectopia or Chiari malformations
• Thick corpus callosum (or mega corpus callosum)
## Establishing the Diagnosis
The
The
Note: Failure to detect either a germline or somatic mosaic pathogenic variant in one of these three genes does not exclude a clinical diagnosis of MPPH syndrome in a proband with the two core clinical and imaging features.
Molecular genetic testing approaches used to identify germline and somatic pathogenic variants can include use of a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
If no germline pathogenic variant is found in any of the three genes, sequence analysis for
Note: Sensitivity to detect low-level mosaicism of a somatic pathogenic variant is greatest using massively parallel sequencing (i.e., next-generation sequencing) in tissues other than blood, and in particular will be of high yield when analyzing affected tissues.
Molecular Genetic Testing Used in MPPH Syndrome
See
References for the 41 individuals with a molecularly confirmed diagnosis:
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Duplications of 1q43-q44, which include
Mosaicism for a
Most individuals with a
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• Note: Sensitivity to detect low-level mosaicism of a somatic pathogenic variant is greatest using massively parallel sequencing (i.e., next-generation sequencing) in tissues other than blood, and in particular will be of high yield when analyzing affected tissues.
## Clinical Characteristics
MPPH syndrome is a developmental brain disorder characterized by megalencephaly (brain overgrowth) with the cortical malformation bilateral perisylvian polymicrogyria. To date, fewer than than 100 individuals with features of MPPH syndrome have been reported with either a clinical diagnosis (presence of the 2 core clinical and imaging findings: megalencephaly and polymicrogyria) , and/or a molecularly confirmed diagnosis [
MPPH Syndrome: Frequency of Select Features
BPP = bilateral perisylvian polymicrogyria; PMG = polymicrogyria
In individuals with MPPH syndrome who develop hydrocephalus, brain overgrowth persists after surgical intervention (e.g., neurosurgical shunting), an observation consistent with true brain overgrowth [
Extent and severity of the cortical malformations (e.g., severity and distribution of PMG) (See
Age of onset and severity of epilepsy. Early-onset epilepsy (particularly in the newborn period), and generalized epilepsy are typically associated with more severe developmental and cognitive issues.
Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
Renal anomalies (e.g., duplicated renal collecting system)
Medulloblastoma [
PMG appears to be more severe and widespread, typically extending to the frontal and/or occipital lobes. These extensive cortical malformations correlate with increased severity of epilepsy and intellectual disability [
Postaxial polydactyly is more commonly observed in individuals with
In general, no differences in phenotype have been observed between individuals with a molecularly confirmed diagnosis and those with only a clinical diagnosis. The exceptions are several individuals with a molecularly confirmed diagnosis of MPPH syndrome who had BPP but lacked the core clinical feature of megalencephaly [
Penetrance is predicted to be 100% in individuals with a germline variant in
MPPH syndrome has been reported to date in fewer than 100 individuals from various ethnic backgrounds. Therefore, data regarding prevalence are limited.
• Extent and severity of the cortical malformations (e.g., severity and distribution of PMG) (See
• Age of onset and severity of epilepsy. Early-onset epilepsy (particularly in the newborn period), and generalized epilepsy are typically associated with more severe developmental and cognitive issues.
•
• Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
• Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
• Renal anomalies (e.g., duplicated renal collecting system)
• Medulloblastoma [
• Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
• Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
• Renal anomalies (e.g., duplicated renal collecting system)
• Medulloblastoma [
• Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
• Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
• Renal anomalies (e.g., duplicated renal collecting system)
• Medulloblastoma [
• PMG appears to be more severe and widespread, typically extending to the frontal and/or occipital lobes. These extensive cortical malformations correlate with increased severity of epilepsy and intellectual disability [
• Postaxial polydactyly is more commonly observed in individuals with
## Clinical Description
MPPH syndrome is a developmental brain disorder characterized by megalencephaly (brain overgrowth) with the cortical malformation bilateral perisylvian polymicrogyria. To date, fewer than than 100 individuals with features of MPPH syndrome have been reported with either a clinical diagnosis (presence of the 2 core clinical and imaging findings: megalencephaly and polymicrogyria) , and/or a molecularly confirmed diagnosis [
MPPH Syndrome: Frequency of Select Features
BPP = bilateral perisylvian polymicrogyria; PMG = polymicrogyria
In individuals with MPPH syndrome who develop hydrocephalus, brain overgrowth persists after surgical intervention (e.g., neurosurgical shunting), an observation consistent with true brain overgrowth [
Extent and severity of the cortical malformations (e.g., severity and distribution of PMG) (See
Age of onset and severity of epilepsy. Early-onset epilepsy (particularly in the newborn period), and generalized epilepsy are typically associated with more severe developmental and cognitive issues.
Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
Renal anomalies (e.g., duplicated renal collecting system)
Medulloblastoma [
• Extent and severity of the cortical malformations (e.g., severity and distribution of PMG) (See
• Age of onset and severity of epilepsy. Early-onset epilepsy (particularly in the newborn period), and generalized epilepsy are typically associated with more severe developmental and cognitive issues.
•
• Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
• Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
• Renal anomalies (e.g., duplicated renal collecting system)
• Medulloblastoma [
• Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
• Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
• Renal anomalies (e.g., duplicated renal collecting system)
• Medulloblastoma [
• Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
• Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
• Renal anomalies (e.g., duplicated renal collecting system)
• Medulloblastoma [
## Neurologic Findings
In individuals with MPPH syndrome who develop hydrocephalus, brain overgrowth persists after surgical intervention (e.g., neurosurgical shunting), an observation consistent with true brain overgrowth [
Extent and severity of the cortical malformations (e.g., severity and distribution of PMG) (See
Age of onset and severity of epilepsy. Early-onset epilepsy (particularly in the newborn period), and generalized epilepsy are typically associated with more severe developmental and cognitive issues.
• Extent and severity of the cortical malformations (e.g., severity and distribution of PMG) (See
• Age of onset and severity of epilepsy. Early-onset epilepsy (particularly in the newborn period), and generalized epilepsy are typically associated with more severe developmental and cognitive issues.
## Other Findings
Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
Renal anomalies (e.g., duplicated renal collecting system)
Medulloblastoma [
•
• Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
• Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
• Renal anomalies (e.g., duplicated renal collecting system)
• Medulloblastoma [
• Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
• Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
• Renal anomalies (e.g., duplicated renal collecting system)
• Medulloblastoma [
• Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
• Endocrine manifestations (including hypoglycemia, growth hormone deficiency, hypothyroidism, Hashimoto thyroiditis)
• Renal anomalies (e.g., duplicated renal collecting system)
• Medulloblastoma [
## Phenotype Correlations by Gene
PMG appears to be more severe and widespread, typically extending to the frontal and/or occipital lobes. These extensive cortical malformations correlate with increased severity of epilepsy and intellectual disability [
Postaxial polydactyly is more commonly observed in individuals with
• PMG appears to be more severe and widespread, typically extending to the frontal and/or occipital lobes. These extensive cortical malformations correlate with increased severity of epilepsy and intellectual disability [
• Postaxial polydactyly is more commonly observed in individuals with
## Genotype-Phenotype Correlations
In general, no differences in phenotype have been observed between individuals with a molecularly confirmed diagnosis and those with only a clinical diagnosis. The exceptions are several individuals with a molecularly confirmed diagnosis of MPPH syndrome who had BPP but lacked the core clinical feature of megalencephaly [
## Penetrance
Penetrance is predicted to be 100% in individuals with a germline variant in
## Prevalence
MPPH syndrome has been reported to date in fewer than 100 individuals from various ethnic backgrounds. Therefore, data regarding prevalence are limited.
## Genetically Related (Allelic) Disorders
Allelic Disorders
Two individuals with hemimegalencephaly with the same mosaic
Deletions resulting in presumed loss of function
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of MPPH Syndrome
AD = autosomal dominant; AR = autosomal recessive; BCC = basal cell carcinoma; BPP = bilateral perisylvian polymicrogyria; DiffDx = differential diagnosis; FCD = focal cortical dysplasia; MCAP = megalencephaly-capillary malformation; MEG = megalencephaly; MOI = mode(s) of inheritance; PMG = polymicrogyria
Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome are autosomal dominant disorders caused by either an inherited or a
## Management
To establish the extent of disease and needs in an individual diagnosed with megalencephaly-postaxial polydactyly-polymicrogyria-hydrocephalus (MPPH) syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with MPPH syndrome
To incl baseline brain MRI & careful eval for medulloblastoma, incl diffusion-weighted imaging to differentiate early neoplastic transformation w/in dysplastic cerebellar tissue & early consideration of contrast-enhanced studies in suspicious cases
In the presence of hydrocephalus &/or cerebellar tonsillar ectopia, full spinal MRI to evaluate for syringomyelia or syrinx formation
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
GHD = growth hormone deficiency; MOI = mode of inheritance; OFC = occipital frontal circumference
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with MPPH Syndrome
Rapidly enlarging OFC
Obstructive hydrocephalus
Symptoms of ↑ intracranial pressure
Progressive or symptomatic CBTE or Chiari malformation
Eval w/feeding specialist &/or gastroenterologist
Dietary modification &/or placement of a gastrostomy tube as needed
Speech therapy for difficulties w/swallowing & feeding
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Children: through early intervention programs &/or school district
Adults: referral to low vision clinic &/or community vision services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; CBTE = cerebellar tonsillar ectopia; DD/ID = developmental delay / intellectual disability; OFC = occipital frontal circumference
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Given the limited number of individuals reported with MPPH syndrome, formal surveillance guidelines do not exist.
Recommended Surveillance for Individuals with MPPH Syndrome
Eval w/pediatric neurologist
Brain MRI for hydrocephalus &/or cerebellar tonsillar ectopia
Birth ‒ 2 yrs: every 6 mos
Age 2-6 yrs: annually
Age >6 yrs: frequency of brain MRI based on prior results & clinical findings, w/particular attn to apnea or other abnormal patterns of respiration, headaches, changes in gait, or other neurologic problems.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
GHD = growth hormone deficiency
See
Search
• To incl baseline brain MRI & careful eval for medulloblastoma, incl diffusion-weighted imaging to differentiate early neoplastic transformation w/in dysplastic cerebellar tissue & early consideration of contrast-enhanced studies in suspicious cases
• In the presence of hydrocephalus &/or cerebellar tonsillar ectopia, full spinal MRI to evaluate for syringomyelia or syrinx formation
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Rapidly enlarging OFC
• Obstructive hydrocephalus
• Symptoms of ↑ intracranial pressure
• Progressive or symptomatic CBTE or Chiari malformation
• Eval w/feeding specialist &/or gastroenterologist
• Dietary modification &/or placement of a gastrostomy tube as needed
• Speech therapy for difficulties w/swallowing & feeding
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Children: through early intervention programs &/or school district
• Adults: referral to low vision clinic &/or community vision services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Eval w/pediatric neurologist
• Brain MRI for hydrocephalus &/or cerebellar tonsillar ectopia
• Birth ‒ 2 yrs: every 6 mos
• Age 2-6 yrs: annually
• Age >6 yrs: frequency of brain MRI based on prior results & clinical findings, w/particular attn to apnea or other abnormal patterns of respiration, headaches, changes in gait, or other neurologic problems.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with megalencephaly-postaxial polydactyly-polymicrogyria-hydrocephalus (MPPH) syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with MPPH syndrome
To incl baseline brain MRI & careful eval for medulloblastoma, incl diffusion-weighted imaging to differentiate early neoplastic transformation w/in dysplastic cerebellar tissue & early consideration of contrast-enhanced studies in suspicious cases
In the presence of hydrocephalus &/or cerebellar tonsillar ectopia, full spinal MRI to evaluate for syringomyelia or syrinx formation
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
GHD = growth hormone deficiency; MOI = mode of inheritance; OFC = occipital frontal circumference
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl baseline brain MRI & careful eval for medulloblastoma, incl diffusion-weighted imaging to differentiate early neoplastic transformation w/in dysplastic cerebellar tissue & early consideration of contrast-enhanced studies in suspicious cases
• In the presence of hydrocephalus &/or cerebellar tonsillar ectopia, full spinal MRI to evaluate for syringomyelia or syrinx formation
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with MPPH Syndrome
Rapidly enlarging OFC
Obstructive hydrocephalus
Symptoms of ↑ intracranial pressure
Progressive or symptomatic CBTE or Chiari malformation
Eval w/feeding specialist &/or gastroenterologist
Dietary modification &/or placement of a gastrostomy tube as needed
Speech therapy for difficulties w/swallowing & feeding
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Children: through early intervention programs &/or school district
Adults: referral to low vision clinic &/or community vision services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; CBTE = cerebellar tonsillar ectopia; DD/ID = developmental delay / intellectual disability; OFC = occipital frontal circumference
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Rapidly enlarging OFC
• Obstructive hydrocephalus
• Symptoms of ↑ intracranial pressure
• Progressive or symptomatic CBTE or Chiari malformation
• Eval w/feeding specialist &/or gastroenterologist
• Dietary modification &/or placement of a gastrostomy tube as needed
• Speech therapy for difficulties w/swallowing & feeding
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Children: through early intervention programs &/or school district
• Adults: referral to low vision clinic &/or community vision services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Surveillance
Given the limited number of individuals reported with MPPH syndrome, formal surveillance guidelines do not exist.
Recommended Surveillance for Individuals with MPPH Syndrome
Eval w/pediatric neurologist
Brain MRI for hydrocephalus &/or cerebellar tonsillar ectopia
Birth ‒ 2 yrs: every 6 mos
Age 2-6 yrs: annually
Age >6 yrs: frequency of brain MRI based on prior results & clinical findings, w/particular attn to apnea or other abnormal patterns of respiration, headaches, changes in gait, or other neurologic problems.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
GHD = growth hormone deficiency
• Eval w/pediatric neurologist
• Brain MRI for hydrocephalus &/or cerebellar tonsillar ectopia
• Birth ‒ 2 yrs: every 6 mos
• Age 2-6 yrs: annually
• Age >6 yrs: frequency of brain MRI based on prior results & clinical findings, w/particular attn to apnea or other abnormal patterns of respiration, headaches, changes in gait, or other neurologic problems.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
MPPH syndrome is an autosomal dominant disorder typically caused by a
Almost all individuals with MPPH syndrome have the disorder as the result of a
Vertical transmission of a
Parental germline mosaicism was suggested in three families by recurrence of MPPH syndrome in sibs and failure to detect the pathogenic variant in DNA isolated from parental blood samples [
Recommendations for the evaluation of parents of a proband include molecular genetic testing for the pathogenic variant identified in the proband and a baseline neurologic assessment including measurement of head size.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the proband most likely has a
Another possible explanation is parental germline (or somatic and germline) mosaicism [
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. While there may be phenotypic variability within the same family, all sibs who inherit a pathogenic variant will have features of MPPH syndrome.
If the
Each child of an individual with a germline
The risk for transmission to offspring of an individual with somatic mosaicism for an MPPH-related pathogenic variant (i.e., the pathogenic variant is thought to have occurred post-fertilization in one cell of the multicellular embryo) is expected to be less than 50%.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Once the MPPH syndrome-related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MPPH syndrome are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Almost all individuals with MPPH syndrome have the disorder as the result of a
• Vertical transmission of a
• Parental germline mosaicism was suggested in three families by recurrence of MPPH syndrome in sibs and failure to detect the pathogenic variant in DNA isolated from parental blood samples [
• Recommendations for the evaluation of parents of a proband include molecular genetic testing for the pathogenic variant identified in the proband and a baseline neurologic assessment including measurement of head size.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the proband most likely has a
• Another possible explanation is parental germline (or somatic and germline) mosaicism [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. While there may be phenotypic variability within the same family, all sibs who inherit a pathogenic variant will have features of MPPH syndrome.
• If the
• Each child of an individual with a germline
• The risk for transmission to offspring of an individual with somatic mosaicism for an MPPH-related pathogenic variant (i.e., the pathogenic variant is thought to have occurred post-fertilization in one cell of the multicellular embryo) is expected to be less than 50%.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
MPPH syndrome is an autosomal dominant disorder typically caused by a
## Risk to Family Members
Almost all individuals with MPPH syndrome have the disorder as the result of a
Vertical transmission of a
Parental germline mosaicism was suggested in three families by recurrence of MPPH syndrome in sibs and failure to detect the pathogenic variant in DNA isolated from parental blood samples [
Recommendations for the evaluation of parents of a proband include molecular genetic testing for the pathogenic variant identified in the proband and a baseline neurologic assessment including measurement of head size.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the proband most likely has a
Another possible explanation is parental germline (or somatic and germline) mosaicism [
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. While there may be phenotypic variability within the same family, all sibs who inherit a pathogenic variant will have features of MPPH syndrome.
If the
Each child of an individual with a germline
The risk for transmission to offspring of an individual with somatic mosaicism for an MPPH-related pathogenic variant (i.e., the pathogenic variant is thought to have occurred post-fertilization in one cell of the multicellular embryo) is expected to be less than 50%.
• Almost all individuals with MPPH syndrome have the disorder as the result of a
• Vertical transmission of a
• Parental germline mosaicism was suggested in three families by recurrence of MPPH syndrome in sibs and failure to detect the pathogenic variant in DNA isolated from parental blood samples [
• Recommendations for the evaluation of parents of a proband include molecular genetic testing for the pathogenic variant identified in the proband and a baseline neurologic assessment including measurement of head size.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the proband most likely has a
• Another possible explanation is parental germline (or somatic and germline) mosaicism [
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. While there may be phenotypic variability within the same family, all sibs who inherit a pathogenic variant will have features of MPPH syndrome.
• If the
• Each child of an individual with a germline
• The risk for transmission to offspring of an individual with somatic mosaicism for an MPPH-related pathogenic variant (i.e., the pathogenic variant is thought to have occurred post-fertilization in one cell of the multicellular embryo) is expected to be less than 50%.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the MPPH syndrome-related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MPPH syndrome are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
MPPH Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MPPH Syndrome (
Pathogenic gain-of-function variants in these and other genes within the pathway (including
AKT3 is a serine/threonine kinase and the principal target of phosphatidylinositol 3,4,5-trisphosphate (PIP3).
CCND2, a protein that mediates the G1-S transition of the cell cycle, is among the downstream targets of the PI3K-AKT-MTOR pathway [
MPPH Syndrome: Gene-Specific Laboratory Considerations
Genes from
MPPH Syndrome: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Pathogenic gain-of-function variants in these and other genes within the pathway (including
AKT3 is a serine/threonine kinase and the principal target of phosphatidylinositol 3,4,5-trisphosphate (PIP3).
CCND2, a protein that mediates the G1-S transition of the cell cycle, is among the downstream targets of the PI3K-AKT-MTOR pathway [
MPPH Syndrome: Gene-Specific Laboratory Considerations
Genes from
MPPH Syndrome: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
## Cancer and Benign Tumors
## Chapter Notes
Dr Ghayda Mirzaa is a clinical and molecular geneticist at the Seattle Children's Research Institute and the University of Washington School of Medicine. Her research is focused on understanding the developmental basis and genetic causes of developmental brain disorders, including brain growth abnormalities, cortical malformations, and epilepsy. Dr Mirzaa's research team studies the natural history of MPPH syndrome.
We thank our patients and their families and health care providers for their collaboration and contribution to our knowledge of MPPH syndrome.
28 July 2022 (sw) Comprehensive update posted live
17 November 2016 (bp) Review posted live
31 March 2016 (gm) Original submission
• 28 July 2022 (sw) Comprehensive update posted live
• 17 November 2016 (bp) Review posted live
• 31 March 2016 (gm) Original submission
## Author Notes
Dr Ghayda Mirzaa is a clinical and molecular geneticist at the Seattle Children's Research Institute and the University of Washington School of Medicine. Her research is focused on understanding the developmental basis and genetic causes of developmental brain disorders, including brain growth abnormalities, cortical malformations, and epilepsy. Dr Mirzaa's research team studies the natural history of MPPH syndrome.
## Acknowledgments
We thank our patients and their families and health care providers for their collaboration and contribution to our knowledge of MPPH syndrome.
## Revision History
28 July 2022 (sw) Comprehensive update posted live
17 November 2016 (bp) Review posted live
31 March 2016 (gm) Original submission
• 28 July 2022 (sw) Comprehensive update posted live
• 17 November 2016 (bp) Review posted live
• 31 March 2016 (gm) Original submission
## References
## Literature Cited
|
[
"D Alcantara, AE Timms, K Gripp, L Baker, K Park, S Collins, C Cheng, F Stewart, SG Mehta, A Saggar, L Sztriha, M Zombor, O Caluseriu, R Mesterman, MI Van Allen, A Jacquinet, S Ygberg, JA Bernstein, AM Wenger, H Guturu, G Bejerano, N Gomez-Ospina, A Lehman, E Alfei, C Pantaleoni, V Conti, R Guerrini, U Moog, JM Graham, R Hevner, WB Dobyns, M O'Driscoll, GM Mirzaa. Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly.. Brain. 2017;140:2610-22",
"BC Ballif, JA Rosenfeld, R Traylor, A Theisen, PI Bader, RL Ladda, SL Sell, M Steinraths, U Surti, M McGuire, S Williams, SA Farrell, J Filiano, RE Schnur, LB Coffey, RC Tervo, T Stroud, M Marble, M Netzloff, K Hanson, AS Aylsworth, JS Bamforth, D Babu, DM Niyazov, JB Ravnan, RA Schultz, AN Lamb, BS Torchia, BA Bejjani, LG Shaffer. High-resolution array CGH defines critical regions and candidate genes for microcephaly, abnormalities of the corpus callosum, and seizure phenotypes in patients with microdeletions of 1q43q44.. Hum Genet. 2012;131:145-56",
"BK Chung, P Eydoux, CD Van Karnebeek, WT Gibson. Duplication of AKT3 is associated with macrocephaly and speech delay.. Am J Med Genet A. 2014;164A:1868-9",
"M Colombani, M Chouchane, G Pitelet, L Morales, P Callier, JP Pinard, L Lion-François, C Thauvin-Robinet, F Mugneret, F Huet, L Guibaud, L Faivre. A new case of megalencephaly and perisylvian polymicrogyria with post-axial polydactyly and hydrocephalus: MPPH syndrome.. Eur J Med Genet. 2006;49:466-71",
"V Conti, M Pantaleo, C Barba, G Baroni, D Mei, AM Buccoliero, S Giglio, F Giordano, ST Baek, JG Gleeson, R Guerrini. Focal dysplasia of the cerebral cortex and infantile spasms associated with somatic 1q21.1-q44 duplication including the AKT3 gene.. Clin Genet. 2015;88:241-7",
"N Demir, E Peker, I Gülşen, S Kaba, O Tuncer. Megalencephaly, polymicrogyria, polydactyly and hydrocephalus (mpph) syndrome: a new case with occipital encephalocele and cleft palate.. Genet Couns. 2015;26:381-5",
"JA Engelman, J Luo, LC Cantley. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.. Nat Rev Genet. 2006;7:606-19",
"D Gai, E Haan, M Scholar, J Nicholl, S. Yu. Phenotypes of AKT3 deletion: a case report and literature review.. Am J Med Genet A. 2015;167A:174-9",
"L Garavelli, E Guareschi, S Errico, A Simoni, P Bergonzini, M Zollino, F Gurrieri, GM Mancini, R Schot, PJ Van Der Spek, G Frigieri, P Zonari, E Albertini, ED Giustina, S Amarri, G Banchini, WB Dobyns, G Neri. Megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus (MPPH): report of a new case.. Neuropediatrics. 2007;38:200-3",
"M Hadzipasic, MB Karsten, H Olson, L Rodan, H Lidov, SP Prabhu, K Wright, KP Fehnel. Medulloblastoma in the setting of megalencephaly polymicrogyria polydactyly hydrocephalus.. Am J Med Genet A. 2021;185:1614-8",
"A Harada, F Miya, H Utsunomiya, M Kato, T Yamanaka, T Tsunoda, K Kosaki, Y Kanemura, M Yamasaki. Sudden death in a case of megalencephaly capillary malformation associated with a de novo mutation in AKT3.. Childs Nerv Syst. 2015;31:465-71",
"IA Hemming, AR Forrest, P Shipman, KJ Woodward, P Walsh, DG Ravine, JI Heng. Reinforcing the association between distal 1q CNVs and structural brain disorder: A case of a complex 1q43-q44 CNV and a review of the literature.. Am J Med Genet B Neuropsychiatr Genet. 2016;171B:458-67",
"SS Jamuar, AT Lam, M Kircher, AM D'Gama, J Wang, BJ Barry, X Zhang, RS Hill, JN Partlow, A Rozzo, S Servattalab, BK Mehta, M Topcu, D Amrom, E Andermann, B Dan, E Parrini, R Guerrini, IE Scheffer, SF Berkovic, RJ Leventer, Y Shen, BL Wu, AJ Barkovich, M Sahin, BS Chang, M Bamshad, DA Nickerson, J Shendure, A Poduri, TW Yu, CA Walsh. Somatic mutations in cerebral cortical malformations.. N Engl J Med. 2014;371:733-43",
"A Kariminejad, F Radmanesh, AR Rezayi, SH Tonekaboni, JG Gleeson. Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome: a case report.. J Child Neurol. 2013;28:651-7",
"R Koyama-Nasu, Y Nasu-Nishimura, T Todo, Y Ino, N Saito, H Aburatani, K Funato, K Echizen, H Sugano, R Haruta, M Matsui, R Takahashi, E Manabe, T Oda, T. Akiyama. The critical role of cyclin D2 in cell cycle progression and tumorigenicity of glioblastoma stem cells.. Oncogene. 2013;32:3840-5",
"MJ Lindhurst, JC Sapp, JK Teer, JJ Johnston, EM Finn, K Peters, J Turner, JL Cannons, D Bick, L Blakemore, C Blumhorst, K Brockmann, P Calder, N Cherman, MA Deardorff, DB Everman, G Golas, RM Greenstein, BM Kato, KM Keppler-Noreuil, SA Kuznetsov, RT Miyamoto, K Newman, D Ng, K O'Brien, S Rothenberg, DJ Schwartzentruber, V Singhal, R Tirabosco, J Upton, S Wientroub, EH Zackai, K Hoag, T Whitewood-Neal, PG Robey, PL Schwartzberg, TN Darling, LL Tosi, JC Mullikin, LG Biesecker. A mosaic activating mutation in AKT1 associated with the Proteus syndrome.. N Engl J Med. 2011;365:611-9",
"G Mirzaa, NN Dodge, I Glass, C Day, K Gripp, L Nicholson, V Straub, T Voit, WB Dobyns. Megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus: a rare brain malformation syndrome associated with mental retardation and seizures.. Neuropediatrics. 2004;35:353-9",
"G Mirzaa, DA Parry, AE Fry, KA Giamanco, J Schwartzentruber, M Vanstone, CV Logan, N Roberts, CA Johnson, S Singh, SS Kholmanskikh, C Adams, RD Hodge, RF Hevner, DT Bonthron, KP Braun, L Faivre, JB Rivière, J St-Onge, KW Gripp, GM Mancini, K Pang, E Sweeney, H van Esch, N Verbeek, D Wieczorek, M Steinraths, J Majewski, KM Boycott, DT Pilz, ME Ross, WB Dobyns, EG Sheridan. De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.. Nat Genet. 2014;46:510-5",
"GM Mirzaa, CD Campbell, N Solovieff, CP Goold, LA Jansen, S Menon, AE Timms, V Conti, JD Biag, C Olds, EA Boyle, S Collins, G Ishak, SL Poliachik, KM Girisha, KS Yeung, BH Chung, E Rahikkala, SA Gunter, SS McDaniel, CF Macmurdo, JA Bernstein, B Martin, RJ Leary, S Mahan, S Liu, M Weaver, MO Dorschner, S Jhangiani, DM Muzny, E Boerwinkle, RA Gibbs, JR Lupski, J Shendure, RP Saneto, EJ Novotny, CJ Wilson, WR Sellers, MP Morrissey, RF Hevner, JG Ojemann, R Guerrini, LO Murphy, W Winckler, WB Dobyns. Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism.. JAMA Neurol. 2016;73:836-45",
"GM Mirzaa, V Conti, AE Timms, CD Smyser, S Ahmed, M Carter, S Barnett, RB Hufnagel, A Goldstein, Y Narumi-Kishimoto, C Olds, S Collins, K Johnston, JF Deleuze, P Nitschké, K Friend, C Harris, A Goetsch, B Martin, EA Boyle, E Parrini, D Mei, L Tattini, A Slavotinek, E Blair, C Barnett, J Shendure, J Chelly, WB Dobyns, R Guerrini. Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study.. Lancet Neurol. 2015;14:1182-95",
"GM Mirzaa, RL Conway, KW Gripp, T Lerman-Sagie, DH Siegel, LS deVries, D Lev, N Kramer, E Hopkins, JM Graham, WB Dobyns. Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis.. Am J Med Genet A. 2012;158A:269-91",
"GM Mirzaa, A Poduri. Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology.. Am J Med Genet C Semin Med Genet. 2014;166C:156-72",
"SC Nagamani, A Erez, C Bay, A Pettigrew, SR Lalani, K Herman, BH Graham, MJ Nowaczyk, M Proud, WJ Craigen, B Hopkins, B Kozel, K Plunkett, P Hixson, P Stankiewicz, A Patel, SW Cheung. Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43-q44.. Eur J Hum Genet. 2012;20:176-9",
"K Nakamura, M Kato, J Tohyama, T Shiohama, K Hayasaka, K Nishiyama, H Kodera, M Nakashima, Y Tsurusaki, N Miyake, N Matsumoto, H. Saitsu. AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH.. Clin Genet. 2014;85:396-8",
"M Nellist, R Schot, M Hoogeveen-Westerveld, RF Neuteboom, EJ van der Louw, MH Lequin, K Bindels-de Heus, BJ Sibbles, R de Coo, A Brooks, GM Mancini. Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia.. Mol Genet Metab. 2015;114:467-73",
"WL Osterling, RS Boyer, GL Hedlund, JF Bale. Jr. MPPH syndrome: two new cases.. Pediatr Neurol. 2011;44:370-3",
"F Pirozzi, B Lee, N Horsley, DD Burkardt, WB Dobyns, JM Graham, ML Dentici, C Cesario, J Schallner, J Porrmann, N Di Donato, PA Sanchez-Lara, GM Mirzaa. Proximal variants in CCND2 associated with microcephaly, short stature, and developmental delay: A case series and review of inverse brain growth phenotypes.. Am J Med Genet A. 2021;185:2719-38",
"T Pisano, M Meloni, C Cianchetti, M Falchi, A Nucaro, D Pruna. Megalencephaly, polymicrogyria, and hydrocephalus (MPPH) syndrome: a new case with syndactyly.. J Child Neurol 2008;23:916-8",
"A Poduri, GD Evrony, X Cai, PC Elhosary, R Beroukhim, MK Lehtinen, LB Hills, EL Heinzen, A Hill, RS Hill, BJ Barry, BF Bourgeois, JJ Riviello, AJ Barkovich, PM Black, KL Ligon, CA Walsh. Somatic activation of AKT3 causes hemispheric developmental brain malformations.. Neuron. 2012;74:41-8",
"JB Rivière, GM Mirzaa, BJ O'Roak, M Beddaoui, D Alcantara, RL Conway, J St-Onge, JA Schwartzentruber, KW Gripp, SM Nikkel, T Worthylake, CT Sullivan, TR Ward, HE Butler, NA Kramer, B Albrecht, CM Armour, L Armstrong, O Caluseriu, C Cytrynbaum, BA Drolet, AM Innes, JL Lauzon, AE Lin, GM Mancini, WS Meschino, JD Reggin, AK Saggar, T Lerman-Sagie, G Uyanik, R Weksberg, B Zirn, CL Beaulieu. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.. Nat Genet. 2012;44:934-40",
"X Shi, Y Lim, AK Myers, BL Stallings, A Mccoy, J Zeiger, J Scheck, G Cho, ED Marsh, GM Mirzaa, T Tao, JA Golden. PIK3R2/Pik3r2 Activating Mutations Result in Brain Overgrowth and EEG Changes.. Ann Neurol. 2020;88:1077-94",
"R Szalai, BI Melegh, A Till, R Ripszam, G Csabi, A Acharya, I Schrauwen, SM Leal, S Komoly, G Kosztolanyi, K Hadzsiev. Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings.. Exp Mol Pathol. 2020;115",
"WJ Tapper, N Foulds, NC Cross, P Aranaz, J Score, C Hidalgo-Curtis, DO Robinson, J Gibson, S Ennis, IK Temple, A. Collins. Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations.. PloS One. 2014;9",
"G Terrone, N Voisin, A Abdullah Alfaiz, G Cappuccio, G Vitiello, N Guex, A D'Amico, A James Barkovich, N Brunetti-Pierri, E Del Giudice, A. Reymond. De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia.. Eur J Hum Genet. 2016;24:1359-62",
"J Tohyama, N Akasaka, N Saito, J Yoshimura, K Nishiyama, M Kato. Megalencephaly and polymicrogyria with polydactyly syndrome.. Pediatr Neurol 2007;37:148-51",
"HG Tore, AM McKinney, VA Nagar, B Lohman, CL Truwit, C Raybaud. Syndrome of megalencephaly, polydactyly, and polymicrogyria lacking frank hydrocephalus, with associated MR imaging findings.. AJNR Am J Neuroradiol. 2009;30:1620-2",
"B Vanhaesebroeck, L Stephens, P. Hawkins. PI3K signalling: the path to discovery and understanding.. Nat Rev Mol Cell Biol. 2012;13:195-203",
"AJ Verkerk, R Schot, L van Waterschoot, H Douben, PJ Poddighe, MH Lequin, LS de Vries, P Terhal, JM Hahnemann, IF de Coo, MC de Wit, LS Wafelman, L Garavelli, WB Dobyns, PJ Van der Spek, A de Klein, GM Mancini. Unbalanced der(5)t(5;20) translocation associated with megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus.. Am J Med Genet A. 2010;152A:1488-97",
"D Wang, S Zeesman, MA Tarnopolsky, MJ Nowaczyk. Duplication of AKT3 as a cause of macrocephaly in duplication 1q43q44.. Am J Med Genet A. 2013;161A:2016-9",
"TG Zamora, KD Roberts. Four-year follow-up of megalencephaly, polymicrogyria, postaxial polydactyly and hydrocephalus (MPPH) syndrome.. BMJ Case Rep. 2013;2013"
] |
17/11/2016
|
28/7/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mps1
|
mps1
|
[
"Alpha-L-Iduronidase Deficiency",
"IDUA Deficiency",
"MPS I",
"Alpha-L-Iduronidase Deficiency",
"IDUA Deficiency",
"MPS I",
"Severe MPS I (Hurler Syndrome)",
"Attenuated MPS I (Hurler-Scheie Syndrome / Scheie Syndrome)",
"Alpha-L-iduronidase",
"IDUA",
"Mucopolysaccharidosis Type I"
] |
Mucopolysaccharidosis Type I
|
Lorne A Clarke
|
Summary Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options. The diagnosis of MPS I is established in a proband with suggestive clinical and laboratory findings by: detection of deficient activity of the lysosomal enzyme α-L-iduronidase (IDUA) in combination with elevation of glycosaminoglycan levels; and/or identification of biallelic pathogenic variants in Enzyme replacement therapy (ERT) with laronidase (Aldurazyme MPS I is inherited in an autosomal recessive manner. At conception, each child of a couple in which both parents are heterozygous for a
|
Severe MPS I (Hurler syndrome)
Attenuated MPS I (Hurler-Scheie syndrome / Scheie syndrome)
For synonyms and outdated names see
• Severe MPS I (Hurler syndrome)
• Attenuated MPS I (Hurler-Scheie syndrome / Scheie syndrome)
## Diagnosis
Note: The approach to NBS for mucopolysaccharidosis type I (MPS I) is currently in evolution. Although single-tier α-L-iduronidase (IDUA) enzyme activity measurement was the original and remains the most common approach taken in the United States, the potential adoption of a second tier involving measurement of dried blood spot glycosaminoglycans is currently under way by some centers. The addition of the second tier greatly increases the positive predictive value of NBS for MPS I [
Single-tier NBS for mucopolysaccharidosis type I (MPS I) is primarily based on quantification of IDUA enzyme activity on dried blood spots.
IDUA enzyme activity values below the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing and clinical evaluation. Follow-up biochemical testing includes confirmation of deficiency of IDUA enzyme activity in blood as well as demonstration of elevation in urinary glycosaminoglycan levels.
Positive NBS results should be reviewed by a clinical specialist with experience in MPS I to ensure that the appropriate additional laboratory testing and clinical assessment is performed and correctly interpreted to determine whether this a true positive NBS result and to definitively establish the diagnosis of MPS I.
A symptomatic individual who has findings associated with either attenuated MPS I or severe untreated MPS I (Hurler syndrome) may present because of any of the following: NBS not performed, false negative NBS result, and/or caregivers not adherent with the recommended assessment plan following a positive NBS result.
Supportive (particularly when multiple findings are present) but nonspecific clinical findings and preliminary laboratory findings can include the following.
Coarse facial features
Early frequent upper respiratory infections including otitis media
Inguinal or umbilical hernia
Hepatosplenomegaly
Characteristic skeletal findings (gibbus deformity, limitation of joint range of motion)
Noninflammatory arthropathy
Characteristic ocular findings (corneal clouding)
Hydrocephalus
Developmental delay
Note: Clinical findings vary by disease severity. Clinical findings alone are not diagnostic.
Neither the quantitative nor the qualitative method can diagnose a specific lysosomal enzyme deficiency, including MPS I; however, an abnormality detected by either or both methods indicates the likely presence of an MPS disorder.
GAG electrophoresis can exclude and include certain MPS disorders; however, definitive diagnosis requires additional testing (see
Both methods have reduced sensitivity, particularly when urine is dilute.
The diagnosis of MPS I
Note: (1) Due to the presence of IDUA pseudodeficiency, the establishment of the diagnosis of MPS I requires the demonstration of BOTH deficiency of IDUA enzyme activity AND elevation of urine GAGs. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When NBS results and/or clinical and preliminary laboratory findings suggest the diagnosis of MPS I, molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Mucopolysaccharidosis Type I
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The detection rate for two pathogenic variants detectable by sequence analysis in 556 patients was 97% [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Whole-gene deletions and intragenic deletions of exons 1-2 and exon 14 have been reported [
IDUA enzyme activity can be measured in most tissues; typically, peripheral blood leukocytes, plasma, or cultured fibroblasts are used.
All individuals with MPS I have no or very little IDUA enzyme activity detected by the standard methods used for diagnostics.
Detailed studies using fibroblasts from individuals with MPS I have revealed that as little as 0.13% of normal IDUA enzyme activity appears to be sufficient to produce a mild phenotype [
The presence of pseudodeficiency alleles also renders interpretation of IDUA enzyme activity difficult. Pseudodeficiency relates to the finding of reduced or undetectable IDUA enzyme activity with the use of artificial substrates, but no evidence of altered glycosaminoglycan metabolism with the use of radiolabeled (35S) GAG [
• Single-tier NBS for mucopolysaccharidosis type I (MPS I) is primarily based on quantification of IDUA enzyme activity on dried blood spots.
• IDUA enzyme activity values below the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing and clinical evaluation. Follow-up biochemical testing includes confirmation of deficiency of IDUA enzyme activity in blood as well as demonstration of elevation in urinary glycosaminoglycan levels.
• Positive NBS results should be reviewed by a clinical specialist with experience in MPS I to ensure that the appropriate additional laboratory testing and clinical assessment is performed and correctly interpreted to determine whether this a true positive NBS result and to definitively establish the diagnosis of MPS I.
• Coarse facial features
• Early frequent upper respiratory infections including otitis media
• Inguinal or umbilical hernia
• Hepatosplenomegaly
• Characteristic skeletal findings (gibbus deformity, limitation of joint range of motion)
• Noninflammatory arthropathy
• Characteristic ocular findings (corneal clouding)
• Hydrocephalus
• Developmental delay
• Neither the quantitative nor the qualitative method can diagnose a specific lysosomal enzyme deficiency, including MPS I; however, an abnormality detected by either or both methods indicates the likely presence of an MPS disorder.
• GAG electrophoresis can exclude and include certain MPS disorders; however, definitive diagnosis requires additional testing (see
• Both methods have reduced sensitivity, particularly when urine is dilute.
• For an introduction to multigene panels click
• All individuals with MPS I have no or very little IDUA enzyme activity detected by the standard methods used for diagnostics.
• Detailed studies using fibroblasts from individuals with MPS I have revealed that as little as 0.13% of normal IDUA enzyme activity appears to be sufficient to produce a mild phenotype [
• The presence of pseudodeficiency alleles also renders interpretation of IDUA enzyme activity difficult. Pseudodeficiency relates to the finding of reduced or undetectable IDUA enzyme activity with the use of artificial substrates, but no evidence of altered glycosaminoglycan metabolism with the use of radiolabeled (35S) GAG [
## Suggestive Findings
Note: The approach to NBS for mucopolysaccharidosis type I (MPS I) is currently in evolution. Although single-tier α-L-iduronidase (IDUA) enzyme activity measurement was the original and remains the most common approach taken in the United States, the potential adoption of a second tier involving measurement of dried blood spot glycosaminoglycans is currently under way by some centers. The addition of the second tier greatly increases the positive predictive value of NBS for MPS I [
Single-tier NBS for mucopolysaccharidosis type I (MPS I) is primarily based on quantification of IDUA enzyme activity on dried blood spots.
IDUA enzyme activity values below the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing and clinical evaluation. Follow-up biochemical testing includes confirmation of deficiency of IDUA enzyme activity in blood as well as demonstration of elevation in urinary glycosaminoglycan levels.
Positive NBS results should be reviewed by a clinical specialist with experience in MPS I to ensure that the appropriate additional laboratory testing and clinical assessment is performed and correctly interpreted to determine whether this a true positive NBS result and to definitively establish the diagnosis of MPS I.
A symptomatic individual who has findings associated with either attenuated MPS I or severe untreated MPS I (Hurler syndrome) may present because of any of the following: NBS not performed, false negative NBS result, and/or caregivers not adherent with the recommended assessment plan following a positive NBS result.
Supportive (particularly when multiple findings are present) but nonspecific clinical findings and preliminary laboratory findings can include the following.
Coarse facial features
Early frequent upper respiratory infections including otitis media
Inguinal or umbilical hernia
Hepatosplenomegaly
Characteristic skeletal findings (gibbus deformity, limitation of joint range of motion)
Noninflammatory arthropathy
Characteristic ocular findings (corneal clouding)
Hydrocephalus
Developmental delay
Note: Clinical findings vary by disease severity. Clinical findings alone are not diagnostic.
Neither the quantitative nor the qualitative method can diagnose a specific lysosomal enzyme deficiency, including MPS I; however, an abnormality detected by either or both methods indicates the likely presence of an MPS disorder.
GAG electrophoresis can exclude and include certain MPS disorders; however, definitive diagnosis requires additional testing (see
Both methods have reduced sensitivity, particularly when urine is dilute.
• Single-tier NBS for mucopolysaccharidosis type I (MPS I) is primarily based on quantification of IDUA enzyme activity on dried blood spots.
• IDUA enzyme activity values below the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing and clinical evaluation. Follow-up biochemical testing includes confirmation of deficiency of IDUA enzyme activity in blood as well as demonstration of elevation in urinary glycosaminoglycan levels.
• Positive NBS results should be reviewed by a clinical specialist with experience in MPS I to ensure that the appropriate additional laboratory testing and clinical assessment is performed and correctly interpreted to determine whether this a true positive NBS result and to definitively establish the diagnosis of MPS I.
• Coarse facial features
• Early frequent upper respiratory infections including otitis media
• Inguinal or umbilical hernia
• Hepatosplenomegaly
• Characteristic skeletal findings (gibbus deformity, limitation of joint range of motion)
• Noninflammatory arthropathy
• Characteristic ocular findings (corneal clouding)
• Hydrocephalus
• Developmental delay
• Neither the quantitative nor the qualitative method can diagnose a specific lysosomal enzyme deficiency, including MPS I; however, an abnormality detected by either or both methods indicates the likely presence of an MPS disorder.
• GAG electrophoresis can exclude and include certain MPS disorders; however, definitive diagnosis requires additional testing (see
• Both methods have reduced sensitivity, particularly when urine is dilute.
## Scenario 1 – Abnormal Newborn Screening (NBS) Result
Note: The approach to NBS for mucopolysaccharidosis type I (MPS I) is currently in evolution. Although single-tier α-L-iduronidase (IDUA) enzyme activity measurement was the original and remains the most common approach taken in the United States, the potential adoption of a second tier involving measurement of dried blood spot glycosaminoglycans is currently under way by some centers. The addition of the second tier greatly increases the positive predictive value of NBS for MPS I [
Single-tier NBS for mucopolysaccharidosis type I (MPS I) is primarily based on quantification of IDUA enzyme activity on dried blood spots.
IDUA enzyme activity values below the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing and clinical evaluation. Follow-up biochemical testing includes confirmation of deficiency of IDUA enzyme activity in blood as well as demonstration of elevation in urinary glycosaminoglycan levels.
Positive NBS results should be reviewed by a clinical specialist with experience in MPS I to ensure that the appropriate additional laboratory testing and clinical assessment is performed and correctly interpreted to determine whether this a true positive NBS result and to definitively establish the diagnosis of MPS I.
• Single-tier NBS for mucopolysaccharidosis type I (MPS I) is primarily based on quantification of IDUA enzyme activity on dried blood spots.
• IDUA enzyme activity values below the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing and clinical evaluation. Follow-up biochemical testing includes confirmation of deficiency of IDUA enzyme activity in blood as well as demonstration of elevation in urinary glycosaminoglycan levels.
• Positive NBS results should be reviewed by a clinical specialist with experience in MPS I to ensure that the appropriate additional laboratory testing and clinical assessment is performed and correctly interpreted to determine whether this a true positive NBS result and to definitively establish the diagnosis of MPS I.
## Scenario 2 – Symptomatic Individual
A symptomatic individual who has findings associated with either attenuated MPS I or severe untreated MPS I (Hurler syndrome) may present because of any of the following: NBS not performed, false negative NBS result, and/or caregivers not adherent with the recommended assessment plan following a positive NBS result.
Supportive (particularly when multiple findings are present) but nonspecific clinical findings and preliminary laboratory findings can include the following.
Coarse facial features
Early frequent upper respiratory infections including otitis media
Inguinal or umbilical hernia
Hepatosplenomegaly
Characteristic skeletal findings (gibbus deformity, limitation of joint range of motion)
Noninflammatory arthropathy
Characteristic ocular findings (corneal clouding)
Hydrocephalus
Developmental delay
Note: Clinical findings vary by disease severity. Clinical findings alone are not diagnostic.
Neither the quantitative nor the qualitative method can diagnose a specific lysosomal enzyme deficiency, including MPS I; however, an abnormality detected by either or both methods indicates the likely presence of an MPS disorder.
GAG electrophoresis can exclude and include certain MPS disorders; however, definitive diagnosis requires additional testing (see
Both methods have reduced sensitivity, particularly when urine is dilute.
• Coarse facial features
• Early frequent upper respiratory infections including otitis media
• Inguinal or umbilical hernia
• Hepatosplenomegaly
• Characteristic skeletal findings (gibbus deformity, limitation of joint range of motion)
• Noninflammatory arthropathy
• Characteristic ocular findings (corneal clouding)
• Hydrocephalus
• Developmental delay
• Neither the quantitative nor the qualitative method can diagnose a specific lysosomal enzyme deficiency, including MPS I; however, an abnormality detected by either or both methods indicates the likely presence of an MPS disorder.
• GAG electrophoresis can exclude and include certain MPS disorders; however, definitive diagnosis requires additional testing (see
• Both methods have reduced sensitivity, particularly when urine is dilute.
## Establishing the Diagnosis
The diagnosis of MPS I
Note: (1) Due to the presence of IDUA pseudodeficiency, the establishment of the diagnosis of MPS I requires the demonstration of BOTH deficiency of IDUA enzyme activity AND elevation of urine GAGs. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When NBS results and/or clinical and preliminary laboratory findings suggest the diagnosis of MPS I, molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Mucopolysaccharidosis Type I
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The detection rate for two pathogenic variants detectable by sequence analysis in 556 patients was 97% [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Whole-gene deletions and intragenic deletions of exons 1-2 and exon 14 have been reported [
IDUA enzyme activity can be measured in most tissues; typically, peripheral blood leukocytes, plasma, or cultured fibroblasts are used.
All individuals with MPS I have no or very little IDUA enzyme activity detected by the standard methods used for diagnostics.
Detailed studies using fibroblasts from individuals with MPS I have revealed that as little as 0.13% of normal IDUA enzyme activity appears to be sufficient to produce a mild phenotype [
The presence of pseudodeficiency alleles also renders interpretation of IDUA enzyme activity difficult. Pseudodeficiency relates to the finding of reduced or undetectable IDUA enzyme activity with the use of artificial substrates, but no evidence of altered glycosaminoglycan metabolism with the use of radiolabeled (35S) GAG [
• For an introduction to multigene panels click
• All individuals with MPS I have no or very little IDUA enzyme activity detected by the standard methods used for diagnostics.
• Detailed studies using fibroblasts from individuals with MPS I have revealed that as little as 0.13% of normal IDUA enzyme activity appears to be sufficient to produce a mild phenotype [
• The presence of pseudodeficiency alleles also renders interpretation of IDUA enzyme activity difficult. Pseudodeficiency relates to the finding of reduced or undetectable IDUA enzyme activity with the use of artificial substrates, but no evidence of altered glycosaminoglycan metabolism with the use of radiolabeled (35S) GAG [
## Molecular Testing
When NBS results and/or clinical and preliminary laboratory findings suggest the diagnosis of MPS I, molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Mucopolysaccharidosis Type I
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The detection rate for two pathogenic variants detectable by sequence analysis in 556 patients was 97% [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Whole-gene deletions and intragenic deletions of exons 1-2 and exon 14 have been reported [
• For an introduction to multigene panels click
## IDUA Enzyme Activity
IDUA enzyme activity can be measured in most tissues; typically, peripheral blood leukocytes, plasma, or cultured fibroblasts are used.
All individuals with MPS I have no or very little IDUA enzyme activity detected by the standard methods used for diagnostics.
Detailed studies using fibroblasts from individuals with MPS I have revealed that as little as 0.13% of normal IDUA enzyme activity appears to be sufficient to produce a mild phenotype [
The presence of pseudodeficiency alleles also renders interpretation of IDUA enzyme activity difficult. Pseudodeficiency relates to the finding of reduced or undetectable IDUA enzyme activity with the use of artificial substrates, but no evidence of altered glycosaminoglycan metabolism with the use of radiolabeled (35S) GAG [
• All individuals with MPS I have no or very little IDUA enzyme activity detected by the standard methods used for diagnostics.
• Detailed studies using fibroblasts from individuals with MPS I have revealed that as little as 0.13% of normal IDUA enzyme activity appears to be sufficient to produce a mild phenotype [
• The presence of pseudodeficiency alleles also renders interpretation of IDUA enzyme activity difficult. Pseudodeficiency relates to the finding of reduced or undetectable IDUA enzyme activity with the use of artificial substrates, but no evidence of altered glycosaminoglycan metabolism with the use of radiolabeled (35S) GAG [
## Clinical Characteristics
Mucopolysaccharidosis type I (MPS I), a progressive multisystem disorder with features ranging over a wide continuum, is considered the prototypic lysosomal storage disease. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified [
An accurate determination of the proportion of individuals with severe or attenuated MPS I has not been published. Data from the international MPS I Registry available in 2011 showed that of the 891 individuals included in the registry, 57% were classified as having Hurler syndrome, 23.5% as having Hurler-Scheie syndrome, and 10% as having Scheie syndrome; 8.6% were classified as either unknown or indeterminate. The potential ascertainment bias of registry data and the lack of a clear definition of phenotypic features for each of the subcategories should be considered in interpretation of the data [
Mucopolysaccharidosis Type I: Comparison of Phenotypes by Select Features
The age of the affected individual considerably affects the phenotypic features.
Severe MPS I is characterized by a chronic and progressive disease course involving multiple organs and tissues [
MPS I registry data show that by age six months the median growth for individuals with severe MPS I begins to deviate from normal, falling below the third percentile of normal by age four years [
The clavicles are short, thickened, and irregular. Long bones are short with wide shafts; the knees are prone to valgus and varus deformities. Endochondral growth plates are thickened and disordered. Typically, the pelvis is poorly formed. The femoral heads are small and coxa valga is common. Involvement of the femoral heads and acetabula leads to progressive and debilitating hip deformity. Progressive arthropathy leading to severe joint deformity is universal; significant and functionally impactful joint stiffness is common by age two years.
Phalangeal dysostosis and synovial thickening lead to a characteristic claw hand deformity. Carpal tunnel syndrome and interphalangeal joint involvement commonly lead to poor hand function. Carpal tunnel syndrome is often missed because of its insidious onset; it often presents with few symptoms or signs other than thenar atrophy.
For unknown reasons, many children with severe MPS I periodically experience loose stools and diarrhea, sometimes alternating with periods of severe constipation. These problems may or may not diminish with age; they are exacerbated by muscle weakness and physical inactivity, as well as antibiotic use for other medical complications.
Children with severe MPS I develop only limited language skills, likely related to the triad of developmental delay, chronic hearing loss, and enlarged tongue.
In contrast to
If development is normal by age 24 months and if moderate somatic involvement is evident (e.g., mild hepatomegaly, relatively normal joint range of motion, mild dysostosis on skeletal radiographs, mild corneal clouding), an individual should be classified as having attenuated MPS I.
Children with attenuated MPS I have variable growth restriction that may not be apparent until later childhood [
Progressive arthropathy affecting all joints and eventually leading to loss of or severe restriction in range of motion is universal. Carpal tunnel syndrome was present at a median age of nine years 11 months in 138 individuals with attenuated MPS I included in the MPS I Registry [
Coronary disease may also be a feature of attenuated MPS I.
Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I. Cervical myelopathy may present initially as reduced activity or exercise intolerance and may not be recognized until the injury is irreversible.
There is a close correlation of genotype to phenotype in MPS I based on data from 538 individuals within the international MPS I registry [
Attenuated MPS I is usually associated with at least one missense variant; registry data showed that 95.6% (151/158) of individuals with attenuated MPS I had at least one missense variant. It is postulated that the missense variant permits some residual enzyme activity.
Exceptions include the following variants associated with attenuated MPS I:
While affected individuals have traditionally been classified as having one of three MPS I syndromes – Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome – no biochemical differences have been identified and the clinical findings overlap; thus, affected individuals are best described as having either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options.
MPS I is seen in all populations at a frequency of approximately 1:100,000 for the severe form and 1:500,000 for the attenuated form [
## Clinical Description
Mucopolysaccharidosis type I (MPS I), a progressive multisystem disorder with features ranging over a wide continuum, is considered the prototypic lysosomal storage disease. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified [
An accurate determination of the proportion of individuals with severe or attenuated MPS I has not been published. Data from the international MPS I Registry available in 2011 showed that of the 891 individuals included in the registry, 57% were classified as having Hurler syndrome, 23.5% as having Hurler-Scheie syndrome, and 10% as having Scheie syndrome; 8.6% were classified as either unknown or indeterminate. The potential ascertainment bias of registry data and the lack of a clear definition of phenotypic features for each of the subcategories should be considered in interpretation of the data [
Mucopolysaccharidosis Type I: Comparison of Phenotypes by Select Features
The age of the affected individual considerably affects the phenotypic features.
Severe MPS I is characterized by a chronic and progressive disease course involving multiple organs and tissues [
MPS I registry data show that by age six months the median growth for individuals with severe MPS I begins to deviate from normal, falling below the third percentile of normal by age four years [
The clavicles are short, thickened, and irregular. Long bones are short with wide shafts; the knees are prone to valgus and varus deformities. Endochondral growth plates are thickened and disordered. Typically, the pelvis is poorly formed. The femoral heads are small and coxa valga is common. Involvement of the femoral heads and acetabula leads to progressive and debilitating hip deformity. Progressive arthropathy leading to severe joint deformity is universal; significant and functionally impactful joint stiffness is common by age two years.
Phalangeal dysostosis and synovial thickening lead to a characteristic claw hand deformity. Carpal tunnel syndrome and interphalangeal joint involvement commonly lead to poor hand function. Carpal tunnel syndrome is often missed because of its insidious onset; it often presents with few symptoms or signs other than thenar atrophy.
For unknown reasons, many children with severe MPS I periodically experience loose stools and diarrhea, sometimes alternating with periods of severe constipation. These problems may or may not diminish with age; they are exacerbated by muscle weakness and physical inactivity, as well as antibiotic use for other medical complications.
Children with severe MPS I develop only limited language skills, likely related to the triad of developmental delay, chronic hearing loss, and enlarged tongue.
In contrast to
If development is normal by age 24 months and if moderate somatic involvement is evident (e.g., mild hepatomegaly, relatively normal joint range of motion, mild dysostosis on skeletal radiographs, mild corneal clouding), an individual should be classified as having attenuated MPS I.
Children with attenuated MPS I have variable growth restriction that may not be apparent until later childhood [
Progressive arthropathy affecting all joints and eventually leading to loss of or severe restriction in range of motion is universal. Carpal tunnel syndrome was present at a median age of nine years 11 months in 138 individuals with attenuated MPS I included in the MPS I Registry [
Coronary disease may also be a feature of attenuated MPS I.
Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I. Cervical myelopathy may present initially as reduced activity or exercise intolerance and may not be recognized until the injury is irreversible.
## Severe MPS I (Hurler Syndrome)
Severe MPS I is characterized by a chronic and progressive disease course involving multiple organs and tissues [
MPS I registry data show that by age six months the median growth for individuals with severe MPS I begins to deviate from normal, falling below the third percentile of normal by age four years [
The clavicles are short, thickened, and irregular. Long bones are short with wide shafts; the knees are prone to valgus and varus deformities. Endochondral growth plates are thickened and disordered. Typically, the pelvis is poorly formed. The femoral heads are small and coxa valga is common. Involvement of the femoral heads and acetabula leads to progressive and debilitating hip deformity. Progressive arthropathy leading to severe joint deformity is universal; significant and functionally impactful joint stiffness is common by age two years.
Phalangeal dysostosis and synovial thickening lead to a characteristic claw hand deformity. Carpal tunnel syndrome and interphalangeal joint involvement commonly lead to poor hand function. Carpal tunnel syndrome is often missed because of its insidious onset; it often presents with few symptoms or signs other than thenar atrophy.
For unknown reasons, many children with severe MPS I periodically experience loose stools and diarrhea, sometimes alternating with periods of severe constipation. These problems may or may not diminish with age; they are exacerbated by muscle weakness and physical inactivity, as well as antibiotic use for other medical complications.
Children with severe MPS I develop only limited language skills, likely related to the triad of developmental delay, chronic hearing loss, and enlarged tongue.
In contrast to
## Attenuated MPS I (Hurler-Scheie Syndrome / Scheie Syndrome)
If development is normal by age 24 months and if moderate somatic involvement is evident (e.g., mild hepatomegaly, relatively normal joint range of motion, mild dysostosis on skeletal radiographs, mild corneal clouding), an individual should be classified as having attenuated MPS I.
Children with attenuated MPS I have variable growth restriction that may not be apparent until later childhood [
Progressive arthropathy affecting all joints and eventually leading to loss of or severe restriction in range of motion is universal. Carpal tunnel syndrome was present at a median age of nine years 11 months in 138 individuals with attenuated MPS I included in the MPS I Registry [
Coronary disease may also be a feature of attenuated MPS I.
Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I. Cervical myelopathy may present initially as reduced activity or exercise intolerance and may not be recognized until the injury is irreversible.
## Genotype-Phenotype Correlations
There is a close correlation of genotype to phenotype in MPS I based on data from 538 individuals within the international MPS I registry [
Attenuated MPS I is usually associated with at least one missense variant; registry data showed that 95.6% (151/158) of individuals with attenuated MPS I had at least one missense variant. It is postulated that the missense variant permits some residual enzyme activity.
Exceptions include the following variants associated with attenuated MPS I:
## Nomenclature
While affected individuals have traditionally been classified as having one of three MPS I syndromes – Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome – no biochemical differences have been identified and the clinical findings overlap; thus, affected individuals are best described as having either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options.
## Prevalence
MPS I is seen in all populations at a frequency of approximately 1:100,000 for the severe form and 1:500,000 for the attenuated form [
## Genetically Related (Allelic) Disorders
No phenotypes other those discussed in this
## Differential Diagnosis
Genes and Disorders of Interest in the Differential Diagnosis of Mucopolysaccharidosis Type I
AR = autosomal recessive; DiffDx = differential diagnosis; ML = mucolipidosis; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked
See also
In these conditions, the enzyme α-L-iduronidase is synthesized in adequate amounts but is not transported to the lysosome because of a defect in the receptor-mediated lysosomal targeting process.
## Management
Guidelines for the management of mucopolysaccharidosis type I (MPS I) have been developed [
To establish the extent of disease and determination of phenotype (i.e., severe or attenuated) in an individual diagnosed with MPS I, the evaluations summarized in
Mucopolysaccharidosis Type I: Recommended Evaluations Following Initial Diagnosis in a Newborn
Consultation w/PT, OT, & speech therapist
Consider referral to developmental pediatrician. Experience with the nuances of developmental assessment of children with MPS or other multisystem disorders is critical.
MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
After a new diagnosis of MPS I in a child, the closest hospital and local pediatrician should also be informed.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Mucopolysaccharidosis Type I: Recommended Evaluations in All Individuals
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
There is no cure for MPS I.
A central component of management of MPS I is the initiation of treatment early in the natural history of disease, as symptoms and disease complications are difficult or impossible to reverse. It is essential to promptly determine whether the individual fits the phenotype of severe or attenuated MPS I, as the only therapeutic approach that has been demonstrated to alter the natural history of the central nervous system (CNS) manifestations characteristic of severe MPS I is hematopoietic stem cell transplantation (HSCT), and the age of initiation of HSCT directly influences the ultimate outcome of affected individuals. Additionally, the age of initiation of enzyme replacement therapy in individuals with attenuated MPS I influences the long-term outcome (see
Mucopolysaccharidosis Type I: Targeted Treatment
Improved survival
Reduction in facial coarseness & hepatosplenomegaly, & improvement in hearing
Initial stabilization & improvement in myocardial function w/regression of hypertrophy & normalization of chamber dimensions; however, long-term follow up shows continued progression of valvular involvement
HSCT is the only therapeutic approach that alters the natural history of neurocognitive disease in MPS I.
HSCT has more limited impact on cardiac valvular, ocular, & skeletal manifestations.
Outcome from HSCT is significantly influenced by disease burden at time of diagnosis (& thus age of affected person).
HSCT has been successful in ↓ rate of progression of some findings in children w/severe MPS I.
Premedication w/anti-inflammatory & antihistamine drugs
Intravenous weekly infusion of 100 U/kg of Aldurazyme
Package insert provides details that may differ by country.
↓ & sustained urinary GAG levels
Normalization of hepatic & splenic volume
Stabilization (but not improvement) in respiratory function
Gradual ↑ in shoulder range of motion (typically w/in 1st 2 years, then plateauing)
Improvements in mobility w/in 1st 2 years
Improvement in quality of life index
Currently licensed widely for use in
Aldurazyme
The effect on rate of disease progression & effect when started very early in a person w/attenuated disease has not been comprehensively studied.
ERT does not impact corneal involvement, cardiac valvular disease progression, progressive arthropathy of involved large joints & hands, & progressive spinal diseases w/cord compression.
Carpal tunnel syndrome remains a potential complication.
GAG = glycosaminoglycan
HSCT is not curative but does significantly alter the natural history of the disorder.
HSCT should be used only in carefully selected children with extensive pre-transplantation clinical assessment and counseling in whom systematic long-term monitoring will be possible [
The degree to which HSCT relieves neurologic complications other than progressive intellectual decline is not clear. In children undergoing HSCT before evidence of significant developmental delay (i.e., usually age 12-18 months), HSCT appears to slow the course of cognitive decline. Children showing significant cognitive impairment prior to undergoing HSCT do not show correction of existing impairment.
In part because of increased longevity after HSCT, treated individuals develop increasing pain and stiffness of the hips and knees, carpal tunnel syndrome, spinal cord compression, and progressive thoracolumbar kyphosis. The age of HSCT appears to influence the age of onset of carpal tunnel syndrome and cervical compression.
The skeletal manifestations and corneal clouding continue to progress in children treated with HSCT and in untreated children [
Individuals who have received HSCT require continued multidisciplinary follow up and monitoring related to MPS I complications.
Comparative sib studies indicate improved outcomes when ERT is initiated early in the disease course.
Response is usually within 12 weeks, with some individuals achieving normal values.
As measured by timed-walk measurements; after two years mobility may be variably affected by hip, knee, and spinal disease progression.
Due to the multisystem involvement and progressive nature of this disorder, treatment of affected individuals is complex and requires the support of a multidisciplinary team consisting of metabolic/genetic physicians, specialist physicians including orthopedics, general surgery, ophthalmology, ENT, cardiology, neurosurgery, pulmonary, and developmental pediatrics, as well as specialists in neuropsychology, physiotherapy, occupational therapy, genetic counseling, and social work.
Various orthopedic approaches can be undertaken, particularly in individuals with attenuated disease. Joint replacement and atlanto-occipital stabilization may be necessary. These procedures must be performed at appropriate times in the individual's clinical course and must take into account the presence of other disease complications.
Carpal tunnel syndrome should be treated especially in individuals with attenuated MPS I and individuals with severe MPS I who have had HSCT. Most individuals lack typical symptoms (pain, tingling, or numbness) until severe compression occurs [
Dysostosis multiplex can lead to instability of the spine, including the atlanto-axial joint. Careful positioning and avoidance of hyperextension of the neck are necessary.
Induction of anesthesia for any purpose can be difficult because of the difficulty of maintaining an adequate airway. Smaller-than-anticipated endotracheal tubes may be required for endotracheal intubation because the trachea may be narrowed and the vocal cords thickened.
Intubation may require fiberoptic laryngoscopy.
Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem.
The recommended minimal schedule of assessments is highlighted in
Persons with MPS I, regardless of disease severity and mode of treatment, should be actively followed at a center that is experienced with the care of individuals with MPS disease.
Mucopolysaccharidosis Type I: Recommended Surveillance
Cranial ultrasound exam & other brain imaging studies; MRI can show ventriculomegaly, but imaging studies often cannot reliably distinguish between brain atrophy & brain compression.
Lumbar puncture w/measurement of opening pressure of CSF is preferred method to assess degree of pressure elevation [
CSF = cerebrospinal fluid; OFC = occipitofrontal circumference
Testing of all at-risk sibs of any age is warranted in order to initiate therapy as early in the course of disease as possible. For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, either test for the familial
See
Women with MPS I who become pregnant require assessment and frequent monitoring of cardiorespiratory and spinal cord involvement.
With the success of ERT for MPS I demonstrated by clinical trials, an increased effort is under way to improve responsiveness to ERT and to develop other forms of therapy directed at areas/organs that may not be responsive to ERT, such as skeletal and neurologic involvement.
A clinical trial of intrathecal ERT is currently under way in individuals who have evidence of spinal cord involvement. To date, this method has reduced CSF GAG levels and CSF pressure and has been found to be safe. The efficacy of intrathecal ERT is unclear [
Search
• Consultation w/PT, OT, & speech therapist
• Consider referral to developmental pediatrician. Experience with the nuances of developmental assessment of children with MPS or other multisystem disorders is critical.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Improved survival
• Reduction in facial coarseness & hepatosplenomegaly, & improvement in hearing
• Initial stabilization & improvement in myocardial function w/regression of hypertrophy & normalization of chamber dimensions; however, long-term follow up shows continued progression of valvular involvement
• HSCT is the only therapeutic approach that alters the natural history of neurocognitive disease in MPS I.
• HSCT has more limited impact on cardiac valvular, ocular, & skeletal manifestations.
• Outcome from HSCT is significantly influenced by disease burden at time of diagnosis (& thus age of affected person).
• HSCT has been successful in ↓ rate of progression of some findings in children w/severe MPS I.
• Premedication w/anti-inflammatory & antihistamine drugs
• Intravenous weekly infusion of 100 U/kg of Aldurazyme
• Package insert provides details that may differ by country.
• ↓ & sustained urinary GAG levels
• Normalization of hepatic & splenic volume
• Stabilization (but not improvement) in respiratory function
• Gradual ↑ in shoulder range of motion (typically w/in 1st 2 years, then plateauing)
• Improvements in mobility w/in 1st 2 years
• Improvement in quality of life index
• Currently licensed widely for use in
• Aldurazyme
• The effect on rate of disease progression & effect when started very early in a person w/attenuated disease has not been comprehensively studied.
• ERT does not impact corneal involvement, cardiac valvular disease progression, progressive arthropathy of involved large joints & hands, & progressive spinal diseases w/cord compression.
• Carpal tunnel syndrome remains a potential complication.
• Dysostosis multiplex can lead to instability of the spine, including the atlanto-axial joint. Careful positioning and avoidance of hyperextension of the neck are necessary.
• Induction of anesthesia for any purpose can be difficult because of the difficulty of maintaining an adequate airway. Smaller-than-anticipated endotracheal tubes may be required for endotracheal intubation because the trachea may be narrowed and the vocal cords thickened.
• Intubation may require fiberoptic laryngoscopy.
• Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem.
• Cranial ultrasound exam & other brain imaging studies; MRI can show ventriculomegaly, but imaging studies often cannot reliably distinguish between brain atrophy & brain compression.
• Lumbar puncture w/measurement of opening pressure of CSF is preferred method to assess degree of pressure elevation [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and determination of phenotype (i.e., severe or attenuated) in an individual diagnosed with MPS I, the evaluations summarized in
Mucopolysaccharidosis Type I: Recommended Evaluations Following Initial Diagnosis in a Newborn
Consultation w/PT, OT, & speech therapist
Consider referral to developmental pediatrician. Experience with the nuances of developmental assessment of children with MPS or other multisystem disorders is critical.
MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
After a new diagnosis of MPS I in a child, the closest hospital and local pediatrician should also be informed.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Mucopolysaccharidosis Type I: Recommended Evaluations in All Individuals
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Consultation w/PT, OT, & speech therapist
• Consider referral to developmental pediatrician. Experience with the nuances of developmental assessment of children with MPS or other multisystem disorders is critical.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There is no cure for MPS I.
A central component of management of MPS I is the initiation of treatment early in the natural history of disease, as symptoms and disease complications are difficult or impossible to reverse. It is essential to promptly determine whether the individual fits the phenotype of severe or attenuated MPS I, as the only therapeutic approach that has been demonstrated to alter the natural history of the central nervous system (CNS) manifestations characteristic of severe MPS I is hematopoietic stem cell transplantation (HSCT), and the age of initiation of HSCT directly influences the ultimate outcome of affected individuals. Additionally, the age of initiation of enzyme replacement therapy in individuals with attenuated MPS I influences the long-term outcome (see
Mucopolysaccharidosis Type I: Targeted Treatment
Improved survival
Reduction in facial coarseness & hepatosplenomegaly, & improvement in hearing
Initial stabilization & improvement in myocardial function w/regression of hypertrophy & normalization of chamber dimensions; however, long-term follow up shows continued progression of valvular involvement
HSCT is the only therapeutic approach that alters the natural history of neurocognitive disease in MPS I.
HSCT has more limited impact on cardiac valvular, ocular, & skeletal manifestations.
Outcome from HSCT is significantly influenced by disease burden at time of diagnosis (& thus age of affected person).
HSCT has been successful in ↓ rate of progression of some findings in children w/severe MPS I.
Premedication w/anti-inflammatory & antihistamine drugs
Intravenous weekly infusion of 100 U/kg of Aldurazyme
Package insert provides details that may differ by country.
↓ & sustained urinary GAG levels
Normalization of hepatic & splenic volume
Stabilization (but not improvement) in respiratory function
Gradual ↑ in shoulder range of motion (typically w/in 1st 2 years, then plateauing)
Improvements in mobility w/in 1st 2 years
Improvement in quality of life index
Currently licensed widely for use in
Aldurazyme
The effect on rate of disease progression & effect when started very early in a person w/attenuated disease has not been comprehensively studied.
ERT does not impact corneal involvement, cardiac valvular disease progression, progressive arthropathy of involved large joints & hands, & progressive spinal diseases w/cord compression.
Carpal tunnel syndrome remains a potential complication.
GAG = glycosaminoglycan
HSCT is not curative but does significantly alter the natural history of the disorder.
HSCT should be used only in carefully selected children with extensive pre-transplantation clinical assessment and counseling in whom systematic long-term monitoring will be possible [
The degree to which HSCT relieves neurologic complications other than progressive intellectual decline is not clear. In children undergoing HSCT before evidence of significant developmental delay (i.e., usually age 12-18 months), HSCT appears to slow the course of cognitive decline. Children showing significant cognitive impairment prior to undergoing HSCT do not show correction of existing impairment.
In part because of increased longevity after HSCT, treated individuals develop increasing pain and stiffness of the hips and knees, carpal tunnel syndrome, spinal cord compression, and progressive thoracolumbar kyphosis. The age of HSCT appears to influence the age of onset of carpal tunnel syndrome and cervical compression.
The skeletal manifestations and corneal clouding continue to progress in children treated with HSCT and in untreated children [
Individuals who have received HSCT require continued multidisciplinary follow up and monitoring related to MPS I complications.
Comparative sib studies indicate improved outcomes when ERT is initiated early in the disease course.
Response is usually within 12 weeks, with some individuals achieving normal values.
As measured by timed-walk measurements; after two years mobility may be variably affected by hip, knee, and spinal disease progression.
Due to the multisystem involvement and progressive nature of this disorder, treatment of affected individuals is complex and requires the support of a multidisciplinary team consisting of metabolic/genetic physicians, specialist physicians including orthopedics, general surgery, ophthalmology, ENT, cardiology, neurosurgery, pulmonary, and developmental pediatrics, as well as specialists in neuropsychology, physiotherapy, occupational therapy, genetic counseling, and social work.
Various orthopedic approaches can be undertaken, particularly in individuals with attenuated disease. Joint replacement and atlanto-occipital stabilization may be necessary. These procedures must be performed at appropriate times in the individual's clinical course and must take into account the presence of other disease complications.
Carpal tunnel syndrome should be treated especially in individuals with attenuated MPS I and individuals with severe MPS I who have had HSCT. Most individuals lack typical symptoms (pain, tingling, or numbness) until severe compression occurs [
Dysostosis multiplex can lead to instability of the spine, including the atlanto-axial joint. Careful positioning and avoidance of hyperextension of the neck are necessary.
Induction of anesthesia for any purpose can be difficult because of the difficulty of maintaining an adequate airway. Smaller-than-anticipated endotracheal tubes may be required for endotracheal intubation because the trachea may be narrowed and the vocal cords thickened.
Intubation may require fiberoptic laryngoscopy.
Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem.
• Improved survival
• Reduction in facial coarseness & hepatosplenomegaly, & improvement in hearing
• Initial stabilization & improvement in myocardial function w/regression of hypertrophy & normalization of chamber dimensions; however, long-term follow up shows continued progression of valvular involvement
• HSCT is the only therapeutic approach that alters the natural history of neurocognitive disease in MPS I.
• HSCT has more limited impact on cardiac valvular, ocular, & skeletal manifestations.
• Outcome from HSCT is significantly influenced by disease burden at time of diagnosis (& thus age of affected person).
• HSCT has been successful in ↓ rate of progression of some findings in children w/severe MPS I.
• Premedication w/anti-inflammatory & antihistamine drugs
• Intravenous weekly infusion of 100 U/kg of Aldurazyme
• Package insert provides details that may differ by country.
• ↓ & sustained urinary GAG levels
• Normalization of hepatic & splenic volume
• Stabilization (but not improvement) in respiratory function
• Gradual ↑ in shoulder range of motion (typically w/in 1st 2 years, then plateauing)
• Improvements in mobility w/in 1st 2 years
• Improvement in quality of life index
• Currently licensed widely for use in
• Aldurazyme
• The effect on rate of disease progression & effect when started very early in a person w/attenuated disease has not been comprehensively studied.
• ERT does not impact corneal involvement, cardiac valvular disease progression, progressive arthropathy of involved large joints & hands, & progressive spinal diseases w/cord compression.
• Carpal tunnel syndrome remains a potential complication.
• Dysostosis multiplex can lead to instability of the spine, including the atlanto-axial joint. Careful positioning and avoidance of hyperextension of the neck are necessary.
• Induction of anesthesia for any purpose can be difficult because of the difficulty of maintaining an adequate airway. Smaller-than-anticipated endotracheal tubes may be required for endotracheal intubation because the trachea may be narrowed and the vocal cords thickened.
• Intubation may require fiberoptic laryngoscopy.
• Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem.
## Targeted Therapies
Mucopolysaccharidosis Type I: Targeted Treatment
Improved survival
Reduction in facial coarseness & hepatosplenomegaly, & improvement in hearing
Initial stabilization & improvement in myocardial function w/regression of hypertrophy & normalization of chamber dimensions; however, long-term follow up shows continued progression of valvular involvement
HSCT is the only therapeutic approach that alters the natural history of neurocognitive disease in MPS I.
HSCT has more limited impact on cardiac valvular, ocular, & skeletal manifestations.
Outcome from HSCT is significantly influenced by disease burden at time of diagnosis (& thus age of affected person).
HSCT has been successful in ↓ rate of progression of some findings in children w/severe MPS I.
Premedication w/anti-inflammatory & antihistamine drugs
Intravenous weekly infusion of 100 U/kg of Aldurazyme
Package insert provides details that may differ by country.
↓ & sustained urinary GAG levels
Normalization of hepatic & splenic volume
Stabilization (but not improvement) in respiratory function
Gradual ↑ in shoulder range of motion (typically w/in 1st 2 years, then plateauing)
Improvements in mobility w/in 1st 2 years
Improvement in quality of life index
Currently licensed widely for use in
Aldurazyme
The effect on rate of disease progression & effect when started very early in a person w/attenuated disease has not been comprehensively studied.
ERT does not impact corneal involvement, cardiac valvular disease progression, progressive arthropathy of involved large joints & hands, & progressive spinal diseases w/cord compression.
Carpal tunnel syndrome remains a potential complication.
GAG = glycosaminoglycan
HSCT is not curative but does significantly alter the natural history of the disorder.
HSCT should be used only in carefully selected children with extensive pre-transplantation clinical assessment and counseling in whom systematic long-term monitoring will be possible [
The degree to which HSCT relieves neurologic complications other than progressive intellectual decline is not clear. In children undergoing HSCT before evidence of significant developmental delay (i.e., usually age 12-18 months), HSCT appears to slow the course of cognitive decline. Children showing significant cognitive impairment prior to undergoing HSCT do not show correction of existing impairment.
In part because of increased longevity after HSCT, treated individuals develop increasing pain and stiffness of the hips and knees, carpal tunnel syndrome, spinal cord compression, and progressive thoracolumbar kyphosis. The age of HSCT appears to influence the age of onset of carpal tunnel syndrome and cervical compression.
The skeletal manifestations and corneal clouding continue to progress in children treated with HSCT and in untreated children [
Individuals who have received HSCT require continued multidisciplinary follow up and monitoring related to MPS I complications.
Comparative sib studies indicate improved outcomes when ERT is initiated early in the disease course.
Response is usually within 12 weeks, with some individuals achieving normal values.
As measured by timed-walk measurements; after two years mobility may be variably affected by hip, knee, and spinal disease progression.
• Improved survival
• Reduction in facial coarseness & hepatosplenomegaly, & improvement in hearing
• Initial stabilization & improvement in myocardial function w/regression of hypertrophy & normalization of chamber dimensions; however, long-term follow up shows continued progression of valvular involvement
• HSCT is the only therapeutic approach that alters the natural history of neurocognitive disease in MPS I.
• HSCT has more limited impact on cardiac valvular, ocular, & skeletal manifestations.
• Outcome from HSCT is significantly influenced by disease burden at time of diagnosis (& thus age of affected person).
• HSCT has been successful in ↓ rate of progression of some findings in children w/severe MPS I.
• Premedication w/anti-inflammatory & antihistamine drugs
• Intravenous weekly infusion of 100 U/kg of Aldurazyme
• Package insert provides details that may differ by country.
• ↓ & sustained urinary GAG levels
• Normalization of hepatic & splenic volume
• Stabilization (but not improvement) in respiratory function
• Gradual ↑ in shoulder range of motion (typically w/in 1st 2 years, then plateauing)
• Improvements in mobility w/in 1st 2 years
• Improvement in quality of life index
• Currently licensed widely for use in
• Aldurazyme
• The effect on rate of disease progression & effect when started very early in a person w/attenuated disease has not been comprehensively studied.
• ERT does not impact corneal involvement, cardiac valvular disease progression, progressive arthropathy of involved large joints & hands, & progressive spinal diseases w/cord compression.
• Carpal tunnel syndrome remains a potential complication.
## Supportive Care
Due to the multisystem involvement and progressive nature of this disorder, treatment of affected individuals is complex and requires the support of a multidisciplinary team consisting of metabolic/genetic physicians, specialist physicians including orthopedics, general surgery, ophthalmology, ENT, cardiology, neurosurgery, pulmonary, and developmental pediatrics, as well as specialists in neuropsychology, physiotherapy, occupational therapy, genetic counseling, and social work.
Various orthopedic approaches can be undertaken, particularly in individuals with attenuated disease. Joint replacement and atlanto-occipital stabilization may be necessary. These procedures must be performed at appropriate times in the individual's clinical course and must take into account the presence of other disease complications.
Carpal tunnel syndrome should be treated especially in individuals with attenuated MPS I and individuals with severe MPS I who have had HSCT. Most individuals lack typical symptoms (pain, tingling, or numbness) until severe compression occurs [
Dysostosis multiplex can lead to instability of the spine, including the atlanto-axial joint. Careful positioning and avoidance of hyperextension of the neck are necessary.
Induction of anesthesia for any purpose can be difficult because of the difficulty of maintaining an adequate airway. Smaller-than-anticipated endotracheal tubes may be required for endotracheal intubation because the trachea may be narrowed and the vocal cords thickened.
Intubation may require fiberoptic laryngoscopy.
Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem.
• Dysostosis multiplex can lead to instability of the spine, including the atlanto-axial joint. Careful positioning and avoidance of hyperextension of the neck are necessary.
• Induction of anesthesia for any purpose can be difficult because of the difficulty of maintaining an adequate airway. Smaller-than-anticipated endotracheal tubes may be required for endotracheal intubation because the trachea may be narrowed and the vocal cords thickened.
• Intubation may require fiberoptic laryngoscopy.
• Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem.
## Surveillance
The recommended minimal schedule of assessments is highlighted in
Persons with MPS I, regardless of disease severity and mode of treatment, should be actively followed at a center that is experienced with the care of individuals with MPS disease.
Mucopolysaccharidosis Type I: Recommended Surveillance
Cranial ultrasound exam & other brain imaging studies; MRI can show ventriculomegaly, but imaging studies often cannot reliably distinguish between brain atrophy & brain compression.
Lumbar puncture w/measurement of opening pressure of CSF is preferred method to assess degree of pressure elevation [
CSF = cerebrospinal fluid; OFC = occipitofrontal circumference
• Cranial ultrasound exam & other brain imaging studies; MRI can show ventriculomegaly, but imaging studies often cannot reliably distinguish between brain atrophy & brain compression.
• Lumbar puncture w/measurement of opening pressure of CSF is preferred method to assess degree of pressure elevation [
## Evaluation of Relatives at Risk
Testing of all at-risk sibs of any age is warranted in order to initiate therapy as early in the course of disease as possible. For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, either test for the familial
See
## Pregnancy Management
Women with MPS I who become pregnant require assessment and frequent monitoring of cardiorespiratory and spinal cord involvement.
## Therapies Under Investigation
With the success of ERT for MPS I demonstrated by clinical trials, an increased effort is under way to improve responsiveness to ERT and to develop other forms of therapy directed at areas/organs that may not be responsive to ERT, such as skeletal and neurologic involvement.
A clinical trial of intrathecal ERT is currently under way in individuals who have evidence of spinal cord involvement. To date, this method has reduced CSF GAG levels and CSF pressure and has been found to be safe. The efficacy of intrathecal ERT is unclear [
Search
## Genetic Counseling
Mucopolysaccharidosis type 1 (MPS I) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an IDUA disease-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Although MPS I is a heterogeneous disorder, affected sibs will have a clinical course similar to the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both
Molecular genetic testing of
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
In families in which the molecular basis of MPS I is known, prenatal testing should be performed by molecular genetic testing, as enzyme activity measurements (particularly those performed by laboratories with limited experience) have potential inherent difficulties.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an IDUA disease-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Although MPS I is a heterogeneous disorder, affected sibs will have a clinical course similar to the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both
• Molecular genetic testing of
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Mucopolysaccharidosis type 1 (MPS I) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an IDUA disease-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Although MPS I is a heterogeneous disorder, affected sibs will have a clinical course similar to the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an IDUA disease-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Although MPS I is a heterogeneous disorder, affected sibs will have a clinical course similar to the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
If both
Molecular genetic testing of
• If both
• Molecular genetic testing of
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
In families in which the molecular basis of MPS I is known, prenatal testing should be performed by molecular genetic testing, as enzyme activity measurements (particularly those performed by laboratories with limited experience) have potential inherent difficulties.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
United Kingdom
Health Resources & Services Administration
•
• Canada
•
•
•
•
• United Kingdom
•
•
•
•
• Health Resources & Services Administration
•
•
•
## Molecular Genetics
Mucopolysaccharidosis Type I: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Mucopolysaccharidosis Type I (
It has been observed that
Notable
Common pathogenic variant in Japan; causes attenuated MPS I
May change ability of α-L-iduronidase to affect catalysis
Deleterious effect appears to be potentiated by a polymorphism, p.Ala361Thr [
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
See
Common Pathogenic Variants in Persons with Mucopolysaccharidosis Type I by Ethnic Background and/or Geographic Location
The most common pathogenic alleles in individuals of European background with MPS I are p.Trp402Ter and p.Gln70Ter.
Includes persons from the Czech Republic and Slovakia
The p.Arg89Gln and c.613_617dupTGCTC alleles appear to be most frequent in the Japanese population, while the p.Trp402Ter and p.Gln70Ter alleles may be completely absent [
• Common pathogenic variant in Japan; causes attenuated MPS I
• May change ability of α-L-iduronidase to affect catalysis
• Deleterious effect appears to be potentiated by a polymorphism, p.Ala361Thr [
## Molecular Pathogenesis
It has been observed that
Notable
Common pathogenic variant in Japan; causes attenuated MPS I
May change ability of α-L-iduronidase to affect catalysis
Deleterious effect appears to be potentiated by a polymorphism, p.Ala361Thr [
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
See
Common Pathogenic Variants in Persons with Mucopolysaccharidosis Type I by Ethnic Background and/or Geographic Location
The most common pathogenic alleles in individuals of European background with MPS I are p.Trp402Ter and p.Gln70Ter.
Includes persons from the Czech Republic and Slovakia
The p.Arg89Gln and c.613_617dupTGCTC alleles appear to be most frequent in the Japanese population, while the p.Trp402Ter and p.Gln70Ter alleles may be completely absent [
• Common pathogenic variant in Japan; causes attenuated MPS I
• May change ability of α-L-iduronidase to affect catalysis
• Deleterious effect appears to be potentiated by a polymorphism, p.Ala361Thr [
## Chapter Notes
Lorne A Clarke, MD (2002-present) Jonathan Heppner, PhD; University of British Columbia (2011-2016)Cheryl L Portigal, MSc; University of British Columbia (2002-2004)
11 April 2024 (aa) Revision:
25 February 2021 (sw) Comprehensive update posted live
11 February 2016 (bp) Comprehensive update posted live
21 July 2011 (me) Comprehensive update posted live
21 September 2007 (me) Comprehensive update posted live
6 August 2004 (me) Comprehensive update posted live
31 October 2002 (me) Review posted live
14 March 2002 (cp) Original submission
• 11 April 2024 (aa) Revision:
• 25 February 2021 (sw) Comprehensive update posted live
• 11 February 2016 (bp) Comprehensive update posted live
• 21 July 2011 (me) Comprehensive update posted live
• 21 September 2007 (me) Comprehensive update posted live
• 6 August 2004 (me) Comprehensive update posted live
• 31 October 2002 (me) Review posted live
• 14 March 2002 (cp) Original submission
## Author History
Lorne A Clarke, MD (2002-present) Jonathan Heppner, PhD; University of British Columbia (2011-2016)Cheryl L Portigal, MSc; University of British Columbia (2002-2004)
## Revision History
11 April 2024 (aa) Revision:
25 February 2021 (sw) Comprehensive update posted live
11 February 2016 (bp) Comprehensive update posted live
21 July 2011 (me) Comprehensive update posted live
21 September 2007 (me) Comprehensive update posted live
6 August 2004 (me) Comprehensive update posted live
31 October 2002 (me) Review posted live
14 March 2002 (cp) Original submission
• 11 April 2024 (aa) Revision:
• 25 February 2021 (sw) Comprehensive update posted live
• 11 February 2016 (bp) Comprehensive update posted live
• 21 July 2011 (me) Comprehensive update posted live
• 21 September 2007 (me) Comprehensive update posted live
• 6 August 2004 (me) Comprehensive update posted live
• 31 October 2002 (me) Review posted live
• 14 March 2002 (cp) Original submission
## Key Sections in this
## References
## Literature Cited
|
[] |
31/10/2002
|
25/2/2021
|
11/4/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mps3
|
mps3
|
[
"MPS III",
"Sanfilippo Syndrome",
"Sanfilippo Syndrome",
"MPS III",
"MPS IIIB",
"MPS IIIC",
"MPS IIID",
"MPS IIIA",
"Alpha-N-acetylglucosaminidase",
"Heparan-alpha-glucosaminide N-acetyltransferase",
"N-acetylglucosamine-6-sulfatase",
"N-sulphoglucosamine sulphohydrolase",
"GNS",
"HGSNAT",
"NAGLU",
"SGSH",
"Mucopolysaccharidosis Type III"
] |
Mucopolysaccharidosis Type III
|
Victoria F Wagner, Hope Northrup
|
Summary Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections. The diagnosis of MPS III is established in a proband with suggestive clinical and laboratory findings in whom either biallelic pathogenic variants in one of four genes ( MPS III is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the MPS III-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
|
MPS = mucopolysaccharidosis
See
## Diagnosis
Formal diagnostic criteria for mucopolysaccharidosis type III (MPS III) have not been established.
MPS III
Language and motor delays
Behavioral problems including hyperactivity and aggressive or defiant behaviors
Sleep disturbances
Intellectual disability
Progressive developmental regression including loss of toilet training, language (if acquired), and motor skills
Seizures
Gait disorders
Coarse facies
Thick hair and hirsutism
Hepatosplenomegaly
Joint stiffness
Hearing loss
Frequent upper-respiratory and ear infections
Inguinal and/or umbilical hernias
Note: Clinical findings alone are not diagnostic and may vary by disease severity.
While quantitative and qualitative analysis of GAGs cannot diagnose specific lysosomal enzyme deficiencies, including MPS III, an abnormality in either quantitative or qualitative GAG analysis is suggestive of an MPS disorder.
GAG electrophoresis can assist in excluding and including certain MPS disorders; however, definitive diagnosis requires additional testing (see
Both methods of urinary GAG analysis have reduced sensitivity, especially if urine is dilute. Normal results on urinary GAG analysis cannot rule out an MPS disorder, particularly in the case of MPS III.
Brain MRI demonstrates abnormalities such as white matter alterations (diffuse prolonged T
Spine MRI reveals spinal stenosis or spinal cord compression that can lead to narrowing of the central canal.
Note: These findings may not be present in early life, may vary by disease severity, and are not specific to MPS III.
The diagnosis of MPS III
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of MPS III is broad and age dependent, individuals with the distinctive findings described in
Those with a phenotype indistinguishable from many other inherited disorders with intellectual disability, developmental regression, and/or significant behavioral issues are more likely to be diagnosed using genomic testing (see
Those in whom the diagnosis of MPS III has not been considered are more likely to be diagnosed using genomic testing (see
When clinical and laboratory findings suggest the diagnosis of MPS III, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucopolysaccharidosis Type III
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
The detection rate for pathogenic variants in
The detection rate for pathogenic variants in
No data on detection rate of gene-targeted deletion/duplication analysis are available.
In a study of 24 individuals, the detection rate for pathogenic variants in
In DNA analysis of 101 individuals with MPS IIIA, the detection rate for pathogenic variants in
The recommended strategy for enzymatic assay is simultaneous enzyme panel testing of all four enzymatic deficiencies associated with MPS IIIA (N-sulphoglucosamine sulphohydrolase), MPS IIIB (alpha-N-acetylglucosaminidase), MPS IIIC (heparan-alpha-glucosaminide N-acetyltransferase), and MPS IIID (N-acetylglucosamine-6-sulfatase). (Note: For alternate enzyme naming systems used by some laboratories, see
Deficiency of both enzymes associated with MPS IIIA and MPS IIID (N-sulphoglucosamine sulphohydrolase and N-acetylglucosamine-6-sulfatase, respectively) – in the context of normal activity of the enzymes associated with MPS IIIB and MPS IIIC – may suggest a diagnosis of
In fluorometric assays for MPS IIIC, endogenous beta-hexosaminidase is used to convert the intermediate substance into the fluorescence-releasing final product. Therefore, individuals with beta-hexosaminidase deficiencies could receive false positive results for MPS IIIC.
•
• Language and motor delays
• Behavioral problems including hyperactivity and aggressive or defiant behaviors
• Sleep disturbances
• Language and motor delays
• Behavioral problems including hyperactivity and aggressive or defiant behaviors
• Sleep disturbances
•
• Intellectual disability
• Progressive developmental regression including loss of toilet training, language (if acquired), and motor skills
• Seizures
• Gait disorders
• Intellectual disability
• Progressive developmental regression including loss of toilet training, language (if acquired), and motor skills
• Seizures
• Gait disorders
•
• Coarse facies
• Thick hair and hirsutism
• Hepatosplenomegaly
• Joint stiffness
• Hearing loss
• Frequent upper-respiratory and ear infections
• Inguinal and/or umbilical hernias
• Coarse facies
• Thick hair and hirsutism
• Hepatosplenomegaly
• Joint stiffness
• Hearing loss
• Frequent upper-respiratory and ear infections
• Inguinal and/or umbilical hernias
• Language and motor delays
• Behavioral problems including hyperactivity and aggressive or defiant behaviors
• Sleep disturbances
• Intellectual disability
• Progressive developmental regression including loss of toilet training, language (if acquired), and motor skills
• Seizures
• Gait disorders
• Coarse facies
• Thick hair and hirsutism
• Hepatosplenomegaly
• Joint stiffness
• Hearing loss
• Frequent upper-respiratory and ear infections
• Inguinal and/or umbilical hernias
• While quantitative and qualitative analysis of GAGs cannot diagnose specific lysosomal enzyme deficiencies, including MPS III, an abnormality in either quantitative or qualitative GAG analysis is suggestive of an MPS disorder.
• GAG electrophoresis can assist in excluding and including certain MPS disorders; however, definitive diagnosis requires additional testing (see
• Both methods of urinary GAG analysis have reduced sensitivity, especially if urine is dilute. Normal results on urinary GAG analysis cannot rule out an MPS disorder, particularly in the case of MPS III.
•
• Brain MRI demonstrates abnormalities such as white matter alterations (diffuse prolonged T
• Spine MRI reveals spinal stenosis or spinal cord compression that can lead to narrowing of the central canal.
• Brain MRI demonstrates abnormalities such as white matter alterations (diffuse prolonged T
• Spine MRI reveals spinal stenosis or spinal cord compression that can lead to narrowing of the central canal.
• Brain MRI demonstrates abnormalities such as white matter alterations (diffuse prolonged T
• Spine MRI reveals spinal stenosis or spinal cord compression that can lead to narrowing of the central canal.
• Those with a phenotype indistinguishable from many other inherited disorders with intellectual disability, developmental regression, and/or significant behavioral issues are more likely to be diagnosed using genomic testing (see
• Those in whom the diagnosis of MPS III has not been considered are more likely to be diagnosed using genomic testing (see
• The recommended strategy for enzymatic assay is simultaneous enzyme panel testing of all four enzymatic deficiencies associated with MPS IIIA (N-sulphoglucosamine sulphohydrolase), MPS IIIB (alpha-N-acetylglucosaminidase), MPS IIIC (heparan-alpha-glucosaminide N-acetyltransferase), and MPS IIID (N-acetylglucosamine-6-sulfatase). (Note: For alternate enzyme naming systems used by some laboratories, see
• Deficiency of both enzymes associated with MPS IIIA and MPS IIID (N-sulphoglucosamine sulphohydrolase and N-acetylglucosamine-6-sulfatase, respectively) – in the context of normal activity of the enzymes associated with MPS IIIB and MPS IIIC – may suggest a diagnosis of
• In fluorometric assays for MPS IIIC, endogenous beta-hexosaminidase is used to convert the intermediate substance into the fluorescence-releasing final product. Therefore, individuals with beta-hexosaminidase deficiencies could receive false positive results for MPS IIIC.
## Suggestive Findings
MPS III
Language and motor delays
Behavioral problems including hyperactivity and aggressive or defiant behaviors
Sleep disturbances
Intellectual disability
Progressive developmental regression including loss of toilet training, language (if acquired), and motor skills
Seizures
Gait disorders
Coarse facies
Thick hair and hirsutism
Hepatosplenomegaly
Joint stiffness
Hearing loss
Frequent upper-respiratory and ear infections
Inguinal and/or umbilical hernias
Note: Clinical findings alone are not diagnostic and may vary by disease severity.
While quantitative and qualitative analysis of GAGs cannot diagnose specific lysosomal enzyme deficiencies, including MPS III, an abnormality in either quantitative or qualitative GAG analysis is suggestive of an MPS disorder.
GAG electrophoresis can assist in excluding and including certain MPS disorders; however, definitive diagnosis requires additional testing (see
Both methods of urinary GAG analysis have reduced sensitivity, especially if urine is dilute. Normal results on urinary GAG analysis cannot rule out an MPS disorder, particularly in the case of MPS III.
Brain MRI demonstrates abnormalities such as white matter alterations (diffuse prolonged T
Spine MRI reveals spinal stenosis or spinal cord compression that can lead to narrowing of the central canal.
Note: These findings may not be present in early life, may vary by disease severity, and are not specific to MPS III.
•
• Language and motor delays
• Behavioral problems including hyperactivity and aggressive or defiant behaviors
• Sleep disturbances
• Language and motor delays
• Behavioral problems including hyperactivity and aggressive or defiant behaviors
• Sleep disturbances
•
• Intellectual disability
• Progressive developmental regression including loss of toilet training, language (if acquired), and motor skills
• Seizures
• Gait disorders
• Intellectual disability
• Progressive developmental regression including loss of toilet training, language (if acquired), and motor skills
• Seizures
• Gait disorders
•
• Coarse facies
• Thick hair and hirsutism
• Hepatosplenomegaly
• Joint stiffness
• Hearing loss
• Frequent upper-respiratory and ear infections
• Inguinal and/or umbilical hernias
• Coarse facies
• Thick hair and hirsutism
• Hepatosplenomegaly
• Joint stiffness
• Hearing loss
• Frequent upper-respiratory and ear infections
• Inguinal and/or umbilical hernias
• Language and motor delays
• Behavioral problems including hyperactivity and aggressive or defiant behaviors
• Sleep disturbances
• Intellectual disability
• Progressive developmental regression including loss of toilet training, language (if acquired), and motor skills
• Seizures
• Gait disorders
• Coarse facies
• Thick hair and hirsutism
• Hepatosplenomegaly
• Joint stiffness
• Hearing loss
• Frequent upper-respiratory and ear infections
• Inguinal and/or umbilical hernias
• While quantitative and qualitative analysis of GAGs cannot diagnose specific lysosomal enzyme deficiencies, including MPS III, an abnormality in either quantitative or qualitative GAG analysis is suggestive of an MPS disorder.
• GAG electrophoresis can assist in excluding and including certain MPS disorders; however, definitive diagnosis requires additional testing (see
• Both methods of urinary GAG analysis have reduced sensitivity, especially if urine is dilute. Normal results on urinary GAG analysis cannot rule out an MPS disorder, particularly in the case of MPS III.
•
• Brain MRI demonstrates abnormalities such as white matter alterations (diffuse prolonged T
• Spine MRI reveals spinal stenosis or spinal cord compression that can lead to narrowing of the central canal.
• Brain MRI demonstrates abnormalities such as white matter alterations (diffuse prolonged T
• Spine MRI reveals spinal stenosis or spinal cord compression that can lead to narrowing of the central canal.
• Brain MRI demonstrates abnormalities such as white matter alterations (diffuse prolonged T
• Spine MRI reveals spinal stenosis or spinal cord compression that can lead to narrowing of the central canal.
## Establishing the Diagnosis
The diagnosis of MPS III
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of MPS III is broad and age dependent, individuals with the distinctive findings described in
Those with a phenotype indistinguishable from many other inherited disorders with intellectual disability, developmental regression, and/or significant behavioral issues are more likely to be diagnosed using genomic testing (see
Those in whom the diagnosis of MPS III has not been considered are more likely to be diagnosed using genomic testing (see
When clinical and laboratory findings suggest the diagnosis of MPS III, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucopolysaccharidosis Type III
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
The detection rate for pathogenic variants in
The detection rate for pathogenic variants in
No data on detection rate of gene-targeted deletion/duplication analysis are available.
In a study of 24 individuals, the detection rate for pathogenic variants in
In DNA analysis of 101 individuals with MPS IIIA, the detection rate for pathogenic variants in
The recommended strategy for enzymatic assay is simultaneous enzyme panel testing of all four enzymatic deficiencies associated with MPS IIIA (N-sulphoglucosamine sulphohydrolase), MPS IIIB (alpha-N-acetylglucosaminidase), MPS IIIC (heparan-alpha-glucosaminide N-acetyltransferase), and MPS IIID (N-acetylglucosamine-6-sulfatase). (Note: For alternate enzyme naming systems used by some laboratories, see
Deficiency of both enzymes associated with MPS IIIA and MPS IIID (N-sulphoglucosamine sulphohydrolase and N-acetylglucosamine-6-sulfatase, respectively) – in the context of normal activity of the enzymes associated with MPS IIIB and MPS IIIC – may suggest a diagnosis of
In fluorometric assays for MPS IIIC, endogenous beta-hexosaminidase is used to convert the intermediate substance into the fluorescence-releasing final product. Therefore, individuals with beta-hexosaminidase deficiencies could receive false positive results for MPS IIIC.
• Those with a phenotype indistinguishable from many other inherited disorders with intellectual disability, developmental regression, and/or significant behavioral issues are more likely to be diagnosed using genomic testing (see
• Those in whom the diagnosis of MPS III has not been considered are more likely to be diagnosed using genomic testing (see
• The recommended strategy for enzymatic assay is simultaneous enzyme panel testing of all four enzymatic deficiencies associated with MPS IIIA (N-sulphoglucosamine sulphohydrolase), MPS IIIB (alpha-N-acetylglucosaminidase), MPS IIIC (heparan-alpha-glucosaminide N-acetyltransferase), and MPS IIID (N-acetylglucosamine-6-sulfatase). (Note: For alternate enzyme naming systems used by some laboratories, see
• Deficiency of both enzymes associated with MPS IIIA and MPS IIID (N-sulphoglucosamine sulphohydrolase and N-acetylglucosamine-6-sulfatase, respectively) – in the context of normal activity of the enzymes associated with MPS IIIB and MPS IIIC – may suggest a diagnosis of
• In fluorometric assays for MPS IIIC, endogenous beta-hexosaminidase is used to convert the intermediate substance into the fluorescence-releasing final product. Therefore, individuals with beta-hexosaminidase deficiencies could receive false positive results for MPS IIIC.
## Option 1
When clinical and laboratory findings suggest the diagnosis of MPS III, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
## Option 2
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucopolysaccharidosis Type III
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
The detection rate for pathogenic variants in
The detection rate for pathogenic variants in
No data on detection rate of gene-targeted deletion/duplication analysis are available.
In a study of 24 individuals, the detection rate for pathogenic variants in
In DNA analysis of 101 individuals with MPS IIIA, the detection rate for pathogenic variants in
The recommended strategy for enzymatic assay is simultaneous enzyme panel testing of all four enzymatic deficiencies associated with MPS IIIA (N-sulphoglucosamine sulphohydrolase), MPS IIIB (alpha-N-acetylglucosaminidase), MPS IIIC (heparan-alpha-glucosaminide N-acetyltransferase), and MPS IIID (N-acetylglucosamine-6-sulfatase). (Note: For alternate enzyme naming systems used by some laboratories, see
Deficiency of both enzymes associated with MPS IIIA and MPS IIID (N-sulphoglucosamine sulphohydrolase and N-acetylglucosamine-6-sulfatase, respectively) – in the context of normal activity of the enzymes associated with MPS IIIB and MPS IIIC – may suggest a diagnosis of
In fluorometric assays for MPS IIIC, endogenous beta-hexosaminidase is used to convert the intermediate substance into the fluorescence-releasing final product. Therefore, individuals with beta-hexosaminidase deficiencies could receive false positive results for MPS IIIC.
• The recommended strategy for enzymatic assay is simultaneous enzyme panel testing of all four enzymatic deficiencies associated with MPS IIIA (N-sulphoglucosamine sulphohydrolase), MPS IIIB (alpha-N-acetylglucosaminidase), MPS IIIC (heparan-alpha-glucosaminide N-acetyltransferase), and MPS IIID (N-acetylglucosamine-6-sulfatase). (Note: For alternate enzyme naming systems used by some laboratories, see
• Deficiency of both enzymes associated with MPS IIIA and MPS IIID (N-sulphoglucosamine sulphohydrolase and N-acetylglucosamine-6-sulfatase, respectively) – in the context of normal activity of the enzymes associated with MPS IIIB and MPS IIIC – may suggest a diagnosis of
• In fluorometric assays for MPS IIIC, endogenous beta-hexosaminidase is used to convert the intermediate substance into the fluorescence-releasing final product. Therefore, individuals with beta-hexosaminidase deficiencies could receive false positive results for MPS IIIC.
## Clinical Characteristics
Mucopolysaccharidosis type III (MPS III), a multisystem lysosomal storage disease that results from glycosaminoglycan (GAG) accumulation, is characterized by extreme clinical variability. Progressive central nervous system degeneration resulting in severe intellectual disability and developmental regression is the most prominent manifestation. Although often present, the somatic findings characteristic of other mucopolysaccharidoses (MPSs) are generally less clinically striking in individuals with MPS III.
Despite the universal neurologic decline in affected individuals, clinical severity varies within and among the four MPS III subtypes and even among members of the same family. Individuals with MPS III may have rapidly or slowly progressing disease [
Life span of individuals with MPS III is unpredictable, but shortened. Death usually occurs in the second or third decade of life secondary to neurologic disease or respiratory tract infections [
In the following descriptions of clinical involvement in MPS III, it is important to note the potential for bias in the medical literature toward ascertaining/reporting clinical data regarding individuals with the most severe and rapidly progressive disease course.
Seizure disorders, common during later disease stages, are not universal.
Progressive neurodegeneration can result in gait disorders, hyperactive reflexes, or spasticity.
After development plateaus, a progressive loss of motor and cognitive skills begins. In rapidly progressing MPS III, regression may start as early as age three to four years. In those with very mild disease, regression may not become apparent until much later [
Klüver-Bucy syndrome (a distinct set of neurobehavioral manifestations with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis) has been reported in individuals with MPS III [
Early-onset dementia is observed in some individuals, particularly those with later-onset or more slowly progressing disease.
Sleep disturbances, present in 80%-95% of individuals, include difficulties with settling and frequent waking. These sleep disorders are thought to result from irregular sleep/wake patterns; some affected individuals demonstrate complete circadian rhythm reversal [
Joint stiffness or contractures and features of dysostosis multiplex are common, although much less severe than in other MPS disorders. Skeletal manifestations are usually not clinically obvious until after the onset of developmental regression and behavioral concerns.
Scoliosis and hip dysplasia, two of the more common skeletal findings, are usually not severe enough to require surgical correction. Femoral head osteonecrosis is a common cause of hip pain.
Carpal tunnel syndrome and trigger digits can occur [
Low bone mass and vitamin D insufficiency or deficiency are prevalent and can be observed as early as the teenage years. Patients with decreased mobility or a history of anti-seizure medication use are especially at risk for osteoporosis and fractures [
Inguinal and umbilical hernias are common. Inguinal hernias may recur after surgical intervention. Umbilical hernias are not usually treated unless they are large or cause other medical concerns.
With progression of neurodegeneration, many affected individuals develop dysphagia and/or problems with chewing and swallowing food, increasing risks for aspiration pneumonia and weight loss secondary to poor feeding in later disease stages.
The
No genotype-phenotype correlations for pathogenic variants in
Genotype-Phenotype Correlations in Mucopolysaccharidosis Type III
Homozygosity for variants causing premature termination of the protein product (nonsense or frameshift pathogenic variants) results in more severe or rapidly progressing phenotypes [
Homozygosity for nonsense variant
The missense pathogenic variants
Homozygotes or compound heterozygotes for variants
The missense
The four lysosomal enzymes associated with MPS III may be referred to by an alternate naming system (see
Alternate Naming System for MPS III-Related Enzymes
The combined estimated prevalence of MPS III is between 1:50,000 and 1:250,000 depending on the population studied [
Subtypes MPS IIIA and MPS IIIB are the most commonly observed, with estimated incidences of 1:100,000 and 1:200,000, respectively [
Of note, some subtypes of MPS III are more common in certain geographic regions:
MPS IIIA is globally the most common form of MPS III and the most common type observed in many northern and eastern European nations. It is particularly common in the Cayman Islands, with an incidence estimated as high as 1:400 births, secondary to 1/10 carrier frequency of
MPS IIIB is more common in southern European populations.
MPS IIID has a higher-than-usual prevalence in Italian and Turkish populations [
• Homozygosity for variants causing premature termination of the protein product (nonsense or frameshift pathogenic variants) results in more severe or rapidly progressing phenotypes [
• Homozygosity for nonsense variant
• The missense pathogenic variants
• Homozygotes or compound heterozygotes for variants
• The missense
• MPS IIIA is globally the most common form of MPS III and the most common type observed in many northern and eastern European nations. It is particularly common in the Cayman Islands, with an incidence estimated as high as 1:400 births, secondary to 1/10 carrier frequency of
• MPS IIIB is more common in southern European populations.
• MPS IIID has a higher-than-usual prevalence in Italian and Turkish populations [
## Clinical Description
Mucopolysaccharidosis type III (MPS III), a multisystem lysosomal storage disease that results from glycosaminoglycan (GAG) accumulation, is characterized by extreme clinical variability. Progressive central nervous system degeneration resulting in severe intellectual disability and developmental regression is the most prominent manifestation. Although often present, the somatic findings characteristic of other mucopolysaccharidoses (MPSs) are generally less clinically striking in individuals with MPS III.
Despite the universal neurologic decline in affected individuals, clinical severity varies within and among the four MPS III subtypes and even among members of the same family. Individuals with MPS III may have rapidly or slowly progressing disease [
Life span of individuals with MPS III is unpredictable, but shortened. Death usually occurs in the second or third decade of life secondary to neurologic disease or respiratory tract infections [
In the following descriptions of clinical involvement in MPS III, it is important to note the potential for bias in the medical literature toward ascertaining/reporting clinical data regarding individuals with the most severe and rapidly progressive disease course.
Seizure disorders, common during later disease stages, are not universal.
Progressive neurodegeneration can result in gait disorders, hyperactive reflexes, or spasticity.
After development plateaus, a progressive loss of motor and cognitive skills begins. In rapidly progressing MPS III, regression may start as early as age three to four years. In those with very mild disease, regression may not become apparent until much later [
Klüver-Bucy syndrome (a distinct set of neurobehavioral manifestations with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis) has been reported in individuals with MPS III [
Early-onset dementia is observed in some individuals, particularly those with later-onset or more slowly progressing disease.
Sleep disturbances, present in 80%-95% of individuals, include difficulties with settling and frequent waking. These sleep disorders are thought to result from irregular sleep/wake patterns; some affected individuals demonstrate complete circadian rhythm reversal [
Joint stiffness or contractures and features of dysostosis multiplex are common, although much less severe than in other MPS disorders. Skeletal manifestations are usually not clinically obvious until after the onset of developmental regression and behavioral concerns.
Scoliosis and hip dysplasia, two of the more common skeletal findings, are usually not severe enough to require surgical correction. Femoral head osteonecrosis is a common cause of hip pain.
Carpal tunnel syndrome and trigger digits can occur [
Low bone mass and vitamin D insufficiency or deficiency are prevalent and can be observed as early as the teenage years. Patients with decreased mobility or a history of anti-seizure medication use are especially at risk for osteoporosis and fractures [
Inguinal and umbilical hernias are common. Inguinal hernias may recur after surgical intervention. Umbilical hernias are not usually treated unless they are large or cause other medical concerns.
With progression of neurodegeneration, many affected individuals develop dysphagia and/or problems with chewing and swallowing food, increasing risks for aspiration pneumonia and weight loss secondary to poor feeding in later disease stages.
## Phenotype Correlations by Gene
The
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for pathogenic variants in
Genotype-Phenotype Correlations in Mucopolysaccharidosis Type III
Homozygosity for variants causing premature termination of the protein product (nonsense or frameshift pathogenic variants) results in more severe or rapidly progressing phenotypes [
Homozygosity for nonsense variant
The missense pathogenic variants
Homozygotes or compound heterozygotes for variants
The missense
• Homozygosity for variants causing premature termination of the protein product (nonsense or frameshift pathogenic variants) results in more severe or rapidly progressing phenotypes [
• Homozygosity for nonsense variant
• The missense pathogenic variants
• Homozygotes or compound heterozygotes for variants
• The missense
## Nomenclature
The four lysosomal enzymes associated with MPS III may be referred to by an alternate naming system (see
Alternate Naming System for MPS III-Related Enzymes
## Prevalence
The combined estimated prevalence of MPS III is between 1:50,000 and 1:250,000 depending on the population studied [
Subtypes MPS IIIA and MPS IIIB are the most commonly observed, with estimated incidences of 1:100,000 and 1:200,000, respectively [
Of note, some subtypes of MPS III are more common in certain geographic regions:
MPS IIIA is globally the most common form of MPS III and the most common type observed in many northern and eastern European nations. It is particularly common in the Cayman Islands, with an incidence estimated as high as 1:400 births, secondary to 1/10 carrier frequency of
MPS IIIB is more common in southern European populations.
MPS IIID has a higher-than-usual prevalence in Italian and Turkish populations [
• MPS IIIA is globally the most common form of MPS III and the most common type observed in many northern and eastern European nations. It is particularly common in the Cayman Islands, with an incidence estimated as high as 1:400 births, secondary to 1/10 carrier frequency of
• MPS IIIB is more common in southern European populations.
• MPS IIID has a higher-than-usual prevalence in Italian and Turkish populations [
## Genetically Related (Allelic) Disorders
Germline pathogenic variants in
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Mucopolysaccharidosis Type III
Coarse facies
Frequent ear infections
Inguinal & umbilical hernias
Dysostosis multiplex
Corneal clouding
Significant DD seen in 1st year of life
Death at age ~2 yrs from neurologic decline & multisystem involvement
Coarse facies
Frequent upper-respiratory & ear infections
Dysostosis multiplex
Slight corneal clouding
Normal to mildly impaired cognitive development
Coarse facies
Frequent upper-respiratory & ear infections
Inguinal & umbilical hernias
DD & cognitive decline in severe form of disease
Hepatosplenomegaly
Dysostosis multiplex
Placid behavior in contrast to aggressive or hyperactive
Abnormal heparan & dermatan sulfate in urine GAG analysis
Corneal clouding
Hydrocephalus
Coarse facies
Frequent upper-respiratory & ear infections
Inguinal & umbilical hernias
DD & cognitive decline in severe form of disease
Behavioral abnormalities
Hepatosplenomegaly
Dysostosis multiplex
Observed almost exclusively in males
Abnormal heparan & dermatan sulfate in urine GAG analysis
Hydrocephalus
Hepatosplenomegaly
DD & cognitive impairment
Psychomotor regression
Hirsutism
Coarse facies
Ichthyosis
Abnormal enzymatic activity for multiple sulfatases
Speech delay
DD & cognitive impairment
Sleep disturbance
Behavioral outbursts
Hyperactivity
Infantile hypotonia & failure to thrive
Mild-to-moderate ID w/out regression
Characteristic dysmorphic facies
Stereotypic "lick & flip" & "self-hug" behaviors
AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; ML = mucolipidosis; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked
Smith-Magenis syndrome is caused either by a 17p11.2 deletion that includes
• Coarse facies
• Frequent ear infections
• Inguinal & umbilical hernias
• Dysostosis multiplex
• Corneal clouding
• Significant DD seen in 1st year of life
• Death at age ~2 yrs from neurologic decline & multisystem involvement
• Coarse facies
• Frequent upper-respiratory & ear infections
• Dysostosis multiplex
• Slight corneal clouding
• Normal to mildly impaired cognitive development
• Coarse facies
• Frequent upper-respiratory & ear infections
• Inguinal & umbilical hernias
• DD & cognitive decline in severe form of disease
• Hepatosplenomegaly
• Dysostosis multiplex
• Placid behavior in contrast to aggressive or hyperactive
• Abnormal heparan & dermatan sulfate in urine GAG analysis
• Corneal clouding
• Hydrocephalus
• Coarse facies
• Frequent upper-respiratory & ear infections
• Inguinal & umbilical hernias
• DD & cognitive decline in severe form of disease
• Behavioral abnormalities
• Hepatosplenomegaly
• Dysostosis multiplex
• Observed almost exclusively in males
• Abnormal heparan & dermatan sulfate in urine GAG analysis
• Hydrocephalus
• Hepatosplenomegaly
• DD & cognitive impairment
• Psychomotor regression
• Hirsutism
• Coarse facies
• Ichthyosis
• Abnormal enzymatic activity for multiple sulfatases
• Speech delay
• DD & cognitive impairment
• Sleep disturbance
• Behavioral outbursts
• Hyperactivity
• Infantile hypotonia & failure to thrive
• Mild-to-moderate ID w/out regression
• Characteristic dysmorphic facies
• Stereotypic "lick & flip" & "self-hug" behaviors
## Management
To establish the extent of disease and needs in an individual diagnosed with mucopolysaccharidosis type III (MPS III), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mucopolysaccharidosis Type III
ASD = autism spectrum disorder; BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; OT = occupational therapist; PT = physical therapist
It is important to note that developmental advances made by individuals with MPS III secondary to implementation of therapy may be short-lived as a result of the progressive nature of disease.
Treatment of Manifestations in Individuals with Mucopolysaccharidosis Type III
Treatment as determined by psychiatrist
Creation of physically safe environment at home
Consider use of melatonin or other medication [
Consider polysomnogram if suspicion of sleep apnea.
Treatment as determined by orthopedist
PT or hydrotherapy for joint stiffness
Vitamin D therapy in the context of low BMD [
Treatment as determined by otolaryngologist
Consider airway clearance therapy, particularly in later disease stages.
The importance of routine immunizations & annual influenza vaccines should be emphasized.
Pneumococcal vaccine may be considered.
ASM = anti-seizure medication; BMD = bone mineral density; OT = occupational therapy; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
As MPS III is a neurodegenerative, progressive, and life-limiting illness, resources for palliative care that are available to help reduce suffering from disease manifestations or improve quality of life should be considered and discussed with family members. Specific support resources desired by families will vary, but options for palliative care include respite care, assistance with symptom management, psychological and other forms of support, assistance with medical decision making, and assistance with creating and updating a care plan.
Due to the progression of MPS III manifestations over time, improvements in symptoms resulting from proper management are not typically long lasting. Consequently, monitoring for deterioration in the affected individual is an appropriate and important part of surveillance.
Recommended Surveillance for Individuals with Mucopolysaccharidosis Type III
Monitor joint mobility; assessment by orthopedist.
Monitor BMD w/DXA & vitamin D metabolism studies.
BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry
Though airway management during procedures with anesthesia is not typically difficult, anesthesia conducted in ill-equipped medical centers or by personnel with limited experience with patients with difficult airways is not recommended [
Hip surgery is not recommended for individuals with MPS III due to the development of osteonecrosis and collapse of the femoral head [
To minimize risks posed by unpredictable behavior, children with MPS III should be supervised around or have their environment adapted to avoid the following for their safety:
Sharp or fragile furniture
Sharp or fragile toys
Large electronics
High structures or surfaces that pose risks of falls and other injuries
See
Very few individuals with MPS III are known to have reproduced. In one case report a woman with slowly progressive MPS IIIB had an unremarkable pregnancy and a healthy child [
Despite ongoing research for a variety of therapeutic options for affected individuals, no treatments are currently clinically available for treatment of primary manifestations of MPS III.
Other methods of ERT administration, such as intrathecal injections, are effective in delivering ERT to normalize substrate storage in the CNS of MPS III animal models [
In vitro studies have shown that siRNA targeting of genes that play a role in synthesis of heparan sulfate leads to decreased heparan sulfate synthesis, decreased GAG storage, and a reversal of the phenotype in fibroblasts of patients with MPS IIIC [
Although genistein inhibits heparan sulfate synthesis and decreases accumulation of heparan sulfate in plasma and urine, it does not improve manifestations of MPS III at doses of 5 mg/kg/day or 10 mg/kg/day [
The use of a variety of MPS III-related gene-encoding viral vectors in mouse and canine models of MPS IIIA, MPS IIIB, and MPS IIID has increased deficient enzyme activity and decreased GAG storage [
In children with MPS IIIA or MPS IIIB, intracerebral gene therapy has been well tolerated; findings suggest neurocognitive benefits, including moderate improvements in sleep and behavior. The most remarkable results are observed in the youngest patients, suggesting that earlier therapy may be more beneficial [
Search
• Treatment as determined by psychiatrist
• Creation of physically safe environment at home
• Consider use of melatonin or other medication [
• Consider polysomnogram if suspicion of sleep apnea.
• Treatment as determined by orthopedist
• PT or hydrotherapy for joint stiffness
• Vitamin D therapy in the context of low BMD [
• Treatment as determined by otolaryngologist
• Consider airway clearance therapy, particularly in later disease stages.
• The importance of routine immunizations & annual influenza vaccines should be emphasized.
• Pneumococcal vaccine may be considered.
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Monitor joint mobility; assessment by orthopedist.
• Monitor BMD w/DXA & vitamin D metabolism studies.
• Sharp or fragile furniture
• Sharp or fragile toys
• Large electronics
• High structures or surfaces that pose risks of falls and other injuries
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with mucopolysaccharidosis type III (MPS III), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mucopolysaccharidosis Type III
ASD = autism spectrum disorder; BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; OT = occupational therapist; PT = physical therapist
## Treatment of Manifestations
It is important to note that developmental advances made by individuals with MPS III secondary to implementation of therapy may be short-lived as a result of the progressive nature of disease.
Treatment of Manifestations in Individuals with Mucopolysaccharidosis Type III
Treatment as determined by psychiatrist
Creation of physically safe environment at home
Consider use of melatonin or other medication [
Consider polysomnogram if suspicion of sleep apnea.
Treatment as determined by orthopedist
PT or hydrotherapy for joint stiffness
Vitamin D therapy in the context of low BMD [
Treatment as determined by otolaryngologist
Consider airway clearance therapy, particularly in later disease stages.
The importance of routine immunizations & annual influenza vaccines should be emphasized.
Pneumococcal vaccine may be considered.
ASM = anti-seizure medication; BMD = bone mineral density; OT = occupational therapy; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
As MPS III is a neurodegenerative, progressive, and life-limiting illness, resources for palliative care that are available to help reduce suffering from disease manifestations or improve quality of life should be considered and discussed with family members. Specific support resources desired by families will vary, but options for palliative care include respite care, assistance with symptom management, psychological and other forms of support, assistance with medical decision making, and assistance with creating and updating a care plan.
• Treatment as determined by psychiatrist
• Creation of physically safe environment at home
• Consider use of melatonin or other medication [
• Consider polysomnogram if suspicion of sleep apnea.
• Treatment as determined by orthopedist
• PT or hydrotherapy for joint stiffness
• Vitamin D therapy in the context of low BMD [
• Treatment as determined by otolaryngologist
• Consider airway clearance therapy, particularly in later disease stages.
• The importance of routine immunizations & annual influenza vaccines should be emphasized.
• Pneumococcal vaccine may be considered.
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Palliative Care
As MPS III is a neurodegenerative, progressive, and life-limiting illness, resources for palliative care that are available to help reduce suffering from disease manifestations or improve quality of life should be considered and discussed with family members. Specific support resources desired by families will vary, but options for palliative care include respite care, assistance with symptom management, psychological and other forms of support, assistance with medical decision making, and assistance with creating and updating a care plan.
## Surveillance
Due to the progression of MPS III manifestations over time, improvements in symptoms resulting from proper management are not typically long lasting. Consequently, monitoring for deterioration in the affected individual is an appropriate and important part of surveillance.
Recommended Surveillance for Individuals with Mucopolysaccharidosis Type III
Monitor joint mobility; assessment by orthopedist.
Monitor BMD w/DXA & vitamin D metabolism studies.
BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry
• Monitor joint mobility; assessment by orthopedist.
• Monitor BMD w/DXA & vitamin D metabolism studies.
## Agents/Circumstances to Avoid
Though airway management during procedures with anesthesia is not typically difficult, anesthesia conducted in ill-equipped medical centers or by personnel with limited experience with patients with difficult airways is not recommended [
Hip surgery is not recommended for individuals with MPS III due to the development of osteonecrosis and collapse of the femoral head [
To minimize risks posed by unpredictable behavior, children with MPS III should be supervised around or have their environment adapted to avoid the following for their safety:
Sharp or fragile furniture
Sharp or fragile toys
Large electronics
High structures or surfaces that pose risks of falls and other injuries
• Sharp or fragile furniture
• Sharp or fragile toys
• Large electronics
• High structures or surfaces that pose risks of falls and other injuries
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Very few individuals with MPS III are known to have reproduced. In one case report a woman with slowly progressive MPS IIIB had an unremarkable pregnancy and a healthy child [
## Therapies Under Investigation
Despite ongoing research for a variety of therapeutic options for affected individuals, no treatments are currently clinically available for treatment of primary manifestations of MPS III.
Other methods of ERT administration, such as intrathecal injections, are effective in delivering ERT to normalize substrate storage in the CNS of MPS III animal models [
In vitro studies have shown that siRNA targeting of genes that play a role in synthesis of heparan sulfate leads to decreased heparan sulfate synthesis, decreased GAG storage, and a reversal of the phenotype in fibroblasts of patients with MPS IIIC [
Although genistein inhibits heparan sulfate synthesis and decreases accumulation of heparan sulfate in plasma and urine, it does not improve manifestations of MPS III at doses of 5 mg/kg/day or 10 mg/kg/day [
The use of a variety of MPS III-related gene-encoding viral vectors in mouse and canine models of MPS IIIA, MPS IIIB, and MPS IIID has increased deficient enzyme activity and decreased GAG storage [
In children with MPS IIIA or MPS IIIB, intracerebral gene therapy has been well tolerated; findings suggest neurocognitive benefits, including moderate improvements in sleep and behavior. The most remarkable results are observed in the youngest patients, suggesting that earlier therapy may be more beneficial [
Search
## Genetic Counseling
Mucopolysaccharidosis type III (MPS III) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the MPS III-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Mucopolysaccharidosis type III (MPS III) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the MPS III-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Australia
Canada
United Kingdom
•
•
•
• Australia
•
•
•
•
• Canada
•
•
• United Kingdom
•
•
•
## Molecular Genetics
Mucopolysaccharidosis Type III: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Mucopolysaccharidosis Type III (
Notable Pathogenic Variants in Genes Causing Mucopolysaccharidosis Type III
Homozygotes w/rapidly progressing MPS IIIA
Common in northern European populations & founder variant in the Cayman Islands [
Variants listed in the table have been provided by the authors.
Genes are listed alphabetically.
Klüver-Bucy syndrome, a neurobehavioral phenotype that can be observed in MPS III
See
See
• Homozygotes w/rapidly progressing MPS IIIA
• Common in northern European populations & founder variant in the Cayman Islands [
## Molecular Pathogenesis
Notable Pathogenic Variants in Genes Causing Mucopolysaccharidosis Type III
Homozygotes w/rapidly progressing MPS IIIA
Common in northern European populations & founder variant in the Cayman Islands [
Variants listed in the table have been provided by the authors.
Genes are listed alphabetically.
Klüver-Bucy syndrome, a neurobehavioral phenotype that can be observed in MPS III
See
See
• Homozygotes w/rapidly progressing MPS IIIA
• Common in northern European populations & founder variant in the Cayman Islands [
## References
## Literature Cited
## Chapter Notes
Victoria Wagner, MS, CGC, is a genetic counselor at McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and is involved in general and developmental screening genetics clinics. She also has clinical and research interests in the lysosomal storage diseases (LSDs), particularly in the mucopolysaccharidoses (MPSs).
Hope Northrup, MD, is a geneticist and physician scientist at McGovern Medical School at UTHealth Houston. Her research and clinical interests include tuberous sclerosis complex (TSC) and a variety of inborn errors of metabolism – most notably, phenylketonuria (PKU) and LSDs.
19 September 2019 (bp) Review posted live
13 March 2019 (vw) Original submission
• 19 September 2019 (bp) Review posted live
• 13 March 2019 (vw) Original submission
## Author Notes
Victoria Wagner, MS, CGC, is a genetic counselor at McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and is involved in general and developmental screening genetics clinics. She also has clinical and research interests in the lysosomal storage diseases (LSDs), particularly in the mucopolysaccharidoses (MPSs).
Hope Northrup, MD, is a geneticist and physician scientist at McGovern Medical School at UTHealth Houston. Her research and clinical interests include tuberous sclerosis complex (TSC) and a variety of inborn errors of metabolism – most notably, phenylketonuria (PKU) and LSDs.
## Revision History
19 September 2019 (bp) Review posted live
13 March 2019 (vw) Original submission
• 19 September 2019 (bp) Review posted live
• 13 March 2019 (vw) Original submission
|
[
"F Andrade, L Aldámiz-Echevarría, M Llarena, ML Couce. Sanfilippo syndrome: Overall review.. Pediatr Int. 2015;57:331-8",
"EG Berger-Plantinga, JA Vanneste, JE Groener, MJ van Schooneveld. Adult-onset dementia and retinitis pigmentosa due to mucopolysaccharidosis III-C in two sisters.. J Neurol. 2004;251:479-81",
"I Canals, N Benetó, M Cozar, L Vilageliu, D. Grinberg. EXTL2 and EXTL3 inhibition with siRNAs as a promising substrate reduction therapy for Sanfilippo C syndrome.. Sci Rep. 2015;5:13654",
"KJ Champion, MJ Basehore, T Wood, A Destrée, P Vannuffel, I Maystadt. Identification and characterization of a novel homozygous deletion in the alpha-N-acetylglucosaminidase gene in a patient with Sanfilippo type B syndrome (mucopolysaccharidosis IIIB).. Mol Genet Metab. 2010;100:51-6",
"BM Clark, J Sprung, TN Weingarten, ME Warner. Anesthesia for patients with mucopolysaccharidoses: Comprehensive review of the literature with emphasis on airway management.. Bosn J Basic Med Sci. 2018;18:1-7",
"EM Cross, DJ Hare. Behavioural phenotypes of the mucopolysaccharide disorders: a systematic literature review of cognitive, motor, social, linguistic and behavioural presentation in the MPS disorders.. J Inherit Metab Dis. 2013;36:189-200",
"J de Ruijter, MJ Valstar, M Narajczyk, G Wegrzyn, W Kulik, L Ijlst, T Wagemans, WM van der Wal, FA Wijburg. Genistein in Sanfilippo disease: a randomized controlled crossover trial.. Ann Neurol. 2012;71:110-20",
"H Hu, C Hübner, Z Lukacs, L Musante, E Gill, TF Wienker, HH Ropers, E Knierim, M Schuelke. Klüver-Bucy syndrome associated with a recessive variant in HGSNAT in two siblings with Mucopolysaccharidosis type IIIC (Sanfilippo C).. Eur J Hum Genet. 2017;25:253-6",
"SA Jones, C Breen, F Heap, S Rust, J de Ruijter, E Tump, JP Marchal, L Pan, Y Qiu, JK Chung, N Nair, PA Haslett, AJ Barbier, FA Wijburg. A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA.. Mol Genet Metab. 2016;118:198-205",
"S Kalkan Ucar, B Ozbaran, N Demiral, Z Yuncu, S Erermis, M. Coker. Clinical overview of children with mucopolysaccharidosis type IIIA and effect of Risperidone treatment on children and their mothers psychological status.. Brain Dev. 2010;32:156-61",
"SA Khan, H Peracha, D Ballhausen, A Wiesbauer, M Rohrbach, M Gautschi, RW Mason, R Giugliani, Y Suzuki, KE Orii, T Orii, S Tomatsu. Epidemiology of mucopolysaccharidoses.. Mol Genet Metab. 2017;121:227-40",
"B King, S Hassiotis, T Rozaklis, H Beard, PJ Trim, MF Snel, JJ Hopwood, KM Hemsley. Low-dose, continuous enzyme replacement therapy ameliorates brain pathology in the neurodegenerative lysosomal disorder mucopolysaccharidosis type IIIA.. J Neurochem. 2016;137:409-22",
"C Lavery, CJ Hendriksz, SA Jones. Mortality in patients with Sanfilippo syndrome.. Orphanet J Rare Dis. 2017;12:168",
"LV Mahon, M Lomax, S Grant, E Cross, DJ Hare, JE Wraith, S Jones, B Bigger, K Langford-Smith, M Canal. Assessment of sleep in children with mucopolysaccharidosis type III.. PLoS One. 2014;9",
"A Meyer, K Kossow, A Gal, C Steglich, C Mühlhausen, K Ullrich, T Braulke, N. Muschol. The mutation p.Ser298Pro in the sulphamidase gene (SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis type IIIA (Sanfilippo A syndrome).. Hum Mutat. 2008;29:770",
"SCM Nijmeijer, RHACM de Bruin-Bon, FA Wijburg, IM Kuipers. Cardiac disease in mucopolysaccharidosis type III.. J Inherit Metab Dis. 2019;42:276-85",
"BG Nur, H Nur, E Mihci. Bone mineral density in patients with mucopolysaccharidosis type III.. J Bone Miner Metab. 2017;35:338-43",
"M Potegal, B Yund, K Rudser, A Ahmed, K Delaney, I Nestrasil, CB Whitley, EG Shapiro. Mucopolysaccharidosis Type IIIA presents as a variant of Klüver-Bucy syndrome.. J Clin Exp Neuropsychol. 2013;35:608-16",
"PL Rady, S Surendran, AT Vu, JC Hawkins, K Michals-Matalon, SK Tyring, J Merren, AK Kumar, R Matalon. Founder mutation R245H of Sanfilippo syndrome type A in the Cayman Islands.. Genet Test. 2002;6:211-5",
"GJ Ruijter, MJ Valstar, JM van de Kamp, RM van der Helm, S Durand, OP van Diggelen, RA Wevers, BJ Poorthuis, AV Pshezhetsky, FA Wijburg. Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands.. Mol Genet Metab. 2008;93:104-11",
"M Scarpa, PJ Orchard, A Schulz, PI Dickson, ME Haskins, ML Escolar, R Giugliani. Treatment of brain disease in the mucopolysaccharidoses.. Mol Genet Metab. 2017;122S:25-34",
"M Tardieu, M Zérah, B Husson, S de Bournonville, K Deiva, C Adamsbaum, F Vincent, M Hocquemiller, C Broissand, V Furlan, A Ballabio, A Fraldi, RG Crystal, T Baugnon, T Roujeau, JM Heard, O Danos. Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial.. Hum Gene Ther. 2014;25:506-16",
"M Tardieu, M Zérah, ML Gougeon, J Ausseil, S de Bournonville, B Husson, D Zafeiriou, G Parenti, P Bourget, B Poirier, V Furlan, C Artaud, T Baugnon, T Roujeau, RG Crystal, C Meyer, K Deiva, JM Heard. Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial.. Lancet Neurol. 2017;16:712-20",
"MJ Valstar, AM Bertoli-Avella, MW Wessels, GJ Ruijter, B de Graaf, R Olmer, P Elfferich, S Neijs, R Kariminejad, F Suheyl Ezgü, A Tokatli, B Czartoryska, AN Bosschaart, F van den Bos-Terpstra, H Puissant, F Bürger, H Omran, D Eckert, M Filocamo, E Simeonov, PJ Willems, RA Wevers, MF Niermeijer, DJ Halley, BJ Poorthuis, OP van Diggelen. Mucopolysaccharidosis type IIID: 12 new patients and 15 novel mutations.. Hum Mutat. 2010a;31:E1348-60",
"MJ Valstar, HT Bruggenwirth, R Olmer, RA Wevers, FW Verheijen, BJ Poorthuis, DJ Halley, FA Wijburg. Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype.. J Inherit Metab Dis. 2010b;33:759-67",
"MJ Valstar, S Neijs, HT Bruggenwirth, R Olmer, GJ Ruijter, RA Wevers, OP van Diggelen, BJ Poorthuis, DJ Halley, FA Wijburg. Mucopolysaccharidosis type IIIA: clinical spectrum and genotype-phenotype correlations.. Ann Neurol. 2010c;68:876-87",
"WM Verhoeven, R Csepán, CL Marcelis, DJ Lefeber, JI Egger, S Tuinier. Sanfilippo B in an elderly female psychiatric patient: a rare but relevant diagnosis in presenile dementia.. Acta Psychiatr Scand. 2010;122:162-5",
"B Weber, XH Guo, WJ Kleijer, JJ van de Kamp, BJ Poorthuis, JJ Hopwood. Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes.. Eur J Hum Genet. 1999;7:34-44",
"KK White, LA Karol, DR White, S Hale. Musculoskeletal manifestations of Sanfilippo Syndrome (mucopolysaccharidosis type III).. J Pediatr Orthop. 2011;31:594-8",
"CB Whitley, M Cleary, KE Mengel, P Harmatz, E Shapiro, I Nestrasil, P Haslett, D Whiteman, D Alexanderian. Observational prospective natural history of patients with Sanfilippo syndrome type B.. J Pediatr. 2018;197:198-206.e2",
"HG Zhao, EL Aronovich, CB Whitley. Genotype-phenotype correspondence in Sanfilippo syndrome type B.. Am J Hum Genet. 1998;62:53-63",
"T Zelei, K Csetneki, Z Vokó, C. Siffel. Epidemiology of Sanfilippo syndrome: results of a systematic literature review.. Orphanet J Rare Dis. 2018;13:53"
] |
19/9/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mps4a
|
mps4a
|
[
"Morquio A Disease",
"Morquio Syndrome Type A",
"MPS IVA",
"MPS IVA",
"Morquio Syndrome Type A",
"Morquio A Disease",
"N-acetylgalactosamine-6-sulfatase",
"GALNS",
"Mucopolysaccharidosis Type IVA"
] |
Mucopolysaccharidosis Type IVA
|
Debra S Regier, Matthew Oetgen, Pranoot Tanpaiboon
|
Summary The phenotypic spectrum of mucopolysaccharidosis IVA (MPS IVA) is a continuum that ranges from a severe and rapidly progressive early-onset form to a slowly progressive later-onset form. Children with MPS IVA typically have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years, often first manifesting as kyphoscoliosis, genu valgum (knock-knee), and pectus carinatum; the slowly progressive form may not become evident until late childhood or adolescence, often first manifesting as hip problems (pain, stiffness, and Legg Perthes disease). Progressive bone and joint involvement leads to short stature, and eventually to disabling pain and arthritis. Involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord is a common complication that results in neurologic impairment. Children with MPS IVA have normal intellectual abilities at the outset of the disease. The diagnosis of MPS IVA is established in a proband by identification of low N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity in cultured fibroblasts or leukocytes or by identification of biallelic pathogenic variants in MPS IVA is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
Mucopolysaccharidosis IVA (MPS IVA)
The majority of affected individuals do not have distinctive clinical findings at birth. However, some features may be present at birth including prominent forehead, pectus carinatum, kyphosis, and abnormal spine radiograph (see
History of adenoidectomy, tonsillectomy, hernia repair, ear ventilation tubes (general findings for all MPS disorders)
History of cervical spine decompression and/or fusion or a history of surgery for limb alignments (unique to MPS IVA among all MPS disorders)
Respiratory compromise (sleep apnea, endurance limitations, snoring)
Cardiac valve abnormalities
Dental abnormalities
Marked disproportionate short stature with short trunk and normal limbs (arm span exceeds height)
Ulnar deviation of the wrists (
Pectus carinatum and flaring of the lower rib cage (
Gibbus (short-segment structural thoracolumbar kyphosis resulting in sharp angulation of the back), kyphosis, and scoliosis
Genu valgum (knock-knee) (
Hypermobile joints
Waddling gait with frequent falls
Odontoid hypoplasia with subsequent cervical instability (
Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture) (
Gibbus (structural kyphosis) with wedging of one or more adjacent vertebrae (
Note: The radiographic abnormalities of the lumbar spine can be detected at birth in infants with rapidly progressive disease [
Scoliosis
Pectus carinatum or (less frequently) excavatum
Short ulnas, ulnar deviation of the radial epiphysis, and delayed bone maturation
Short metacarpals with the proximal ends of the second to fifth metacarpals rounded or pointed [
Flared iliac wings, flattening of femoral epiphyses (
Note: Skeletal abnormalities are observed before physical abnormalities [
Note: The presence of KS (on qualitative analysis) with or without abnormal quantitative urine GAGs has been observed in some affected individuals.
Elevated KS indicates deficiency of either the enzyme N-acetylgalactosamine 6-sulfatase (in MPS IVA) or the enzyme B-galactosidase (in
Note: Urine KS levels in younger individuals are higher than in older individuals due to the decrease in cartilage formation in older persons. The urine KS levels in individuals with MPS IVA and healthy controls were highest at age one to five years and declined with age; the levels reached a plateau after age 20 years [
Elevated C6S indicates deficiency of the enzyme N-acetylgalactosamine 6-sulfatase (MPS IVA).
Both qualitative and quantitative urine GAGs can be normal in some affected individuals. Thus, further enzymatic or molecular evaluation of a child with clinical evidence of MPS IV is warranted even when GAG analysis is normal.
The diagnosis of MPS IVA
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Mucopolysaccharidosis Type IVA
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Deep intronic variants may be detected by whole genome sequencing and mRNA analysis [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Approximately 2.7%-3.6% of variants are secondary to gross deletions [
One individual had maternal uniparental isodisomy of the telomeric end of chromosome 16, leading to disease [
Clinical findings strongly indicate MPS IVA and urine GAG analysis is normal; AND/OR
Molecular genetic testing fails to identify biallelic pathogenic variants in
In addition, establishing a diagnosis of MPS IVA by enzyme analysis may aid in interpretation of sequencing variants of uncertain significance. GALNS enzyme activity can be measured in cultured fibroblasts or leukocytes. Because each laboratory has its own normal range of enzyme activity, results from different laboratories cannot be directly compared. The level of residual enzyme activity may correlate with disease severity.
Note: (1) Low enzyme activity can be caused by other disorders including:
Mucolipidosis II and mucolipidosis III (see
(2) Because the clinical manifestations of MPS IVA and MPS IVB are indistinguishable, it is customary to measure B-galactosidase enzyme activity at the same time.
• The majority of affected individuals do not have distinctive clinical findings at birth. However, some features may be present at birth including prominent forehead, pectus carinatum, kyphosis, and abnormal spine radiograph (see
• History of adenoidectomy, tonsillectomy, hernia repair, ear ventilation tubes (general findings for all MPS disorders)
• History of cervical spine decompression and/or fusion or a history of surgery for limb alignments (unique to MPS IVA among all MPS disorders)
• Respiratory compromise (sleep apnea, endurance limitations, snoring)
• Cardiac valve abnormalities
• Dental abnormalities
• Marked disproportionate short stature with short trunk and normal limbs (arm span exceeds height)
• Ulnar deviation of the wrists (
• Pectus carinatum and flaring of the lower rib cage (
• Gibbus (short-segment structural thoracolumbar kyphosis resulting in sharp angulation of the back), kyphosis, and scoliosis
• Genu valgum (knock-knee) (
• Hypermobile joints
• Waddling gait with frequent falls
• Odontoid hypoplasia with subsequent cervical instability (
• Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture) (
• Gibbus (structural kyphosis) with wedging of one or more adjacent vertebrae (
• Note: The radiographic abnormalities of the lumbar spine can be detected at birth in infants with rapidly progressive disease [
• Scoliosis
• Pectus carinatum or (less frequently) excavatum
• Short ulnas, ulnar deviation of the radial epiphysis, and delayed bone maturation
• Short metacarpals with the proximal ends of the second to fifth metacarpals rounded or pointed [
• Flared iliac wings, flattening of femoral epiphyses (
• Note: The presence of KS (on qualitative analysis) with or without abnormal quantitative urine GAGs has been observed in some affected individuals.
• Elevated KS indicates deficiency of either the enzyme N-acetylgalactosamine 6-sulfatase (in MPS IVA) or the enzyme B-galactosidase (in
• Note: Urine KS levels in younger individuals are higher than in older individuals due to the decrease in cartilage formation in older persons. The urine KS levels in individuals with MPS IVA and healthy controls were highest at age one to five years and declined with age; the levels reached a plateau after age 20 years [
• Elevated C6S indicates deficiency of the enzyme N-acetylgalactosamine 6-sulfatase (MPS IVA).
• Elevated KS indicates deficiency of either the enzyme N-acetylgalactosamine 6-sulfatase (in MPS IVA) or the enzyme B-galactosidase (in
• Note: Urine KS levels in younger individuals are higher than in older individuals due to the decrease in cartilage formation in older persons. The urine KS levels in individuals with MPS IVA and healthy controls were highest at age one to five years and declined with age; the levels reached a plateau after age 20 years [
• Elevated C6S indicates deficiency of the enzyme N-acetylgalactosamine 6-sulfatase (MPS IVA).
• Both qualitative and quantitative urine GAGs can be normal in some affected individuals. Thus, further enzymatic or molecular evaluation of a child with clinical evidence of MPS IV is warranted even when GAG analysis is normal.
• Elevated KS indicates deficiency of either the enzyme N-acetylgalactosamine 6-sulfatase (in MPS IVA) or the enzyme B-galactosidase (in
• Note: Urine KS levels in younger individuals are higher than in older individuals due to the decrease in cartilage formation in older persons. The urine KS levels in individuals with MPS IVA and healthy controls were highest at age one to five years and declined with age; the levels reached a plateau after age 20 years [
• Elevated C6S indicates deficiency of the enzyme N-acetylgalactosamine 6-sulfatase (MPS IVA).
• For an introduction to multigene panels click
• Clinical findings strongly indicate MPS IVA and urine GAG analysis is normal; AND/OR
• Molecular genetic testing fails to identify biallelic pathogenic variants in
• Mucolipidosis II and mucolipidosis III (see
## Suggestive Findings
Mucopolysaccharidosis IVA (MPS IVA)
The majority of affected individuals do not have distinctive clinical findings at birth. However, some features may be present at birth including prominent forehead, pectus carinatum, kyphosis, and abnormal spine radiograph (see
History of adenoidectomy, tonsillectomy, hernia repair, ear ventilation tubes (general findings for all MPS disorders)
History of cervical spine decompression and/or fusion or a history of surgery for limb alignments (unique to MPS IVA among all MPS disorders)
Respiratory compromise (sleep apnea, endurance limitations, snoring)
Cardiac valve abnormalities
Dental abnormalities
Marked disproportionate short stature with short trunk and normal limbs (arm span exceeds height)
Ulnar deviation of the wrists (
Pectus carinatum and flaring of the lower rib cage (
Gibbus (short-segment structural thoracolumbar kyphosis resulting in sharp angulation of the back), kyphosis, and scoliosis
Genu valgum (knock-knee) (
Hypermobile joints
Waddling gait with frequent falls
Odontoid hypoplasia with subsequent cervical instability (
Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture) (
Gibbus (structural kyphosis) with wedging of one or more adjacent vertebrae (
Note: The radiographic abnormalities of the lumbar spine can be detected at birth in infants with rapidly progressive disease [
Scoliosis
Pectus carinatum or (less frequently) excavatum
Short ulnas, ulnar deviation of the radial epiphysis, and delayed bone maturation
Short metacarpals with the proximal ends of the second to fifth metacarpals rounded or pointed [
Flared iliac wings, flattening of femoral epiphyses (
Note: Skeletal abnormalities are observed before physical abnormalities [
Note: The presence of KS (on qualitative analysis) with or without abnormal quantitative urine GAGs has been observed in some affected individuals.
Elevated KS indicates deficiency of either the enzyme N-acetylgalactosamine 6-sulfatase (in MPS IVA) or the enzyme B-galactosidase (in
Note: Urine KS levels in younger individuals are higher than in older individuals due to the decrease in cartilage formation in older persons. The urine KS levels in individuals with MPS IVA and healthy controls were highest at age one to five years and declined with age; the levels reached a plateau after age 20 years [
Elevated C6S indicates deficiency of the enzyme N-acetylgalactosamine 6-sulfatase (MPS IVA).
Both qualitative and quantitative urine GAGs can be normal in some affected individuals. Thus, further enzymatic or molecular evaluation of a child with clinical evidence of MPS IV is warranted even when GAG analysis is normal.
• The majority of affected individuals do not have distinctive clinical findings at birth. However, some features may be present at birth including prominent forehead, pectus carinatum, kyphosis, and abnormal spine radiograph (see
• History of adenoidectomy, tonsillectomy, hernia repair, ear ventilation tubes (general findings for all MPS disorders)
• History of cervical spine decompression and/or fusion or a history of surgery for limb alignments (unique to MPS IVA among all MPS disorders)
• Respiratory compromise (sleep apnea, endurance limitations, snoring)
• Cardiac valve abnormalities
• Dental abnormalities
• Marked disproportionate short stature with short trunk and normal limbs (arm span exceeds height)
• Ulnar deviation of the wrists (
• Pectus carinatum and flaring of the lower rib cage (
• Gibbus (short-segment structural thoracolumbar kyphosis resulting in sharp angulation of the back), kyphosis, and scoliosis
• Genu valgum (knock-knee) (
• Hypermobile joints
• Waddling gait with frequent falls
• Odontoid hypoplasia with subsequent cervical instability (
• Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture) (
• Gibbus (structural kyphosis) with wedging of one or more adjacent vertebrae (
• Note: The radiographic abnormalities of the lumbar spine can be detected at birth in infants with rapidly progressive disease [
• Scoliosis
• Pectus carinatum or (less frequently) excavatum
• Short ulnas, ulnar deviation of the radial epiphysis, and delayed bone maturation
• Short metacarpals with the proximal ends of the second to fifth metacarpals rounded or pointed [
• Flared iliac wings, flattening of femoral epiphyses (
• Note: The presence of KS (on qualitative analysis) with or without abnormal quantitative urine GAGs has been observed in some affected individuals.
• Elevated KS indicates deficiency of either the enzyme N-acetylgalactosamine 6-sulfatase (in MPS IVA) or the enzyme B-galactosidase (in
• Note: Urine KS levels in younger individuals are higher than in older individuals due to the decrease in cartilage formation in older persons. The urine KS levels in individuals with MPS IVA and healthy controls were highest at age one to five years and declined with age; the levels reached a plateau after age 20 years [
• Elevated C6S indicates deficiency of the enzyme N-acetylgalactosamine 6-sulfatase (MPS IVA).
• Elevated KS indicates deficiency of either the enzyme N-acetylgalactosamine 6-sulfatase (in MPS IVA) or the enzyme B-galactosidase (in
• Note: Urine KS levels in younger individuals are higher than in older individuals due to the decrease in cartilage formation in older persons. The urine KS levels in individuals with MPS IVA and healthy controls were highest at age one to five years and declined with age; the levels reached a plateau after age 20 years [
• Elevated C6S indicates deficiency of the enzyme N-acetylgalactosamine 6-sulfatase (MPS IVA).
• Both qualitative and quantitative urine GAGs can be normal in some affected individuals. Thus, further enzymatic or molecular evaluation of a child with clinical evidence of MPS IV is warranted even when GAG analysis is normal.
• Elevated KS indicates deficiency of either the enzyme N-acetylgalactosamine 6-sulfatase (in MPS IVA) or the enzyme B-galactosidase (in
• Note: Urine KS levels in younger individuals are higher than in older individuals due to the decrease in cartilage formation in older persons. The urine KS levels in individuals with MPS IVA and healthy controls were highest at age one to five years and declined with age; the levels reached a plateau after age 20 years [
• Elevated C6S indicates deficiency of the enzyme N-acetylgalactosamine 6-sulfatase (MPS IVA).
## Establishing the Diagnosis
The diagnosis of MPS IVA
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Mucopolysaccharidosis Type IVA
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Deep intronic variants may be detected by whole genome sequencing and mRNA analysis [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Approximately 2.7%-3.6% of variants are secondary to gross deletions [
One individual had maternal uniparental isodisomy of the telomeric end of chromosome 16, leading to disease [
Clinical findings strongly indicate MPS IVA and urine GAG analysis is normal; AND/OR
Molecular genetic testing fails to identify biallelic pathogenic variants in
In addition, establishing a diagnosis of MPS IVA by enzyme analysis may aid in interpretation of sequencing variants of uncertain significance. GALNS enzyme activity can be measured in cultured fibroblasts or leukocytes. Because each laboratory has its own normal range of enzyme activity, results from different laboratories cannot be directly compared. The level of residual enzyme activity may correlate with disease severity.
Note: (1) Low enzyme activity can be caused by other disorders including:
Mucolipidosis II and mucolipidosis III (see
(2) Because the clinical manifestations of MPS IVA and MPS IVB are indistinguishable, it is customary to measure B-galactosidase enzyme activity at the same time.
• For an introduction to multigene panels click
• Clinical findings strongly indicate MPS IVA and urine GAG analysis is normal; AND/OR
• Molecular genetic testing fails to identify biallelic pathogenic variants in
• Mucolipidosis II and mucolipidosis III (see
## Clinical Characteristics
Mucopolysaccharidosis type IVA (MPS IVA) comprises a clinical continuum ranging from a severe and rapidly progressive form to a slowly progressive form. In the past, the two forms were distinguished by height, the subjective assessment of severity of bone deformity, and survival [
Some features including prominent forehead, pectus carinatum, kyphosis, and abnormal spine radiograph may be detected at birth [
In both the severe form and slowly progressive form, the initial presentations vary and individuals may present with only a single finding or several findings. Kyphoscoliosis, genu valgum (
Because descriptions of the natural history of MPS IV published in the past may not have distinguished between MPS IVA (Morquio syndrome type A; accounting for >95% of affected individuals) and
While the skeletal findings of MPS IVA are the hallmark findings, involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord results in neurologic involvement especially when disease is recognized later in life [
Coarse facial features are also present but milder than in other mucopolysaccharidoses (see
Children with MPS IVA typically have normal intellectual ability.
Ligamentous laxity and joint hypermobility are distinctive features of MPS IVA, and are rare among other storage disorders.
Skeletal findings worsen over time. The combination of bone and joint involvement leads to pain and arthritis that result in subsequent disability.
Upper-extremity involvement is also progressive and can impair hand-wrist strength and limit ability to perform some activities of daily living, such as using a fork. Hypermobility and ulnar deviation of the wrist joint due to premature cessation of ulna growth are distinctive features of MPS IVA.
Lower-extremity involvement, which is universal and progressive if untreated [
A longitudinal study using the Pediatric Evaluation of Disability Inventory and the Functional Independence Measure found severely limited joint mobility in persons with MPS IVA, generally with loss of ambulation late in the disease course. Aggressive and long-term intervention by a team of physical therapists and rehabilitative specialists is often needed to optimize mobility (see
At the time of diagnosis, individuals typically have normal developmental milestones and normal intellectual ability. The neurologic findings of MPS IVA are most often secondary to spinal abnormalities in the neck and/or lumbar region. The increased risk for neurologic compromise makes developmental delay and learning disabilities more common in children with MPS IVA than in unaffected children [
Subtle abnormal brain MRI findings such as prominent perivascular space, enlarged lateral ventricles, and prominent frontal CSF were reported in eight of 14 individuals with MPS IVA [
Cardiac complications include ventricular hypertrophy and early-onset severe valvular involvement. Coronary intimal sclerosis has also been reported [
In a multicenter, multinational, cross-sectional study (MorCAP) involving 325 individuals with MPS IVA, valvular regurgitation was more common than valvular stenosis. Among those with valvular regurgitation, tricuspid regurgitation was the most common (35%). Mitral regurgitation, aortic regurgitation, and pulmonary regurgitation were found in 25%, 19%, and 14% of affected individuals, respectively [
Respiratory complications are a major cause of morbidity and mortality. Airway obstruction, sleep-disordered breathing, and restrictive lung disease have been described.
GAG accumulation in the adenoids, tonsils, pharynx, larynx, trachea, and bronchial tree leads to adenotonsillar hypertrophy, tracheal distortion, tracheo- and bronchomalacia, and obstructive sleep apnea [
Because of atlantoaxial instability and upper-airway obstruction, persons with MPS IVA prefer to sleep prone on a flat surface without a pillow in order to keep the neck extended and minimize the tortuosity of the airway.
Restrictive lung disease results from a small thorax, chest wall anomalies, spine deformities, neuromuscular compromise from cervical myelopathy, and hepatomegaly causing upward displacement of the diaphragm [
If respiratory complications are not recognized or are not treated, cor pulmonale and respiratory failure can ensue, leading to early death [
Growth and final height are used as an indicator of severe phenotype. Children with MPS IVA have a normal birth weight and a longer-than-normal birth length. The growth velocity decreases between ages one and three years and growth stops around ages seven to eight years [
Ophthalmologic findings are present in more than 50% of individuals with MPS IVA. Natural history studies have not been performed; thus, it is not possible to predict the age of onset of ophthalmologic findings [
Slowly progressive corneal clouding, found in 50% of affected individuals (ages 1-65 years), is the most common ophthalmologic finding in MPS IVA.
Other less common ophthalmologic findings include: astigmatism, cataracts, punctate lens opacities, open-angle glaucoma, optic disc swelling, optic atrophy, and retinopathy. While rare, these ophthalmologic findings can be serious secondary complications [
Pseudoexophthalmos, the appearance of a bulging eye secondary to a shallow orbit, can cause exposure keratitis and also be of cosmetic concern.
Deciduous teeth erupt normally and are widely spaced and discolored with thin irregular (stippled) enamel and small pointed cusps which flatten over time with normal wear.
Permanent teeth also have hypoplastic enamel, and are widely spaced with flared upper incisors [
Mild-to-moderate hearing loss is common in individuals with MPS IVA. Hearing impairment is often noted toward the end of the first decade.
Mixed (i.e., combined conductive and sensorineural) hearing loss is more common than conductive or sensorineural hearing loss alone.
Conductive hearing loss is secondary to recurrent middle ear infections, serous otitis media, and deformity of the ossicles [
Sensorineural hearing loss secondary to GAG accumulation in the inner ear and/or central nervous system has been described [
Genetic alterations in
The location of variants in the tertiary GALNS protein structure may determine the severity of the phenotype. Variants that interfere with the salt bridge, alter the active site, or destroy the hydrophobic core contribute to a severe phenotype, whereas variants located on the surface of the protein (e.g.,
Several variants have been reported in individuals with severe phenotypes; these include
Much of the older literature and more complete natural history studies were performed prior to understanding of the basis of MPS IVA (N-acetylgalactosamine 6-sulfatase deficiency or biallelic
Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio syndrome type A, was initially characterized by
MPS IVA and MPS IVB are known as Morquio syndrome type A and type B, respectively.
MPS IVA is rare. The prevalence in Australia has been estimated at 1:926,000, and in the UK at 1:599,000. The birth prevalence for MPS IVA ranges from 1:71,000 to 1:179,000 across multiple countries [
## Clinical Description
Mucopolysaccharidosis type IVA (MPS IVA) comprises a clinical continuum ranging from a severe and rapidly progressive form to a slowly progressive form. In the past, the two forms were distinguished by height, the subjective assessment of severity of bone deformity, and survival [
Some features including prominent forehead, pectus carinatum, kyphosis, and abnormal spine radiograph may be detected at birth [
In both the severe form and slowly progressive form, the initial presentations vary and individuals may present with only a single finding or several findings. Kyphoscoliosis, genu valgum (
Because descriptions of the natural history of MPS IV published in the past may not have distinguished between MPS IVA (Morquio syndrome type A; accounting for >95% of affected individuals) and
While the skeletal findings of MPS IVA are the hallmark findings, involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord results in neurologic involvement especially when disease is recognized later in life [
Coarse facial features are also present but milder than in other mucopolysaccharidoses (see
Children with MPS IVA typically have normal intellectual ability.
Ligamentous laxity and joint hypermobility are distinctive features of MPS IVA, and are rare among other storage disorders.
Skeletal findings worsen over time. The combination of bone and joint involvement leads to pain and arthritis that result in subsequent disability.
Upper-extremity involvement is also progressive and can impair hand-wrist strength and limit ability to perform some activities of daily living, such as using a fork. Hypermobility and ulnar deviation of the wrist joint due to premature cessation of ulna growth are distinctive features of MPS IVA.
Lower-extremity involvement, which is universal and progressive if untreated [
A longitudinal study using the Pediatric Evaluation of Disability Inventory and the Functional Independence Measure found severely limited joint mobility in persons with MPS IVA, generally with loss of ambulation late in the disease course. Aggressive and long-term intervention by a team of physical therapists and rehabilitative specialists is often needed to optimize mobility (see
At the time of diagnosis, individuals typically have normal developmental milestones and normal intellectual ability. The neurologic findings of MPS IVA are most often secondary to spinal abnormalities in the neck and/or lumbar region. The increased risk for neurologic compromise makes developmental delay and learning disabilities more common in children with MPS IVA than in unaffected children [
Subtle abnormal brain MRI findings such as prominent perivascular space, enlarged lateral ventricles, and prominent frontal CSF were reported in eight of 14 individuals with MPS IVA [
Cardiac complications include ventricular hypertrophy and early-onset severe valvular involvement. Coronary intimal sclerosis has also been reported [
In a multicenter, multinational, cross-sectional study (MorCAP) involving 325 individuals with MPS IVA, valvular regurgitation was more common than valvular stenosis. Among those with valvular regurgitation, tricuspid regurgitation was the most common (35%). Mitral regurgitation, aortic regurgitation, and pulmonary regurgitation were found in 25%, 19%, and 14% of affected individuals, respectively [
Respiratory complications are a major cause of morbidity and mortality. Airway obstruction, sleep-disordered breathing, and restrictive lung disease have been described.
GAG accumulation in the adenoids, tonsils, pharynx, larynx, trachea, and bronchial tree leads to adenotonsillar hypertrophy, tracheal distortion, tracheo- and bronchomalacia, and obstructive sleep apnea [
Because of atlantoaxial instability and upper-airway obstruction, persons with MPS IVA prefer to sleep prone on a flat surface without a pillow in order to keep the neck extended and minimize the tortuosity of the airway.
Restrictive lung disease results from a small thorax, chest wall anomalies, spine deformities, neuromuscular compromise from cervical myelopathy, and hepatomegaly causing upward displacement of the diaphragm [
If respiratory complications are not recognized or are not treated, cor pulmonale and respiratory failure can ensue, leading to early death [
Growth and final height are used as an indicator of severe phenotype. Children with MPS IVA have a normal birth weight and a longer-than-normal birth length. The growth velocity decreases between ages one and three years and growth stops around ages seven to eight years [
Ophthalmologic findings are present in more than 50% of individuals with MPS IVA. Natural history studies have not been performed; thus, it is not possible to predict the age of onset of ophthalmologic findings [
Slowly progressive corneal clouding, found in 50% of affected individuals (ages 1-65 years), is the most common ophthalmologic finding in MPS IVA.
Other less common ophthalmologic findings include: astigmatism, cataracts, punctate lens opacities, open-angle glaucoma, optic disc swelling, optic atrophy, and retinopathy. While rare, these ophthalmologic findings can be serious secondary complications [
Pseudoexophthalmos, the appearance of a bulging eye secondary to a shallow orbit, can cause exposure keratitis and also be of cosmetic concern.
Deciduous teeth erupt normally and are widely spaced and discolored with thin irregular (stippled) enamel and small pointed cusps which flatten over time with normal wear.
Permanent teeth also have hypoplastic enamel, and are widely spaced with flared upper incisors [
Mild-to-moderate hearing loss is common in individuals with MPS IVA. Hearing impairment is often noted toward the end of the first decade.
Mixed (i.e., combined conductive and sensorineural) hearing loss is more common than conductive or sensorineural hearing loss alone.
Conductive hearing loss is secondary to recurrent middle ear infections, serous otitis media, and deformity of the ossicles [
Sensorineural hearing loss secondary to GAG accumulation in the inner ear and/or central nervous system has been described [
## Musculoskeletal
Skeletal findings worsen over time. The combination of bone and joint involvement leads to pain and arthritis that result in subsequent disability.
Upper-extremity involvement is also progressive and can impair hand-wrist strength and limit ability to perform some activities of daily living, such as using a fork. Hypermobility and ulnar deviation of the wrist joint due to premature cessation of ulna growth are distinctive features of MPS IVA.
Lower-extremity involvement, which is universal and progressive if untreated [
A longitudinal study using the Pediatric Evaluation of Disability Inventory and the Functional Independence Measure found severely limited joint mobility in persons with MPS IVA, generally with loss of ambulation late in the disease course. Aggressive and long-term intervention by a team of physical therapists and rehabilitative specialists is often needed to optimize mobility (see
## Neurologic
At the time of diagnosis, individuals typically have normal developmental milestones and normal intellectual ability. The neurologic findings of MPS IVA are most often secondary to spinal abnormalities in the neck and/or lumbar region. The increased risk for neurologic compromise makes developmental delay and learning disabilities more common in children with MPS IVA than in unaffected children [
Subtle abnormal brain MRI findings such as prominent perivascular space, enlarged lateral ventricles, and prominent frontal CSF were reported in eight of 14 individuals with MPS IVA [
## Cardiac
Cardiac complications include ventricular hypertrophy and early-onset severe valvular involvement. Coronary intimal sclerosis has also been reported [
In a multicenter, multinational, cross-sectional study (MorCAP) involving 325 individuals with MPS IVA, valvular regurgitation was more common than valvular stenosis. Among those with valvular regurgitation, tricuspid regurgitation was the most common (35%). Mitral regurgitation, aortic regurgitation, and pulmonary regurgitation were found in 25%, 19%, and 14% of affected individuals, respectively [
## Respiratory
Respiratory complications are a major cause of morbidity and mortality. Airway obstruction, sleep-disordered breathing, and restrictive lung disease have been described.
GAG accumulation in the adenoids, tonsils, pharynx, larynx, trachea, and bronchial tree leads to adenotonsillar hypertrophy, tracheal distortion, tracheo- and bronchomalacia, and obstructive sleep apnea [
Because of atlantoaxial instability and upper-airway obstruction, persons with MPS IVA prefer to sleep prone on a flat surface without a pillow in order to keep the neck extended and minimize the tortuosity of the airway.
Restrictive lung disease results from a small thorax, chest wall anomalies, spine deformities, neuromuscular compromise from cervical myelopathy, and hepatomegaly causing upward displacement of the diaphragm [
If respiratory complications are not recognized or are not treated, cor pulmonale and respiratory failure can ensue, leading to early death [
## Growth
Growth and final height are used as an indicator of severe phenotype. Children with MPS IVA have a normal birth weight and a longer-than-normal birth length. The growth velocity decreases between ages one and three years and growth stops around ages seven to eight years [
## Eye
Ophthalmologic findings are present in more than 50% of individuals with MPS IVA. Natural history studies have not been performed; thus, it is not possible to predict the age of onset of ophthalmologic findings [
Slowly progressive corneal clouding, found in 50% of affected individuals (ages 1-65 years), is the most common ophthalmologic finding in MPS IVA.
Other less common ophthalmologic findings include: astigmatism, cataracts, punctate lens opacities, open-angle glaucoma, optic disc swelling, optic atrophy, and retinopathy. While rare, these ophthalmologic findings can be serious secondary complications [
Pseudoexophthalmos, the appearance of a bulging eye secondary to a shallow orbit, can cause exposure keratitis and also be of cosmetic concern.
## Dental
Deciduous teeth erupt normally and are widely spaced and discolored with thin irregular (stippled) enamel and small pointed cusps which flatten over time with normal wear.
Permanent teeth also have hypoplastic enamel, and are widely spaced with flared upper incisors [
## Hearing
Mild-to-moderate hearing loss is common in individuals with MPS IVA. Hearing impairment is often noted toward the end of the first decade.
Mixed (i.e., combined conductive and sensorineural) hearing loss is more common than conductive or sensorineural hearing loss alone.
Conductive hearing loss is secondary to recurrent middle ear infections, serous otitis media, and deformity of the ossicles [
Sensorineural hearing loss secondary to GAG accumulation in the inner ear and/or central nervous system has been described [
## Genotype-Phenotype Correlations
Genetic alterations in
The location of variants in the tertiary GALNS protein structure may determine the severity of the phenotype. Variants that interfere with the salt bridge, alter the active site, or destroy the hydrophobic core contribute to a severe phenotype, whereas variants located on the surface of the protein (e.g.,
Several variants have been reported in individuals with severe phenotypes; these include
## Nomenclature
Much of the older literature and more complete natural history studies were performed prior to understanding of the basis of MPS IVA (N-acetylgalactosamine 6-sulfatase deficiency or biallelic
Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio syndrome type A, was initially characterized by
MPS IVA and MPS IVB are known as Morquio syndrome type A and type B, respectively.
## Prevalence
MPS IVA is rare. The prevalence in Australia has been estimated at 1:926,000, and in the UK at 1:599,000. The birth prevalence for MPS IVA ranges from 1:71,000 to 1:179,000 across multiple countries [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Although novel
Note
Other Mucopolysaccharidoses to Consider in the Differential Diagnosis of Mucopolysaccharidosis IVA
Normal intellect
Less coarsening of facial features
Better visual acuity (in general)
Joint hypermobility (unique to MPS IV)
More common occurrence of atlantoaxial instability
AR = autosomal recessive; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked
Note:
• Normal intellect
• Less coarsening of facial features
• Better visual acuity (in general)
• Joint hypermobility (unique to MPS IV)
• More common occurrence of atlantoaxial instability
## Management
To establish the extent of disease and needs in an individual diagnosed with mucopolysaccharidosis type IVA (MPS IVA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mucopolysaccharidosis IVA
Cervical spine radiographs incl AP, neutral lateral, & flexion-extension views
AP & lateral radiographs of entire spine
Brain MRI
MRI of the entire spine (neutral position) focusing on potential sites of cord compression (occipitocervical, cervicothoracic, & thoracolumbar)
Cervical spine flexion-extension MRI when significant spinal cord compression is not detected by standard MRI of the cervical spine
Flexion-extension MRI can identify dynamic changes in canal diameter → cord compression.
Cervical spine flexion-extension MRI under sedation/anesthesia in children w/skeletal dysplasia was safe under adequate supervision & result was useful for surgical decision making [
AP & frog leg lateral radiographs of the pelvis
AP standing radiographs of the lower extremities
Eval by physiatrist (i.e., specialist in physical medicine & rehab) to assess mobility, joint range of motion, & autonomy
6-min walk test (6MWT) & timed 25-ft walk test (T25FW)
EKG
Echocardiogram
Eval by pulmonologist
Fiberoptic exam
Pulmonary function studies
Polysomnography
Pain assessment
Quality of life questionnaire
Age-appropriate ADL questionnaire
Use of community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; AP = anterior-posterior; MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Management of individuals with MPS IVA is best undertaken by the following multiple specialists, coordinated by a physician specializing in the care of individuals with complex medical problems:
Physiatrist (specialist in physical medicine and rehabilitation) to optimize mobility and autonomy
Physical therapist to optimize mobility
Occupational therapist to optimize autonomy
Psychological support to optimize coping skills and quality of life
Education professionals to optimize learning in a medically fragile individual
Consideration of referral to family therapy to help normalize the experience for the affected individual, parents, sibs, and extended family members
Home care for affected individuals with multiple medical equipment needs
Hospice for end-of-life care
Recombinant human GALNS ERT (elosulfase alfa, or Vimizim™) was approved by the FDA in February 2014.
The recommendation dose is 2 mg/kg/week intravenous. Although the treatment with ERT is not curative, ERT could improve endurance and overall quality of life.
Premedication (30-60 minutes prior to each enzyme infusion) with a non-sedating antihistamine (if possible) with or without antipyretics is recommended to prevent infusion-associated reactions.
A Phase III clinical trial demonstrated a statistically significant improvement in the 6MWT distance in the 2 mg/kg weekly dose group compared to the placebo group. The three-minute stair climb test and respiratory function were improved with the treatment but the differences were not statistically significant.
The long-term effects of this treatment on the skeletal features of MPS IVA are still unclear (see
The impact of ERT on mildly affected individuals after 52 weeks of treatment was minimal, lacking significant change on cardiac or pulmonary function.
For published orthopedic management guidelines, see
Growth modulation, also called guided growth (temporary surgical tethering of the growth plate to allow gradual correction of the deformity) or realignment osteotomies have been successful [
Early detection and evaluation may allow surgical tethering of the growth plate to treat mild-to-moderate lower-extremity angular deformities in children with open physes (growth plates). Typically this procedure is less invasive and allows for easier recovery than realignment osteotomies.
Once the growth plates close, distal femoral and proximal tibial osteotomies are needed to acutely or gradually (with the use of external fixators) correct lower-extremity malalignment.
Ankle malalignment is often corrected by a distal tibial osteotomy with distal tibial screw hemiepiphysiodesis [
Hip reconstruction includes either femoral or acetabular osteotomy for mild cases or combined acetabular and femoral osteotomy for severe cases. Augmentation of acetabular bone stock and customized implants by using cortical grafts from the inner table of the ilium are usually required due to a shallow acetabulum [
Total hip arthroplasty may be required in young adults experiencing significant hip pain which cannot be corrected by reconstructive techniques.
To minimize neurologic injury and maximize function, intervention in children is recommended when radiographic signs of cervical compression are present, even in the absence of symptoms.
Affected individuals undergoing surgical fusion typically do well; minor secondary complications can include pin site infections, pressure sores, and long-term difficulty with endotracheal intubation.
Note: It is important for clinicians to be aware that cervical myelopathy from upper cervical instability may result in deteriorating endurance and worsening gait. If myelopathy is suspected, obtain cervical spine radiographs and MRI (see
When kyphosis is <45°, the risk of progressive deformity is less than with a greater curve, but warrants clinical and radiographic monitoring.
When kyphosis is >45°, progression is likely. Although extensive bracing with an orthosis or a cast does not prevent progression of the thoracolumbar kyphosis, it may delay the need for surgical intervention during a period of growth and development.
Anterior and posterior circumferential spinal fusion are indicated if one or more of the following are present:
Progressive thoracolumbar kyphosis >70°
Uncontrolled back pain
Neurologic changes related to spinal stenosis
Elevated heart rates could indicate a compensation mechanism, secondary to small left ventricular diameter and small stroke volume; thus tachycardia treatment with beta-blockers should be avoided. Valve replacement may be considered for symptomatic individuals with progressive valvular problems [
Bacterial endocarditis prophylaxis is recommended for those at high risk, including those with a prosthetic cardiac valve, prosthetic material used for cardiac valve repair, or previous infective endocarditis [
Upper-airway obstruction and obstructive sleep apnea are managed by removal of enlarged tonsils and adenoids at an average age of seven years [
In persons with diffuse narrowing of the airway in whom adenotonsillectomy only temporally relieves upper-airway obstruction, other interventions to consider are: CPAP (continuous positive airway pressure), NIPPV (noninvasive positive pressure ventilation), tracheostomy, and possibly tracheal reconstructive surgery.
Lower-airway obstruction manifest as wheezing and recurrent infection is managed by inhaled and/or oral bronchodilators and, in some instances, corticosteroids.
Restrictive lung disease is managed by supportive treatment.
Due to increased risk for pulmonary infection, all affected individuals should receive influenza and pneumococcal immunizations as well as routine immunizations.
Preoperative assessment should include history of response to anesthesia and any evidence of airway obstruction, cardiac evaluation including electrocardiogram and echocardiography, evaluation of respiratory function (spirometry and polysomnography), and airway fluoroscopy [
Endotracheal intubation likely includes use of a video laryngoscope, fiberoptic bronchoscope with or without a laryngeal mask airway (LMA), a smaller endotracheal tube than expected for age and/or size, and use of LMA for short procedures. These techniques help maintain a neutral neck position. Although nasal intubation is an option, GAG deposits can lead to narrowing of the nasal passages and increased propensity to bleeding [
Intraoperative neurophysiologic monitoring (see
Postoperative narcotic management should be judicious; multimodal analgesics and non-narcotic medications are preferable to avoid exacerbating preexisting respiratory issues, such as sleep apnea.
Postoperative complications including pulmonary edema have been described [
Due to risk of postoperative complications, some individuals may require close monitoring for at least 24-48 hours.
Height of children with MPS IVA is best plotted on growth charts specific for MPS IVA [
Nutrition should be optimized with a balanced diet and adequate vitamin D and calcium to assure bone health.
Corneal opacification often causes reduced vision in early childhood, necessitating corneal transplantation (deep lamellar keratoplasty or penetrating keratoplasty), for which the outcome can vary. Other factors which may cause reduced vision such as retinopathy should be excluded before considering corneal transplantation. Recurrence of opacities within the first year post keratoplasty has been reported, making this a temporary measure for improving quality of life [
Daily oral hygiene care, fissure sealing, and adequate fluoride supplementation help prevent cavities. Orthodontic management to correct malocclusion may be necessary.
Because ventilation tube placement can minimize the long-term scarring associated with chronic middle-ear effusions and recurrent acute otitis media, and improve hearing in the long term, most children have ventilation tubes placed during the preschool years. At the first occasion, a long-lasting tympanostomy tube is recommended due to high risk of recurrent middle-ear effusion and the risk associated with sedation in individuals with MPS IVA [
The progressive hearing impairment observed in most individuals with MPS IVA benefits from hearing aids.
Despite some physical limitation, individuals with MPS IVA have normal intellect and can thrive in an environment with academic and social stimulation. Children routinely attend regular class/school with assistance to prevent physical injury.
The following should be assessed before and after initiation of ERT to determine treatment efficacy:
Annual pain severity and disease burden assessments including quality of life and activities of daily living (See
Annual pulmonary function tests, including maximum voluntary ventilation (MVV) and forced vital capacity (FVC)
Urine KS / urine GAG levels at baseline, then every six months
Note: The benefit of monitoring anti-elosulfase alfa antibodies is unknown.
Every 6-12 months, track growth, pubertal stage, and progress; optimize ambulation.
Annually, assess pain severity and disease burden including quality of life and activities of daily living.
Annually, before and after surgical procedures, or as clinically indicated, perform endurance tests including six-minute walk test or timed 25-foot walk test to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems. Respiratory rate, pulse oximeter, and heart rate should be measured before and after the annual testing.
Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
* Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
For obstructive sleep apnea, annual history focused on sleep patterns and sounds. Evaluation by an otolaryngologist for adenotonsillectomy. Annual in-home screening sleep studies (which monitor oxygen saturation). Polysomnography every three years.
To assess pulmonary function, annual MVV and FVC in children older than age five years until growth stops, then every two to three years. The benefit of noninvasive pulmonary function tests, impulse oscillometry, and thoracoabdominal motion analysis has been demonstrated in children with MPS IV [
Fiberoptic examination at least annually or as clinically indicated [
Monitor for vision and ocular abnormalities with ophthalmologist examination at least annually.
For those with rod and cone retinal dystrophy, perform retinal examination and electroretinography under scotopic and photopic conditions every five years [
Because excessive weight gain causes undue stress on the axial skeleton and may decrease the duration of independent ambulation, it is important to optimize nutrition for growth while maintaining a lean habitus.
Due to small ventricular diameter and stroke volume, beta-blockers should be avoided in the treatment of tachycardia.
It is appropriate to evaluate apparently asymptomatic younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of ERT (see
Molecular genetic testing if the pathogenic variants in the family are known;
Analysis of N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity if the pathogenic variants in the family are not known.
See
The experience of hematopoietic stem cell therapy is limited and has not been well studied. Gene therapy and substrate degradation enzyme therapy are in preclinical trials [
Search
• Cervical spine radiographs incl AP, neutral lateral, & flexion-extension views
• AP & lateral radiographs of entire spine
• Brain MRI
• MRI of the entire spine (neutral position) focusing on potential sites of cord compression (occipitocervical, cervicothoracic, & thoracolumbar)
• Cervical spine flexion-extension MRI when significant spinal cord compression is not detected by standard MRI of the cervical spine
• Flexion-extension MRI can identify dynamic changes in canal diameter → cord compression.
• Cervical spine flexion-extension MRI under sedation/anesthesia in children w/skeletal dysplasia was safe under adequate supervision & result was useful for surgical decision making [
• AP & frog leg lateral radiographs of the pelvis
• AP standing radiographs of the lower extremities
• Eval by physiatrist (i.e., specialist in physical medicine & rehab) to assess mobility, joint range of motion, & autonomy
• 6-min walk test (6MWT) & timed 25-ft walk test (T25FW)
• EKG
• Echocardiogram
• Eval by pulmonologist
• Fiberoptic exam
• Pulmonary function studies
• Polysomnography
• Pain assessment
• Quality of life questionnaire
• Age-appropriate ADL questionnaire
• Use of community or
• Social work involvement for parental support;
• Home nursing referral.
• Physiatrist (specialist in physical medicine and rehabilitation) to optimize mobility and autonomy
• Physical therapist to optimize mobility
• Occupational therapist to optimize autonomy
• Psychological support to optimize coping skills and quality of life
• Education professionals to optimize learning in a medically fragile individual
• Consideration of referral to family therapy to help normalize the experience for the affected individual, parents, sibs, and extended family members
• Home care for affected individuals with multiple medical equipment needs
• Hospice for end-of-life care
• The recommendation dose is 2 mg/kg/week intravenous. Although the treatment with ERT is not curative, ERT could improve endurance and overall quality of life.
• Premedication (30-60 minutes prior to each enzyme infusion) with a non-sedating antihistamine (if possible) with or without antipyretics is recommended to prevent infusion-associated reactions.
• A Phase III clinical trial demonstrated a statistically significant improvement in the 6MWT distance in the 2 mg/kg weekly dose group compared to the placebo group. The three-minute stair climb test and respiratory function were improved with the treatment but the differences were not statistically significant.
• The long-term effects of this treatment on the skeletal features of MPS IVA are still unclear (see
• The impact of ERT on mildly affected individuals after 52 weeks of treatment was minimal, lacking significant change on cardiac or pulmonary function.
• Growth modulation, also called guided growth (temporary surgical tethering of the growth plate to allow gradual correction of the deformity) or realignment osteotomies have been successful [
• Early detection and evaluation may allow surgical tethering of the growth plate to treat mild-to-moderate lower-extremity angular deformities in children with open physes (growth plates). Typically this procedure is less invasive and allows for easier recovery than realignment osteotomies.
• Once the growth plates close, distal femoral and proximal tibial osteotomies are needed to acutely or gradually (with the use of external fixators) correct lower-extremity malalignment.
• Ankle malalignment is often corrected by a distal tibial osteotomy with distal tibial screw hemiepiphysiodesis [
• Hip reconstruction includes either femoral or acetabular osteotomy for mild cases or combined acetabular and femoral osteotomy for severe cases. Augmentation of acetabular bone stock and customized implants by using cortical grafts from the inner table of the ilium are usually required due to a shallow acetabulum [
• Total hip arthroplasty may be required in young adults experiencing significant hip pain which cannot be corrected by reconstructive techniques.
• To minimize neurologic injury and maximize function, intervention in children is recommended when radiographic signs of cervical compression are present, even in the absence of symptoms.
• Affected individuals undergoing surgical fusion typically do well; minor secondary complications can include pin site infections, pressure sores, and long-term difficulty with endotracheal intubation.
• Note: It is important for clinicians to be aware that cervical myelopathy from upper cervical instability may result in deteriorating endurance and worsening gait. If myelopathy is suspected, obtain cervical spine radiographs and MRI (see
• When kyphosis is <45°, the risk of progressive deformity is less than with a greater curve, but warrants clinical and radiographic monitoring.
• When kyphosis is >45°, progression is likely. Although extensive bracing with an orthosis or a cast does not prevent progression of the thoracolumbar kyphosis, it may delay the need for surgical intervention during a period of growth and development.
• Anterior and posterior circumferential spinal fusion are indicated if one or more of the following are present:
• Progressive thoracolumbar kyphosis >70°
• Uncontrolled back pain
• Neurologic changes related to spinal stenosis
• Progressive thoracolumbar kyphosis >70°
• Uncontrolled back pain
• Neurologic changes related to spinal stenosis
• Progressive thoracolumbar kyphosis >70°
• Uncontrolled back pain
• Neurologic changes related to spinal stenosis
• Annual pain severity and disease burden assessments including quality of life and activities of daily living (See
• Annual pulmonary function tests, including maximum voluntary ventilation (MVV) and forced vital capacity (FVC)
• Urine KS / urine GAG levels at baseline, then every six months
• Every 6-12 months, track growth, pubertal stage, and progress; optimize ambulation.
• Annually, assess pain severity and disease burden including quality of life and activities of daily living.
• Annually, before and after surgical procedures, or as clinically indicated, perform endurance tests including six-minute walk test or timed 25-foot walk test to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems. Respiratory rate, pulse oximeter, and heart rate should be measured before and after the annual testing.
• Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
• Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
• Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
• Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
• For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
• In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
• Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
• Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
• MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
• * Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
• For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
• In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
• Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
• Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
• MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
• * Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
• Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
• Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
• For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
• In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
• Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
• Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
• MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
• * Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
• For obstructive sleep apnea, annual history focused on sleep patterns and sounds. Evaluation by an otolaryngologist for adenotonsillectomy. Annual in-home screening sleep studies (which monitor oxygen saturation). Polysomnography every three years.
• To assess pulmonary function, annual MVV and FVC in children older than age five years until growth stops, then every two to three years. The benefit of noninvasive pulmonary function tests, impulse oscillometry, and thoracoabdominal motion analysis has been demonstrated in children with MPS IV [
• Fiberoptic examination at least annually or as clinically indicated [
• Monitor for vision and ocular abnormalities with ophthalmologist examination at least annually.
• For those with rod and cone retinal dystrophy, perform retinal examination and electroretinography under scotopic and photopic conditions every five years [
• Molecular genetic testing if the pathogenic variants in the family are known;
• Analysis of N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with mucopolysaccharidosis type IVA (MPS IVA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mucopolysaccharidosis IVA
Cervical spine radiographs incl AP, neutral lateral, & flexion-extension views
AP & lateral radiographs of entire spine
Brain MRI
MRI of the entire spine (neutral position) focusing on potential sites of cord compression (occipitocervical, cervicothoracic, & thoracolumbar)
Cervical spine flexion-extension MRI when significant spinal cord compression is not detected by standard MRI of the cervical spine
Flexion-extension MRI can identify dynamic changes in canal diameter → cord compression.
Cervical spine flexion-extension MRI under sedation/anesthesia in children w/skeletal dysplasia was safe under adequate supervision & result was useful for surgical decision making [
AP & frog leg lateral radiographs of the pelvis
AP standing radiographs of the lower extremities
Eval by physiatrist (i.e., specialist in physical medicine & rehab) to assess mobility, joint range of motion, & autonomy
6-min walk test (6MWT) & timed 25-ft walk test (T25FW)
EKG
Echocardiogram
Eval by pulmonologist
Fiberoptic exam
Pulmonary function studies
Polysomnography
Pain assessment
Quality of life questionnaire
Age-appropriate ADL questionnaire
Use of community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; AP = anterior-posterior; MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Cervical spine radiographs incl AP, neutral lateral, & flexion-extension views
• AP & lateral radiographs of entire spine
• Brain MRI
• MRI of the entire spine (neutral position) focusing on potential sites of cord compression (occipitocervical, cervicothoracic, & thoracolumbar)
• Cervical spine flexion-extension MRI when significant spinal cord compression is not detected by standard MRI of the cervical spine
• Flexion-extension MRI can identify dynamic changes in canal diameter → cord compression.
• Cervical spine flexion-extension MRI under sedation/anesthesia in children w/skeletal dysplasia was safe under adequate supervision & result was useful for surgical decision making [
• AP & frog leg lateral radiographs of the pelvis
• AP standing radiographs of the lower extremities
• Eval by physiatrist (i.e., specialist in physical medicine & rehab) to assess mobility, joint range of motion, & autonomy
• 6-min walk test (6MWT) & timed 25-ft walk test (T25FW)
• EKG
• Echocardiogram
• Eval by pulmonologist
• Fiberoptic exam
• Pulmonary function studies
• Polysomnography
• Pain assessment
• Quality of life questionnaire
• Age-appropriate ADL questionnaire
• Use of community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Management of individuals with MPS IVA is best undertaken by the following multiple specialists, coordinated by a physician specializing in the care of individuals with complex medical problems:
Physiatrist (specialist in physical medicine and rehabilitation) to optimize mobility and autonomy
Physical therapist to optimize mobility
Occupational therapist to optimize autonomy
Psychological support to optimize coping skills and quality of life
Education professionals to optimize learning in a medically fragile individual
Consideration of referral to family therapy to help normalize the experience for the affected individual, parents, sibs, and extended family members
Home care for affected individuals with multiple medical equipment needs
Hospice for end-of-life care
Recombinant human GALNS ERT (elosulfase alfa, or Vimizim™) was approved by the FDA in February 2014.
The recommendation dose is 2 mg/kg/week intravenous. Although the treatment with ERT is not curative, ERT could improve endurance and overall quality of life.
Premedication (30-60 minutes prior to each enzyme infusion) with a non-sedating antihistamine (if possible) with or without antipyretics is recommended to prevent infusion-associated reactions.
A Phase III clinical trial demonstrated a statistically significant improvement in the 6MWT distance in the 2 mg/kg weekly dose group compared to the placebo group. The three-minute stair climb test and respiratory function were improved with the treatment but the differences were not statistically significant.
The long-term effects of this treatment on the skeletal features of MPS IVA are still unclear (see
The impact of ERT on mildly affected individuals after 52 weeks of treatment was minimal, lacking significant change on cardiac or pulmonary function.
For published orthopedic management guidelines, see
Growth modulation, also called guided growth (temporary surgical tethering of the growth plate to allow gradual correction of the deformity) or realignment osteotomies have been successful [
Early detection and evaluation may allow surgical tethering of the growth plate to treat mild-to-moderate lower-extremity angular deformities in children with open physes (growth plates). Typically this procedure is less invasive and allows for easier recovery than realignment osteotomies.
Once the growth plates close, distal femoral and proximal tibial osteotomies are needed to acutely or gradually (with the use of external fixators) correct lower-extremity malalignment.
Ankle malalignment is often corrected by a distal tibial osteotomy with distal tibial screw hemiepiphysiodesis [
Hip reconstruction includes either femoral or acetabular osteotomy for mild cases or combined acetabular and femoral osteotomy for severe cases. Augmentation of acetabular bone stock and customized implants by using cortical grafts from the inner table of the ilium are usually required due to a shallow acetabulum [
Total hip arthroplasty may be required in young adults experiencing significant hip pain which cannot be corrected by reconstructive techniques.
To minimize neurologic injury and maximize function, intervention in children is recommended when radiographic signs of cervical compression are present, even in the absence of symptoms.
Affected individuals undergoing surgical fusion typically do well; minor secondary complications can include pin site infections, pressure sores, and long-term difficulty with endotracheal intubation.
Note: It is important for clinicians to be aware that cervical myelopathy from upper cervical instability may result in deteriorating endurance and worsening gait. If myelopathy is suspected, obtain cervical spine radiographs and MRI (see
When kyphosis is <45°, the risk of progressive deformity is less than with a greater curve, but warrants clinical and radiographic monitoring.
When kyphosis is >45°, progression is likely. Although extensive bracing with an orthosis or a cast does not prevent progression of the thoracolumbar kyphosis, it may delay the need for surgical intervention during a period of growth and development.
Anterior and posterior circumferential spinal fusion are indicated if one or more of the following are present:
Progressive thoracolumbar kyphosis >70°
Uncontrolled back pain
Neurologic changes related to spinal stenosis
Elevated heart rates could indicate a compensation mechanism, secondary to small left ventricular diameter and small stroke volume; thus tachycardia treatment with beta-blockers should be avoided. Valve replacement may be considered for symptomatic individuals with progressive valvular problems [
Bacterial endocarditis prophylaxis is recommended for those at high risk, including those with a prosthetic cardiac valve, prosthetic material used for cardiac valve repair, or previous infective endocarditis [
Upper-airway obstruction and obstructive sleep apnea are managed by removal of enlarged tonsils and adenoids at an average age of seven years [
In persons with diffuse narrowing of the airway in whom adenotonsillectomy only temporally relieves upper-airway obstruction, other interventions to consider are: CPAP (continuous positive airway pressure), NIPPV (noninvasive positive pressure ventilation), tracheostomy, and possibly tracheal reconstructive surgery.
Lower-airway obstruction manifest as wheezing and recurrent infection is managed by inhaled and/or oral bronchodilators and, in some instances, corticosteroids.
Restrictive lung disease is managed by supportive treatment.
Due to increased risk for pulmonary infection, all affected individuals should receive influenza and pneumococcal immunizations as well as routine immunizations.
Preoperative assessment should include history of response to anesthesia and any evidence of airway obstruction, cardiac evaluation including electrocardiogram and echocardiography, evaluation of respiratory function (spirometry and polysomnography), and airway fluoroscopy [
Endotracheal intubation likely includes use of a video laryngoscope, fiberoptic bronchoscope with or without a laryngeal mask airway (LMA), a smaller endotracheal tube than expected for age and/or size, and use of LMA for short procedures. These techniques help maintain a neutral neck position. Although nasal intubation is an option, GAG deposits can lead to narrowing of the nasal passages and increased propensity to bleeding [
Intraoperative neurophysiologic monitoring (see
Postoperative narcotic management should be judicious; multimodal analgesics and non-narcotic medications are preferable to avoid exacerbating preexisting respiratory issues, such as sleep apnea.
Postoperative complications including pulmonary edema have been described [
Due to risk of postoperative complications, some individuals may require close monitoring for at least 24-48 hours.
Height of children with MPS IVA is best plotted on growth charts specific for MPS IVA [
Nutrition should be optimized with a balanced diet and adequate vitamin D and calcium to assure bone health.
Corneal opacification often causes reduced vision in early childhood, necessitating corneal transplantation (deep lamellar keratoplasty or penetrating keratoplasty), for which the outcome can vary. Other factors which may cause reduced vision such as retinopathy should be excluded before considering corneal transplantation. Recurrence of opacities within the first year post keratoplasty has been reported, making this a temporary measure for improving quality of life [
Daily oral hygiene care, fissure sealing, and adequate fluoride supplementation help prevent cavities. Orthodontic management to correct malocclusion may be necessary.
Because ventilation tube placement can minimize the long-term scarring associated with chronic middle-ear effusions and recurrent acute otitis media, and improve hearing in the long term, most children have ventilation tubes placed during the preschool years. At the first occasion, a long-lasting tympanostomy tube is recommended due to high risk of recurrent middle-ear effusion and the risk associated with sedation in individuals with MPS IVA [
The progressive hearing impairment observed in most individuals with MPS IVA benefits from hearing aids.
Despite some physical limitation, individuals with MPS IVA have normal intellect and can thrive in an environment with academic and social stimulation. Children routinely attend regular class/school with assistance to prevent physical injury.
• Physiatrist (specialist in physical medicine and rehabilitation) to optimize mobility and autonomy
• Physical therapist to optimize mobility
• Occupational therapist to optimize autonomy
• Psychological support to optimize coping skills and quality of life
• Education professionals to optimize learning in a medically fragile individual
• Consideration of referral to family therapy to help normalize the experience for the affected individual, parents, sibs, and extended family members
• Home care for affected individuals with multiple medical equipment needs
• Hospice for end-of-life care
• The recommendation dose is 2 mg/kg/week intravenous. Although the treatment with ERT is not curative, ERT could improve endurance and overall quality of life.
• Premedication (30-60 minutes prior to each enzyme infusion) with a non-sedating antihistamine (if possible) with or without antipyretics is recommended to prevent infusion-associated reactions.
• A Phase III clinical trial demonstrated a statistically significant improvement in the 6MWT distance in the 2 mg/kg weekly dose group compared to the placebo group. The three-minute stair climb test and respiratory function were improved with the treatment but the differences were not statistically significant.
• The long-term effects of this treatment on the skeletal features of MPS IVA are still unclear (see
• The impact of ERT on mildly affected individuals after 52 weeks of treatment was minimal, lacking significant change on cardiac or pulmonary function.
• Growth modulation, also called guided growth (temporary surgical tethering of the growth plate to allow gradual correction of the deformity) or realignment osteotomies have been successful [
• Early detection and evaluation may allow surgical tethering of the growth plate to treat mild-to-moderate lower-extremity angular deformities in children with open physes (growth plates). Typically this procedure is less invasive and allows for easier recovery than realignment osteotomies.
• Once the growth plates close, distal femoral and proximal tibial osteotomies are needed to acutely or gradually (with the use of external fixators) correct lower-extremity malalignment.
• Ankle malalignment is often corrected by a distal tibial osteotomy with distal tibial screw hemiepiphysiodesis [
• Hip reconstruction includes either femoral or acetabular osteotomy for mild cases or combined acetabular and femoral osteotomy for severe cases. Augmentation of acetabular bone stock and customized implants by using cortical grafts from the inner table of the ilium are usually required due to a shallow acetabulum [
• Total hip arthroplasty may be required in young adults experiencing significant hip pain which cannot be corrected by reconstructive techniques.
• To minimize neurologic injury and maximize function, intervention in children is recommended when radiographic signs of cervical compression are present, even in the absence of symptoms.
• Affected individuals undergoing surgical fusion typically do well; minor secondary complications can include pin site infections, pressure sores, and long-term difficulty with endotracheal intubation.
• Note: It is important for clinicians to be aware that cervical myelopathy from upper cervical instability may result in deteriorating endurance and worsening gait. If myelopathy is suspected, obtain cervical spine radiographs and MRI (see
• When kyphosis is <45°, the risk of progressive deformity is less than with a greater curve, but warrants clinical and radiographic monitoring.
• When kyphosis is >45°, progression is likely. Although extensive bracing with an orthosis or a cast does not prevent progression of the thoracolumbar kyphosis, it may delay the need for surgical intervention during a period of growth and development.
• Anterior and posterior circumferential spinal fusion are indicated if one or more of the following are present:
• Progressive thoracolumbar kyphosis >70°
• Uncontrolled back pain
• Neurologic changes related to spinal stenosis
• Progressive thoracolumbar kyphosis >70°
• Uncontrolled back pain
• Neurologic changes related to spinal stenosis
• Progressive thoracolumbar kyphosis >70°
• Uncontrolled back pain
• Neurologic changes related to spinal stenosis
## Enzyme Replacement Therapy (ERT)
Recombinant human GALNS ERT (elosulfase alfa, or Vimizim™) was approved by the FDA in February 2014.
The recommendation dose is 2 mg/kg/week intravenous. Although the treatment with ERT is not curative, ERT could improve endurance and overall quality of life.
Premedication (30-60 minutes prior to each enzyme infusion) with a non-sedating antihistamine (if possible) with or without antipyretics is recommended to prevent infusion-associated reactions.
A Phase III clinical trial demonstrated a statistically significant improvement in the 6MWT distance in the 2 mg/kg weekly dose group compared to the placebo group. The three-minute stair climb test and respiratory function were improved with the treatment but the differences were not statistically significant.
The long-term effects of this treatment on the skeletal features of MPS IVA are still unclear (see
The impact of ERT on mildly affected individuals after 52 weeks of treatment was minimal, lacking significant change on cardiac or pulmonary function.
• The recommendation dose is 2 mg/kg/week intravenous. Although the treatment with ERT is not curative, ERT could improve endurance and overall quality of life.
• Premedication (30-60 minutes prior to each enzyme infusion) with a non-sedating antihistamine (if possible) with or without antipyretics is recommended to prevent infusion-associated reactions.
• A Phase III clinical trial demonstrated a statistically significant improvement in the 6MWT distance in the 2 mg/kg weekly dose group compared to the placebo group. The three-minute stair climb test and respiratory function were improved with the treatment but the differences were not statistically significant.
• The long-term effects of this treatment on the skeletal features of MPS IVA are still unclear (see
• The impact of ERT on mildly affected individuals after 52 weeks of treatment was minimal, lacking significant change on cardiac or pulmonary function.
## Musculoskeletal
For published orthopedic management guidelines, see
Growth modulation, also called guided growth (temporary surgical tethering of the growth plate to allow gradual correction of the deformity) or realignment osteotomies have been successful [
Early detection and evaluation may allow surgical tethering of the growth plate to treat mild-to-moderate lower-extremity angular deformities in children with open physes (growth plates). Typically this procedure is less invasive and allows for easier recovery than realignment osteotomies.
Once the growth plates close, distal femoral and proximal tibial osteotomies are needed to acutely or gradually (with the use of external fixators) correct lower-extremity malalignment.
Ankle malalignment is often corrected by a distal tibial osteotomy with distal tibial screw hemiepiphysiodesis [
Hip reconstruction includes either femoral or acetabular osteotomy for mild cases or combined acetabular and femoral osteotomy for severe cases. Augmentation of acetabular bone stock and customized implants by using cortical grafts from the inner table of the ilium are usually required due to a shallow acetabulum [
Total hip arthroplasty may be required in young adults experiencing significant hip pain which cannot be corrected by reconstructive techniques.
To minimize neurologic injury and maximize function, intervention in children is recommended when radiographic signs of cervical compression are present, even in the absence of symptoms.
Affected individuals undergoing surgical fusion typically do well; minor secondary complications can include pin site infections, pressure sores, and long-term difficulty with endotracheal intubation.
Note: It is important for clinicians to be aware that cervical myelopathy from upper cervical instability may result in deteriorating endurance and worsening gait. If myelopathy is suspected, obtain cervical spine radiographs and MRI (see
When kyphosis is <45°, the risk of progressive deformity is less than with a greater curve, but warrants clinical and radiographic monitoring.
When kyphosis is >45°, progression is likely. Although extensive bracing with an orthosis or a cast does not prevent progression of the thoracolumbar kyphosis, it may delay the need for surgical intervention during a period of growth and development.
Anterior and posterior circumferential spinal fusion are indicated if one or more of the following are present:
Progressive thoracolumbar kyphosis >70°
Uncontrolled back pain
Neurologic changes related to spinal stenosis
• Growth modulation, also called guided growth (temporary surgical tethering of the growth plate to allow gradual correction of the deformity) or realignment osteotomies have been successful [
• Early detection and evaluation may allow surgical tethering of the growth plate to treat mild-to-moderate lower-extremity angular deformities in children with open physes (growth plates). Typically this procedure is less invasive and allows for easier recovery than realignment osteotomies.
• Once the growth plates close, distal femoral and proximal tibial osteotomies are needed to acutely or gradually (with the use of external fixators) correct lower-extremity malalignment.
• Ankle malalignment is often corrected by a distal tibial osteotomy with distal tibial screw hemiepiphysiodesis [
• Hip reconstruction includes either femoral or acetabular osteotomy for mild cases or combined acetabular and femoral osteotomy for severe cases. Augmentation of acetabular bone stock and customized implants by using cortical grafts from the inner table of the ilium are usually required due to a shallow acetabulum [
• Total hip arthroplasty may be required in young adults experiencing significant hip pain which cannot be corrected by reconstructive techniques.
• To minimize neurologic injury and maximize function, intervention in children is recommended when radiographic signs of cervical compression are present, even in the absence of symptoms.
• Affected individuals undergoing surgical fusion typically do well; minor secondary complications can include pin site infections, pressure sores, and long-term difficulty with endotracheal intubation.
• Note: It is important for clinicians to be aware that cervical myelopathy from upper cervical instability may result in deteriorating endurance and worsening gait. If myelopathy is suspected, obtain cervical spine radiographs and MRI (see
• When kyphosis is <45°, the risk of progressive deformity is less than with a greater curve, but warrants clinical and radiographic monitoring.
• When kyphosis is >45°, progression is likely. Although extensive bracing with an orthosis or a cast does not prevent progression of the thoracolumbar kyphosis, it may delay the need for surgical intervention during a period of growth and development.
• Anterior and posterior circumferential spinal fusion are indicated if one or more of the following are present:
• Progressive thoracolumbar kyphosis >70°
• Uncontrolled back pain
• Neurologic changes related to spinal stenosis
• Progressive thoracolumbar kyphosis >70°
• Uncontrolled back pain
• Neurologic changes related to spinal stenosis
• Progressive thoracolumbar kyphosis >70°
• Uncontrolled back pain
• Neurologic changes related to spinal stenosis
## Cardiac
Elevated heart rates could indicate a compensation mechanism, secondary to small left ventricular diameter and small stroke volume; thus tachycardia treatment with beta-blockers should be avoided. Valve replacement may be considered for symptomatic individuals with progressive valvular problems [
Bacterial endocarditis prophylaxis is recommended for those at high risk, including those with a prosthetic cardiac valve, prosthetic material used for cardiac valve repair, or previous infective endocarditis [
## Respiratory
Upper-airway obstruction and obstructive sleep apnea are managed by removal of enlarged tonsils and adenoids at an average age of seven years [
In persons with diffuse narrowing of the airway in whom adenotonsillectomy only temporally relieves upper-airway obstruction, other interventions to consider are: CPAP (continuous positive airway pressure), NIPPV (noninvasive positive pressure ventilation), tracheostomy, and possibly tracheal reconstructive surgery.
Lower-airway obstruction manifest as wheezing and recurrent infection is managed by inhaled and/or oral bronchodilators and, in some instances, corticosteroids.
Restrictive lung disease is managed by supportive treatment.
Due to increased risk for pulmonary infection, all affected individuals should receive influenza and pneumococcal immunizations as well as routine immunizations.
Preoperative assessment should include history of response to anesthesia and any evidence of airway obstruction, cardiac evaluation including electrocardiogram and echocardiography, evaluation of respiratory function (spirometry and polysomnography), and airway fluoroscopy [
Endotracheal intubation likely includes use of a video laryngoscope, fiberoptic bronchoscope with or without a laryngeal mask airway (LMA), a smaller endotracheal tube than expected for age and/or size, and use of LMA for short procedures. These techniques help maintain a neutral neck position. Although nasal intubation is an option, GAG deposits can lead to narrowing of the nasal passages and increased propensity to bleeding [
Intraoperative neurophysiologic monitoring (see
Postoperative narcotic management should be judicious; multimodal analgesics and non-narcotic medications are preferable to avoid exacerbating preexisting respiratory issues, such as sleep apnea.
Postoperative complications including pulmonary edema have been described [
Due to risk of postoperative complications, some individuals may require close monitoring for at least 24-48 hours.
## Growth
Height of children with MPS IVA is best plotted on growth charts specific for MPS IVA [
Nutrition should be optimized with a balanced diet and adequate vitamin D and calcium to assure bone health.
## Eye
Corneal opacification often causes reduced vision in early childhood, necessitating corneal transplantation (deep lamellar keratoplasty or penetrating keratoplasty), for which the outcome can vary. Other factors which may cause reduced vision such as retinopathy should be excluded before considering corneal transplantation. Recurrence of opacities within the first year post keratoplasty has been reported, making this a temporary measure for improving quality of life [
## Dental
Daily oral hygiene care, fissure sealing, and adequate fluoride supplementation help prevent cavities. Orthodontic management to correct malocclusion may be necessary.
## Hearing
Because ventilation tube placement can minimize the long-term scarring associated with chronic middle-ear effusions and recurrent acute otitis media, and improve hearing in the long term, most children have ventilation tubes placed during the preschool years. At the first occasion, a long-lasting tympanostomy tube is recommended due to high risk of recurrent middle-ear effusion and the risk associated with sedation in individuals with MPS IVA [
The progressive hearing impairment observed in most individuals with MPS IVA benefits from hearing aids.
## Learning Environment
Despite some physical limitation, individuals with MPS IVA have normal intellect and can thrive in an environment with academic and social stimulation. Children routinely attend regular class/school with assistance to prevent physical injury.
## Surveillance
The following should be assessed before and after initiation of ERT to determine treatment efficacy:
Annual pain severity and disease burden assessments including quality of life and activities of daily living (See
Annual pulmonary function tests, including maximum voluntary ventilation (MVV) and forced vital capacity (FVC)
Urine KS / urine GAG levels at baseline, then every six months
Note: The benefit of monitoring anti-elosulfase alfa antibodies is unknown.
Every 6-12 months, track growth, pubertal stage, and progress; optimize ambulation.
Annually, assess pain severity and disease burden including quality of life and activities of daily living.
Annually, before and after surgical procedures, or as clinically indicated, perform endurance tests including six-minute walk test or timed 25-foot walk test to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems. Respiratory rate, pulse oximeter, and heart rate should be measured before and after the annual testing.
Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
* Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
For obstructive sleep apnea, annual history focused on sleep patterns and sounds. Evaluation by an otolaryngologist for adenotonsillectomy. Annual in-home screening sleep studies (which monitor oxygen saturation). Polysomnography every three years.
To assess pulmonary function, annual MVV and FVC in children older than age five years until growth stops, then every two to three years. The benefit of noninvasive pulmonary function tests, impulse oscillometry, and thoracoabdominal motion analysis has been demonstrated in children with MPS IV [
Fiberoptic examination at least annually or as clinically indicated [
Monitor for vision and ocular abnormalities with ophthalmologist examination at least annually.
For those with rod and cone retinal dystrophy, perform retinal examination and electroretinography under scotopic and photopic conditions every five years [
• Annual pain severity and disease burden assessments including quality of life and activities of daily living (See
• Annual pulmonary function tests, including maximum voluntary ventilation (MVV) and forced vital capacity (FVC)
• Urine KS / urine GAG levels at baseline, then every six months
• Every 6-12 months, track growth, pubertal stage, and progress; optimize ambulation.
• Annually, assess pain severity and disease burden including quality of life and activities of daily living.
• Annually, before and after surgical procedures, or as clinically indicated, perform endurance tests including six-minute walk test or timed 25-foot walk test to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems. Respiratory rate, pulse oximeter, and heart rate should be measured before and after the annual testing.
• Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
• Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
• Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
• Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
• For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
• In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
• Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
• Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
• MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
• * Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
• For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
• In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
• Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
• Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
• MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
• * Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
• Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
• Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
• For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
• In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
• Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
• Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
• MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
• * Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
• For obstructive sleep apnea, annual history focused on sleep patterns and sounds. Evaluation by an otolaryngologist for adenotonsillectomy. Annual in-home screening sleep studies (which monitor oxygen saturation). Polysomnography every three years.
• To assess pulmonary function, annual MVV and FVC in children older than age five years until growth stops, then every two to three years. The benefit of noninvasive pulmonary function tests, impulse oscillometry, and thoracoabdominal motion analysis has been demonstrated in children with MPS IV [
• Fiberoptic examination at least annually or as clinically indicated [
• Monitor for vision and ocular abnormalities with ophthalmologist examination at least annually.
• For those with rod and cone retinal dystrophy, perform retinal examination and electroretinography under scotopic and photopic conditions every five years [
## Individuals on ERT
The following should be assessed before and after initiation of ERT to determine treatment efficacy:
Annual pain severity and disease burden assessments including quality of life and activities of daily living (See
Annual pulmonary function tests, including maximum voluntary ventilation (MVV) and forced vital capacity (FVC)
Urine KS / urine GAG levels at baseline, then every six months
Note: The benefit of monitoring anti-elosulfase alfa antibodies is unknown.
• Annual pain severity and disease burden assessments including quality of life and activities of daily living (See
• Annual pulmonary function tests, including maximum voluntary ventilation (MVV) and forced vital capacity (FVC)
• Urine KS / urine GAG levels at baseline, then every six months
## All Individuals
Every 6-12 months, track growth, pubertal stage, and progress; optimize ambulation.
Annually, assess pain severity and disease burden including quality of life and activities of daily living.
Annually, before and after surgical procedures, or as clinically indicated, perform endurance tests including six-minute walk test or timed 25-foot walk test to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems. Respiratory rate, pulse oximeter, and heart rate should be measured before and after the annual testing.
Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
* Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
For obstructive sleep apnea, annual history focused on sleep patterns and sounds. Evaluation by an otolaryngologist for adenotonsillectomy. Annual in-home screening sleep studies (which monitor oxygen saturation). Polysomnography every three years.
To assess pulmonary function, annual MVV and FVC in children older than age five years until growth stops, then every two to three years. The benefit of noninvasive pulmonary function tests, impulse oscillometry, and thoracoabdominal motion analysis has been demonstrated in children with MPS IV [
Fiberoptic examination at least annually or as clinically indicated [
Monitor for vision and ocular abnormalities with ophthalmologist examination at least annually.
For those with rod and cone retinal dystrophy, perform retinal examination and electroretinography under scotopic and photopic conditions every five years [
• Every 6-12 months, track growth, pubertal stage, and progress; optimize ambulation.
• Annually, assess pain severity and disease burden including quality of life and activities of daily living.
• Annually, before and after surgical procedures, or as clinically indicated, perform endurance tests including six-minute walk test or timed 25-foot walk test to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems. Respiratory rate, pulse oximeter, and heart rate should be measured before and after the annual testing.
• Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
• Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
• Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
• Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
• For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
• In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
• Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
• Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
• MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
• * Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
• For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
• In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
• Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
• Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
• MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
• * Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
• Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional dexterity test) of the upper extremities
• Assessment of lower-extremity alignment, including standing AP radiographs (as clinically indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation when clinically indicated
• For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or bladder dysfunction or lower back/leg pain).
• In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed information.
• Plain radiographs of the cervical spine (AP, lateral, neutral, and flexion-extension) every two to three years
• Plain radiographs of the spine (AP and lateral views for the thoracolumbar spine) every two to three years
• MRI of the whole spine (neutral position)* annually and flexion-extension MRI of the cervical spine if results are inconclusive
• * Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to cervical MRI to assess for atlantooccipital instability.
• For obstructive sleep apnea, annual history focused on sleep patterns and sounds. Evaluation by an otolaryngologist for adenotonsillectomy. Annual in-home screening sleep studies (which monitor oxygen saturation). Polysomnography every three years.
• To assess pulmonary function, annual MVV and FVC in children older than age five years until growth stops, then every two to three years. The benefit of noninvasive pulmonary function tests, impulse oscillometry, and thoracoabdominal motion analysis has been demonstrated in children with MPS IV [
• Fiberoptic examination at least annually or as clinically indicated [
• Monitor for vision and ocular abnormalities with ophthalmologist examination at least annually.
• For those with rod and cone retinal dystrophy, perform retinal examination and electroretinography under scotopic and photopic conditions every five years [
## Agents/Circumstances to Avoid
Because excessive weight gain causes undue stress on the axial skeleton and may decrease the duration of independent ambulation, it is important to optimize nutrition for growth while maintaining a lean habitus.
Due to small ventricular diameter and stroke volume, beta-blockers should be avoided in the treatment of tachycardia.
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of ERT (see
Molecular genetic testing if the pathogenic variants in the family are known;
Analysis of N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Analysis of N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity if the pathogenic variants in the family are not known.
## Therapies Under Investigation
The experience of hematopoietic stem cell therapy is limited and has not been well studied. Gene therapy and substrate degradation enzyme therapy are in preclinical trials [
Search
## Genetic Counseling
Mucopolysaccharidosis type IVA (MPS IVA) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Accurate recurrence risk counseling relies on carrier testing of both parents to confirm that they are both heterozygous for a
And the child appears to have homozygous
And the child has compound heterozygous
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Accurate recurrence risk counseling relies on carrier testing of both parents to confirm that they are both heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• And the child appears to have homozygous
• And the child has compound heterozygous
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Mucopolysaccharidosis type IVA (MPS IVA) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Accurate recurrence risk counseling relies on carrier testing of both parents to confirm that they are both heterozygous for a
And the child appears to have homozygous
And the child has compound heterozygous
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Accurate recurrence risk counseling relies on carrier testing of both parents to confirm that they are both heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• And the child appears to have homozygous
• And the child has compound heterozygous
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
United Kingdom
•
• Canada
•
•
•
•
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
Mucopolysaccharidosis Type IVA : Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Mucopolysaccharidosis Type IVA (
Mucopolysaccharidosis type IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfatase (GALNS), which cleaves the keratan sulfate at the O-linked sulfate moiety of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The absence of the enzyme GALNS leads to intracellular accumulation of the glycosaminoglycans KS and C6S in the lysosomes of multiple tissues. The accumulation mainly in cornea and bone leads to the pathognomonic findings of corneal clouding and skeletal dysplasia [
Missense, nonsense, splicing and deep intronic variants, as well as small deletions, small insertions, gross insertions/duplications, gross deletions, and complex rearrangements have been found in
Notable
Variants listed in the table have been provided by the authors.
## Pathophysiology
Mucopolysaccharidosis type IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfatase (GALNS), which cleaves the keratan sulfate at the O-linked sulfate moiety of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The absence of the enzyme GALNS leads to intracellular accumulation of the glycosaminoglycans KS and C6S in the lysosomes of multiple tissues. The accumulation mainly in cornea and bone leads to the pathognomonic findings of corneal clouding and skeletal dysplasia [
Missense, nonsense, splicing and deep intronic variants, as well as small deletions, small insertions, gross insertions/duplications, gross deletions, and complex rearrangements have been found in
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Dr Regier is the medical director in the Children's National Rare Disease Institute. Her main interest in in the field of Inborn Errors of Metabolism and educational outcomes research. She has been actively involved in clinical trials and implementation of new treatments for patients with Inborn Errors of Metabolism.
Dr Oetgen, an attending surgeon in the Department of Orthopaedics and Sports Medicine at Children's National Medical Center, has a special interest in the orthopaedic manifestations of genetic conditions affecting pediatric patients, including the mucopolysaccharidoses. He participates in the care of these patients in collaboration with the Children's National Hospital Department of Genetics.
Dr Tanpaiboon is a geneticist and researcher in the Division of Genetics and Metabolism at Children's National Rare Disease Institute. Her main interest is the field of Inborn Errors of Metabolism, particularly the lysosomal storage disorders (LSDs). She has been actively involved in international multicenter clinical trials of enzyme replacement therapy for MPS IVA and other LSDs.
Kathleen Crosby, MS, CGC and Lindsay Kehoe MS, CGC are gratefully acknowledged for providing excellent care for patients and their families
17 June 2021 (sw) Comprehensive update posted live
24 March 2016 (ma) Comprehensive update posted live
11 July 2013 (me) Review posted live
18 January 2013 (pt) Original Submission
• 17 June 2021 (sw) Comprehensive update posted live
• 24 March 2016 (ma) Comprehensive update posted live
• 11 July 2013 (me) Review posted live
• 18 January 2013 (pt) Original Submission
## Author Notes
Dr Regier is the medical director in the Children's National Rare Disease Institute. Her main interest in in the field of Inborn Errors of Metabolism and educational outcomes research. She has been actively involved in clinical trials and implementation of new treatments for patients with Inborn Errors of Metabolism.
Dr Oetgen, an attending surgeon in the Department of Orthopaedics and Sports Medicine at Children's National Medical Center, has a special interest in the orthopaedic manifestations of genetic conditions affecting pediatric patients, including the mucopolysaccharidoses. He participates in the care of these patients in collaboration with the Children's National Hospital Department of Genetics.
Dr Tanpaiboon is a geneticist and researcher in the Division of Genetics and Metabolism at Children's National Rare Disease Institute. Her main interest is the field of Inborn Errors of Metabolism, particularly the lysosomal storage disorders (LSDs). She has been actively involved in international multicenter clinical trials of enzyme replacement therapy for MPS IVA and other LSDs.
## Acknowledgments
Kathleen Crosby, MS, CGC and Lindsay Kehoe MS, CGC are gratefully acknowledged for providing excellent care for patients and their families
## Revision History
17 June 2021 (sw) Comprehensive update posted live
24 March 2016 (ma) Comprehensive update posted live
11 July 2013 (me) Review posted live
18 January 2013 (pt) Original Submission
• 17 June 2021 (sw) Comprehensive update posted live
• 24 March 2016 (ma) Comprehensive update posted live
• 11 July 2013 (me) Review posted live
• 18 January 2013 (pt) Original Submission
## References
## Literature Cited
Ulnar deviation of both wrists and joint enlargement in a male age 15 years with MPS IVA
Shortened forearm and ulnar deviation of the wrist in a male age 15 years with MPS IVA
Pectus anomaly and short neck in a male age 15 years with MPS IVA
Lateral view of chest showing severe pectus carinatum in a male age 15 years with MPS IVA
Severe genu valgum (knock-knee) in a male age 15 years with MPS IVA
Lateral cervical spine radiograph of a female age six years with MPS IVA. Note hypoplastic odontoid (dashed line highlights that the odontoid does not extend superiorly within the C1 ring); platyspondyly (vertebral flattening) (double arrows); and anterior subluxation of C7 on T1 (lines indicate the posterior vertebral bodies of C7 and T1 and arrow indicates anterior translation of C7 on T1).
Lateral spine radiograph of a female age eight years with MPS IVA. Note platyspondyly (flattened vertebrae) with anterior beaking (arrow).
Hip radiograph of a female age eight years with MPS IVA. Note bilateral irregular flattening of the capital femoral epiphyses (thin arrows), irregular dysplastic acetabuli with lateral joint subluxation (thick arrows).
|
[] |
11/7/2013
|
17/6/2021
|
13/3/2014
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mps7
|
mps7
|
[
"Beta-Glucuronidase Deficiency",
"MPS7",
"Sly Syndrome",
"Beta-Glucuronidase Deficiency",
"Sly Syndrome",
"MPS7",
"Beta-glucuronidase",
"GUSB",
"Mucopolysaccharidosis Type VII"
] |
Mucopolysaccharidosis Type VII
|
Angela Sun, Raymond Wang
|
Summary Individuals with mucopolysaccharidosis type VII (MPS VII) can present perinatally with early demise, nonimmune hydrops fetalis, cholestatic jaundice, and hepatosplenomegaly, or in early childhood with developmental delay and characteristic musculoskeletal features (e.g., short neck, short-trunk short stature, pectus deformity, gibbus, and joint stiffness/contractures) and craniofacial features (e.g., macrocephaly, coarse hair, coarse facies, corneal clouding, and macroglossia). Skeletal survey shows features of dysostosis multiplex including thickened cortical bone, abnormal J-shaped sella turcica, paddle- or oar-shaped ribs, short, thickened clavicles, platyspondyly with anterior beaking of the lower thoracic and lumbar vertebrae, and proximal pointing of the metacarpals and metatarsals. Complications include developmental delay, intellectual disability, hepatosplenomegaly, spinal stenosis, recurrent otitis media, hearing loss, pulmonary disease, obstructive sleep apnea, hernias, feeding difficulties, and heart valve disease. The diagnosis of MPS VII is established in a proband with characteristic clinical and radiographic findings, urine glycosaminoglycan (GAG) analysis with elevated concentrations of total GAGs with increased dermatan and chondroitin sulfate, and absent or reduced beta-glucuronidase enzyme activity in leukocytes, fibroblasts, or dried blood spots; and/or biallelic pathogenic variants in MPS VII is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
Formal diagnostic criteria for mucopolysaccharidosis type VII (MPS VII) have not been established.
MPS VII
Fetal demise / neonatal mortality
Nonimmune hydrops fetalis (Note: Presence of hydrops does not necessarily predict subsequent severity of disease in surviving neonates.)
Cholestatic jaundice
Hepatosplenomegaly
Musculoskeletal features (short neck, odontoid hypoplasia, disproportionate short-trunk short stature, pectus carinatum or excavatum, kyphosis, gibbus deformity, scoliosis, contractures, joint stiffness, genu valgum)
Developmental delay / intellectual disability with variable age of onset and severity that is typically evident by age two years
Characteristic craniofacial features (macrocephaly, coarse hair, coarse facies, corneal clouding, thick eyebrows, macroglossia, gingival hypertrophy, small and widely spaced teeth) (See
Recurrent otitis media or respiratory infections
Snoring, enlarged tonsils and adenoids, obstructive sleep apnea
Hearing loss (sensorineural or conductive)
Prominent abdomen with hepatosplenomegaly
Hernias (umbilical and/or inguinal)
Thickening of mitral and/or aortic valve leaflets, valve insufficiency, valve stenosis, left ventricular hypertrophy
The diagnosis of MPS VII
Absent or reduced beta-glucuronidase enzyme activity in leukocytes, fibroblasts, or dried blood spots
AND/OR
Biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Mexican, Brazilian, and Japanese ancestry (see
For an introduction to multigene panels click
When the diagnosis of MPS VII has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucopolysaccharidosis Type VII
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
A homozygous exon 9 deletion was identified in a fetus with nonimmune hydrops [
•
• Fetal demise / neonatal mortality
• Nonimmune hydrops fetalis (Note: Presence of hydrops does not necessarily predict subsequent severity of disease in surviving neonates.)
• Cholestatic jaundice
• Hepatosplenomegaly
• Fetal demise / neonatal mortality
• Nonimmune hydrops fetalis (Note: Presence of hydrops does not necessarily predict subsequent severity of disease in surviving neonates.)
• Cholestatic jaundice
• Hepatosplenomegaly
•
• Musculoskeletal features (short neck, odontoid hypoplasia, disproportionate short-trunk short stature, pectus carinatum or excavatum, kyphosis, gibbus deformity, scoliosis, contractures, joint stiffness, genu valgum)
• Developmental delay / intellectual disability with variable age of onset and severity that is typically evident by age two years
• Characteristic craniofacial features (macrocephaly, coarse hair, coarse facies, corneal clouding, thick eyebrows, macroglossia, gingival hypertrophy, small and widely spaced teeth) (See
• Recurrent otitis media or respiratory infections
• Snoring, enlarged tonsils and adenoids, obstructive sleep apnea
• Hearing loss (sensorineural or conductive)
• Prominent abdomen with hepatosplenomegaly
• Hernias (umbilical and/or inguinal)
• Thickening of mitral and/or aortic valve leaflets, valve insufficiency, valve stenosis, left ventricular hypertrophy
• Musculoskeletal features (short neck, odontoid hypoplasia, disproportionate short-trunk short stature, pectus carinatum or excavatum, kyphosis, gibbus deformity, scoliosis, contractures, joint stiffness, genu valgum)
• Developmental delay / intellectual disability with variable age of onset and severity that is typically evident by age two years
• Characteristic craniofacial features (macrocephaly, coarse hair, coarse facies, corneal clouding, thick eyebrows, macroglossia, gingival hypertrophy, small and widely spaced teeth) (See
• Recurrent otitis media or respiratory infections
• Snoring, enlarged tonsils and adenoids, obstructive sleep apnea
• Hearing loss (sensorineural or conductive)
• Prominent abdomen with hepatosplenomegaly
• Hernias (umbilical and/or inguinal)
• Thickening of mitral and/or aortic valve leaflets, valve insufficiency, valve stenosis, left ventricular hypertrophy
• Fetal demise / neonatal mortality
• Nonimmune hydrops fetalis (Note: Presence of hydrops does not necessarily predict subsequent severity of disease in surviving neonates.)
• Cholestatic jaundice
• Hepatosplenomegaly
• Musculoskeletal features (short neck, odontoid hypoplasia, disproportionate short-trunk short stature, pectus carinatum or excavatum, kyphosis, gibbus deformity, scoliosis, contractures, joint stiffness, genu valgum)
• Developmental delay / intellectual disability with variable age of onset and severity that is typically evident by age two years
• Characteristic craniofacial features (macrocephaly, coarse hair, coarse facies, corneal clouding, thick eyebrows, macroglossia, gingival hypertrophy, small and widely spaced teeth) (See
• Recurrent otitis media or respiratory infections
• Snoring, enlarged tonsils and adenoids, obstructive sleep apnea
• Hearing loss (sensorineural or conductive)
• Prominent abdomen with hepatosplenomegaly
• Hernias (umbilical and/or inguinal)
• Thickening of mitral and/or aortic valve leaflets, valve insufficiency, valve stenosis, left ventricular hypertrophy
• Absent or reduced beta-glucuronidase enzyme activity in leukocytes, fibroblasts, or dried blood spots
• AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
## Suggestive Findings
MPS VII
Fetal demise / neonatal mortality
Nonimmune hydrops fetalis (Note: Presence of hydrops does not necessarily predict subsequent severity of disease in surviving neonates.)
Cholestatic jaundice
Hepatosplenomegaly
Musculoskeletal features (short neck, odontoid hypoplasia, disproportionate short-trunk short stature, pectus carinatum or excavatum, kyphosis, gibbus deformity, scoliosis, contractures, joint stiffness, genu valgum)
Developmental delay / intellectual disability with variable age of onset and severity that is typically evident by age two years
Characteristic craniofacial features (macrocephaly, coarse hair, coarse facies, corneal clouding, thick eyebrows, macroglossia, gingival hypertrophy, small and widely spaced teeth) (See
Recurrent otitis media or respiratory infections
Snoring, enlarged tonsils and adenoids, obstructive sleep apnea
Hearing loss (sensorineural or conductive)
Prominent abdomen with hepatosplenomegaly
Hernias (umbilical and/or inguinal)
Thickening of mitral and/or aortic valve leaflets, valve insufficiency, valve stenosis, left ventricular hypertrophy
•
• Fetal demise / neonatal mortality
• Nonimmune hydrops fetalis (Note: Presence of hydrops does not necessarily predict subsequent severity of disease in surviving neonates.)
• Cholestatic jaundice
• Hepatosplenomegaly
• Fetal demise / neonatal mortality
• Nonimmune hydrops fetalis (Note: Presence of hydrops does not necessarily predict subsequent severity of disease in surviving neonates.)
• Cholestatic jaundice
• Hepatosplenomegaly
•
• Musculoskeletal features (short neck, odontoid hypoplasia, disproportionate short-trunk short stature, pectus carinatum or excavatum, kyphosis, gibbus deformity, scoliosis, contractures, joint stiffness, genu valgum)
• Developmental delay / intellectual disability with variable age of onset and severity that is typically evident by age two years
• Characteristic craniofacial features (macrocephaly, coarse hair, coarse facies, corneal clouding, thick eyebrows, macroglossia, gingival hypertrophy, small and widely spaced teeth) (See
• Recurrent otitis media or respiratory infections
• Snoring, enlarged tonsils and adenoids, obstructive sleep apnea
• Hearing loss (sensorineural or conductive)
• Prominent abdomen with hepatosplenomegaly
• Hernias (umbilical and/or inguinal)
• Thickening of mitral and/or aortic valve leaflets, valve insufficiency, valve stenosis, left ventricular hypertrophy
• Musculoskeletal features (short neck, odontoid hypoplasia, disproportionate short-trunk short stature, pectus carinatum or excavatum, kyphosis, gibbus deformity, scoliosis, contractures, joint stiffness, genu valgum)
• Developmental delay / intellectual disability with variable age of onset and severity that is typically evident by age two years
• Characteristic craniofacial features (macrocephaly, coarse hair, coarse facies, corneal clouding, thick eyebrows, macroglossia, gingival hypertrophy, small and widely spaced teeth) (See
• Recurrent otitis media or respiratory infections
• Snoring, enlarged tonsils and adenoids, obstructive sleep apnea
• Hearing loss (sensorineural or conductive)
• Prominent abdomen with hepatosplenomegaly
• Hernias (umbilical and/or inguinal)
• Thickening of mitral and/or aortic valve leaflets, valve insufficiency, valve stenosis, left ventricular hypertrophy
• Fetal demise / neonatal mortality
• Nonimmune hydrops fetalis (Note: Presence of hydrops does not necessarily predict subsequent severity of disease in surviving neonates.)
• Cholestatic jaundice
• Hepatosplenomegaly
• Musculoskeletal features (short neck, odontoid hypoplasia, disproportionate short-trunk short stature, pectus carinatum or excavatum, kyphosis, gibbus deformity, scoliosis, contractures, joint stiffness, genu valgum)
• Developmental delay / intellectual disability with variable age of onset and severity that is typically evident by age two years
• Characteristic craniofacial features (macrocephaly, coarse hair, coarse facies, corneal clouding, thick eyebrows, macroglossia, gingival hypertrophy, small and widely spaced teeth) (See
• Recurrent otitis media or respiratory infections
• Snoring, enlarged tonsils and adenoids, obstructive sleep apnea
• Hearing loss (sensorineural or conductive)
• Prominent abdomen with hepatosplenomegaly
• Hernias (umbilical and/or inguinal)
• Thickening of mitral and/or aortic valve leaflets, valve insufficiency, valve stenosis, left ventricular hypertrophy
## Establishing the Diagnosis
The diagnosis of MPS VII
Absent or reduced beta-glucuronidase enzyme activity in leukocytes, fibroblasts, or dried blood spots
AND/OR
Biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Mexican, Brazilian, and Japanese ancestry (see
For an introduction to multigene panels click
When the diagnosis of MPS VII has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucopolysaccharidosis Type VII
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
A homozygous exon 9 deletion was identified in a fetus with nonimmune hydrops [
• Absent or reduced beta-glucuronidase enzyme activity in leukocytes, fibroblasts, or dried blood spots
• AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
## Option 1
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Mexican, Brazilian, and Japanese ancestry (see
For an introduction to multigene panels click
## Option 2
When the diagnosis of MPS VII has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mucopolysaccharidosis Type VII
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
A homozygous exon 9 deletion was identified in a fetus with nonimmune hydrops [
## Clinical Characteristics
Individuals with mucopolysaccharidosis type VII (MPS VII) can present perinatally with early demise, nonimmune hydrops fetalis, cholestatic jaundice, and hepatosplenomegaly, or in early childhood with developmental delay and characteristic musculoskeletal and craniofacial features. To date, <200 individuals have been identified with biallelic pathogenic variants in
Mucopolysaccharidosis Type VII: Frequency of Select Features
GI = gastrointestinal
As adolescent weight tends to be above the 50th centile, the prevalence of overweight is higher especially for individuals who are not independently ambulatory. A study of intravenous enzyme replacement therapy initiated prior to age five years found improved growth velocity and z scores after 48 weeks of treatment, but long-term effects of therapy on final adult height and weight are not known [
Genotype-phenotype correlations have been suggested, though sample size is small [
MPS type VII is an ultrarare disorder with a global prevalence estimated to be <200 individuals [
## Clinical Description
Individuals with mucopolysaccharidosis type VII (MPS VII) can present perinatally with early demise, nonimmune hydrops fetalis, cholestatic jaundice, and hepatosplenomegaly, or in early childhood with developmental delay and characteristic musculoskeletal and craniofacial features. To date, <200 individuals have been identified with biallelic pathogenic variants in
Mucopolysaccharidosis Type VII: Frequency of Select Features
GI = gastrointestinal
As adolescent weight tends to be above the 50th centile, the prevalence of overweight is higher especially for individuals who are not independently ambulatory. A study of intravenous enzyme replacement therapy initiated prior to age five years found improved growth velocity and z scores after 48 weeks of treatment, but long-term effects of therapy on final adult height and weight are not known [
## Genotype-Phenotype Correlations
Genotype-phenotype correlations have been suggested, though sample size is small [
## Prevalence
MPS type VII is an ultrarare disorder with a global prevalence estimated to be <200 individuals [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes and Disorders of Interest in the Differential Diagnosis of Mucopolysaccharidosis Type VII
AR = autosomal recessive; ML = mucolipidosis; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked
## Management
No clinical practice guidelines for mucopolysaccharidosis type VII (MPS VII) have been published. Due to the clinical disease variability, these recommendations are intended to be a general guide, and management should be tailored to the specific individual.
To establish the extent of disease and needs in an individual diagnosed with MPS VII, the evaluations summarized in
Mucopolysaccharidosis Type VII: Recommended Evaluations Following Initial Diagnosis
Assessment of growth incl upper to lower segment ratios
Skeletal survey incl cervical flexion-extension radiographs
Consultation w/orthopedist
Assessment for hyperreflexia & clonus
MRI of whole spine to assess for spinal stenosis
MRI or abdominal ultrasound to assess liver & spleen volume/dimensions
Assessment for hernias
EKG
Echocardiogram
Community or
Social work involvement for parental support
MOI = mode of inheritance; MPS VII = mucopolysaccharidosis type VII
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
As with enzyme replacement therapy for other MPS disorders, vestronidase alfa does not cross the blood-brain barrier and thus does not treat central nervous system disease.
Vestronidase alfa is administered at a dose of 4 mg/kg rounded to the next whole vial. Premedication with a non-sedating antihistamine with or without an antipyretic is recommended prior to the infusion. Given the need for long-term treatment, a portacath may be helpful for intravenous access.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Mucopolysaccharidosis Type VII: Treatment of Manifestations
Surgical fusion for atlantoaxial instability
Surgical treatment of scoliosis as needed
Spine monitoring during surgeries
Surgical decompression for spinal stenosis
Wrist splints & surgery as needed for carpal tunnel syndrome
Early intervention services
Speech therapy
School support (IEP)
Tonsillectomy & adenoidectomy
Positive pressure ventilation
Tympanostomy tubes
Hearing aids
Thickeners as needed
Gastrostomy tube placement
ADL = activities of daily living; IEP = individualized education plan; OT = occupational therapy; PT = physical therapy
Due to the broad clinical disease spectrum, surveillance should be tailored to the individual. To monitor existing manifestations, the individual's response to treatment, and the emergence of new manifestations, the evaluations summarized in
Mucopolysaccharidosis Type VII: Recommended Surveillance
Neurologic exam
Spine MRI
Sleep study
Pulmonary function tests
Echocardiogram
EKG
Every 2 yrs or until organomegaly is improved on treatment.
Ultrasound can be done if sedation for MRI is a concern but does not provide volumetric data.
ERT = enzyme replacement therapy; OFC = occipitofrontal circumference
Atlantoaxial instability can cause serious neurologic injury. Individuals who have not had cervical fusion should not participate in activities that may result in cervical spine injury such as gymnastics. Cervical spine precautions must be taken during intubation for anesthesia.
Testing of all at-risk sibs of any age is warranted to identify as early as possible those who would benefit from prompt initiation of enzyme replacement therapy and preventive measures.
See
Search
• Assessment of growth incl upper to lower segment ratios
• Skeletal survey incl cervical flexion-extension radiographs
• Consultation w/orthopedist
• Assessment for hyperreflexia & clonus
• MRI of whole spine to assess for spinal stenosis
• MRI or abdominal ultrasound to assess liver & spleen volume/dimensions
• Assessment for hernias
• EKG
• Echocardiogram
• Community or
• Social work involvement for parental support
• Surgical fusion for atlantoaxial instability
• Surgical treatment of scoliosis as needed
• Spine monitoring during surgeries
• Surgical decompression for spinal stenosis
• Wrist splints & surgery as needed for carpal tunnel syndrome
• Early intervention services
• Speech therapy
• School support (IEP)
• Tonsillectomy & adenoidectomy
• Positive pressure ventilation
• Tympanostomy tubes
• Hearing aids
• Thickeners as needed
• Gastrostomy tube placement
• Neurologic exam
• Spine MRI
• Sleep study
• Pulmonary function tests
• Echocardiogram
• EKG
• Every 2 yrs or until organomegaly is improved on treatment.
• Ultrasound can be done if sedation for MRI is a concern but does not provide volumetric data.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MPS VII, the evaluations summarized in
Mucopolysaccharidosis Type VII: Recommended Evaluations Following Initial Diagnosis
Assessment of growth incl upper to lower segment ratios
Skeletal survey incl cervical flexion-extension radiographs
Consultation w/orthopedist
Assessment for hyperreflexia & clonus
MRI of whole spine to assess for spinal stenosis
MRI or abdominal ultrasound to assess liver & spleen volume/dimensions
Assessment for hernias
EKG
Echocardiogram
Community or
Social work involvement for parental support
MOI = mode of inheritance; MPS VII = mucopolysaccharidosis type VII
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assessment of growth incl upper to lower segment ratios
• Skeletal survey incl cervical flexion-extension radiographs
• Consultation w/orthopedist
• Assessment for hyperreflexia & clonus
• MRI of whole spine to assess for spinal stenosis
• MRI or abdominal ultrasound to assess liver & spleen volume/dimensions
• Assessment for hernias
• EKG
• Echocardiogram
• Community or
• Social work involvement for parental support
## Treatment of Manifestations
As with enzyme replacement therapy for other MPS disorders, vestronidase alfa does not cross the blood-brain barrier and thus does not treat central nervous system disease.
Vestronidase alfa is administered at a dose of 4 mg/kg rounded to the next whole vial. Premedication with a non-sedating antihistamine with or without an antipyretic is recommended prior to the infusion. Given the need for long-term treatment, a portacath may be helpful for intravenous access.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Mucopolysaccharidosis Type VII: Treatment of Manifestations
Surgical fusion for atlantoaxial instability
Surgical treatment of scoliosis as needed
Spine monitoring during surgeries
Surgical decompression for spinal stenosis
Wrist splints & surgery as needed for carpal tunnel syndrome
Early intervention services
Speech therapy
School support (IEP)
Tonsillectomy & adenoidectomy
Positive pressure ventilation
Tympanostomy tubes
Hearing aids
Thickeners as needed
Gastrostomy tube placement
ADL = activities of daily living; IEP = individualized education plan; OT = occupational therapy; PT = physical therapy
• Surgical fusion for atlantoaxial instability
• Surgical treatment of scoliosis as needed
• Spine monitoring during surgeries
• Surgical decompression for spinal stenosis
• Wrist splints & surgery as needed for carpal tunnel syndrome
• Early intervention services
• Speech therapy
• School support (IEP)
• Tonsillectomy & adenoidectomy
• Positive pressure ventilation
• Tympanostomy tubes
• Hearing aids
• Thickeners as needed
• Gastrostomy tube placement
## Targeted Therapy
As with enzyme replacement therapy for other MPS disorders, vestronidase alfa does not cross the blood-brain barrier and thus does not treat central nervous system disease.
Vestronidase alfa is administered at a dose of 4 mg/kg rounded to the next whole vial. Premedication with a non-sedating antihistamine with or without an antipyretic is recommended prior to the infusion. Given the need for long-term treatment, a portacath may be helpful for intravenous access.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Mucopolysaccharidosis Type VII: Treatment of Manifestations
Surgical fusion for atlantoaxial instability
Surgical treatment of scoliosis as needed
Spine monitoring during surgeries
Surgical decompression for spinal stenosis
Wrist splints & surgery as needed for carpal tunnel syndrome
Early intervention services
Speech therapy
School support (IEP)
Tonsillectomy & adenoidectomy
Positive pressure ventilation
Tympanostomy tubes
Hearing aids
Thickeners as needed
Gastrostomy tube placement
ADL = activities of daily living; IEP = individualized education plan; OT = occupational therapy; PT = physical therapy
• Surgical fusion for atlantoaxial instability
• Surgical treatment of scoliosis as needed
• Spine monitoring during surgeries
• Surgical decompression for spinal stenosis
• Wrist splints & surgery as needed for carpal tunnel syndrome
• Early intervention services
• Speech therapy
• School support (IEP)
• Tonsillectomy & adenoidectomy
• Positive pressure ventilation
• Tympanostomy tubes
• Hearing aids
• Thickeners as needed
• Gastrostomy tube placement
## Surveillance
Due to the broad clinical disease spectrum, surveillance should be tailored to the individual. To monitor existing manifestations, the individual's response to treatment, and the emergence of new manifestations, the evaluations summarized in
Mucopolysaccharidosis Type VII: Recommended Surveillance
Neurologic exam
Spine MRI
Sleep study
Pulmonary function tests
Echocardiogram
EKG
Every 2 yrs or until organomegaly is improved on treatment.
Ultrasound can be done if sedation for MRI is a concern but does not provide volumetric data.
ERT = enzyme replacement therapy; OFC = occipitofrontal circumference
• Neurologic exam
• Spine MRI
• Sleep study
• Pulmonary function tests
• Echocardiogram
• EKG
• Every 2 yrs or until organomegaly is improved on treatment.
• Ultrasound can be done if sedation for MRI is a concern but does not provide volumetric data.
## Agents/Circumstances to Avoid
Atlantoaxial instability can cause serious neurologic injury. Individuals who have not had cervical fusion should not participate in activities that may result in cervical spine injury such as gymnastics. Cervical spine precautions must be taken during intubation for anesthesia.
## Evaluation of Relatives at Risk
Testing of all at-risk sibs of any age is warranted to identify as early as possible those who would benefit from prompt initiation of enzyme replacement therapy and preventive measures.
See
## Therapies Under Investigation
Search
## Genetic Counseling
Mucopolysaccharidosis type VII (MPS VII) is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Based on limited case reports, affected sibs appear to manifest similar disease courses [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carriers usually have low-normal or slightly deficient beta-glucuronidase enzyme activity; thus, molecular genetic testing is required to determine carrier status.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with MPS VII, particularly if both partners are of the same ancestral background. Founder variants have been identified in the Mexican, Japanese, and Brazilian populations (see
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Based on limited case reports, affected sibs appear to manifest similar disease courses [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with MPS VII, particularly if both partners are of the same ancestral background. Founder variants have been identified in the Mexican, Japanese, and Brazilian populations (see
## Mode of Inheritance
Mucopolysaccharidosis type VII (MPS VII) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Based on limited case reports, affected sibs appear to manifest similar disease courses [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Based on limited case reports, affected sibs appear to manifest similar disease courses [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carriers usually have low-normal or slightly deficient beta-glucuronidase enzyme activity; thus, molecular genetic testing is required to determine carrier status.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with MPS VII, particularly if both partners are of the same ancestral background. Founder variants have been identified in the Mexican, Japanese, and Brazilian populations (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with MPS VII, particularly if both partners are of the same ancestral background. Founder variants have been identified in the Mexican, Japanese, and Brazilian populations (see
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
United Kingdom
•
• Canada
•
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
Mucopolysaccharidosis Type VII: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Mucopolysaccharidosis Type VII (
Mucopolysaccharidosis type VII is caused by deficiency of the lysosomal enzyme beta-glucuronidase, which is involved in the degradation of chondroitin sulfate, dermatan sulfate, and heparan sulfate. The partially degraded glycosaminoglycans accumulate in the lysosomes of many tissues, leading to cell and organ dysfunction.
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Mucopolysaccharidosis type VII is caused by deficiency of the lysosomal enzyme beta-glucuronidase, which is involved in the degradation of chondroitin sulfate, dermatan sulfate, and heparan sulfate. The partially degraded glycosaminoglycans accumulate in the lysosomes of many tissues, leading to cell and organ dysfunction.
Variants listed in the table have been provided by the authors.
## Chapter Notes
The authors wish to thank the individuals with mucopolysaccharidosis type VII (MPS VII) and their families along with international research efforts that continue to improve our understanding of MPS VII.
4 January 2024 (sw) Review posted live
7 July 2023 (as) Original submission
• 4 January 2024 (sw) Review posted live
• 7 July 2023 (as) Original submission
## Acknowledgments
The authors wish to thank the individuals with mucopolysaccharidosis type VII (MPS VII) and their families along with international research efforts that continue to improve our understanding of MPS VII.
## Revision History
4 January 2024 (sw) Review posted live
7 July 2023 (as) Original submission
• 4 January 2024 (sw) Review posted live
• 7 July 2023 (as) Original submission
## Key Sections in this
## References
## Literature Cited
Serial images of a male with mucopolysaccharidosis type VII at ages (A) 2.5 months, (B) six months, (C) one year, (D) three years, (E) five years, (F) six years, (G) seven years, (H) eight years, (I) nine years, and (J) 11 years, showing characteristic craniofacial features (macrocephaly, progressively coarse facies, thick eyebrows, and widely spaced teeth).
Reprinted with permission from
|
[] |
4/1/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mpv17-mtdep
|
mpv17-mtdep
|
[
"Mitochondrial DNA Depletion Syndrome 6 (MTDPS6), Hepatocerebral Type",
"MPV17 Deficiency",
"MPV17 Hepatocerebral Mitochondrial DNA Depletion Syndrome",
"Mitochondrial DNA Depletion Syndrome 6 (MTDPS6), Hepatocerebral Type",
"MPV17 Deficiency",
"MPV17 Hepatocerebral Mitochondrial DNA Depletion Syndrome",
"MPV17-Related Encephalohepatopathy, Including Navajo Neurohepatopathy",
"MPV17-Related Neuromyopathy",
"Mitochondrial inner membrane protein Mpv17",
"MPV17",
"MPV17-Related Mitochondrial DNA Maintenance Defect"
] |
Ayman W El-Hattab, Julia Wang, Hongzheng Dai, Mohammed Almannai, Fernando Scaglia, William J Craigen, Lee-Jun C Wong
|
Summary Hepatic manifestations (liver dysfunction that typically progresses to liver failure, cholestasis, hepatomegaly, and steatosis); Neurologic involvement (developmental delay, hypotonia, microcephaly, and motor and sensory peripheral neuropathy); Gastrointestinal manifestations (gastrointestinal dysmotility, feeding difficulties, and failure to thrive); and Metabolic derangements (lactic acidosis and hypoglycemia). Less frequent manifestations include renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. Progressive liver disease often leads to death in infancy or early childhood. Hepatocellular carcinoma has been reported. The diagnosis of Liver function to assess progression of liver disease; Serum alpha fetoprotein (AFP) concentration and hepatic ultrasound examination for evidence of hepatocellular carcinoma; Development, neurologic status, and nutritional status.
|
For other genetic causes of these phenotypes see
See also
## Diagnosis
Hepatic
Liver dysfunction or failure
Cholestasis and steatosis
Hepatomegaly
Neurologic
Developmental delay
Hypotonia
Microcephaly
Motor and sensory peripheral neuropathy
Gastrointestinal
Gastrointestinal dysmotility
Feeding difficulties
Failure to thrive
White matter abnormalities
Brain stem signal abnormalities
Basal ganglia signal abnormalities
Serum testing
Elevated hepatic transaminases and hyperbilirubinemia
Lactic acidosis
Hypoglycemia
Liver histology
Steatosis
Cirrhosis
Mitochondrial DNA analysis in liver and muscle [
Mitochondrial DNA content:
Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
Multiple mtDNA deletions have been occasionally described in muscle and liver.
Electron transport chain (ETC) assays in liver and muscle tissue of affected individuals typically show decreased activity of multiple complexes with complex I having reduced activity in 80% of affected individuals [
Note: Neither mtDNA analysis nor ETC assays are required to make the diagnosis of
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
Exome array (when clinically available) may be considered if exome sequencing is not diagnostic, particularly when evidence supports autosomal dominant inheritance.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Affected individuals of Navajo descent are commonly homozygotes for the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Hepatic
• Liver dysfunction or failure
• Cholestasis and steatosis
• Hepatomegaly
• Liver dysfunction or failure
• Cholestasis and steatosis
• Hepatomegaly
• Neurologic
• Developmental delay
• Hypotonia
• Microcephaly
• Motor and sensory peripheral neuropathy
• Developmental delay
• Hypotonia
• Microcephaly
• Motor and sensory peripheral neuropathy
• Gastrointestinal
• Gastrointestinal dysmotility
• Feeding difficulties
• Failure to thrive
• Gastrointestinal dysmotility
• Feeding difficulties
• Failure to thrive
• Liver dysfunction or failure
• Cholestasis and steatosis
• Hepatomegaly
• Developmental delay
• Hypotonia
• Microcephaly
• Motor and sensory peripheral neuropathy
• Gastrointestinal dysmotility
• Feeding difficulties
• Failure to thrive
• White matter abnormalities
• Brain stem signal abnormalities
• Basal ganglia signal abnormalities
• Serum testing
• Elevated hepatic transaminases and hyperbilirubinemia
• Lactic acidosis
• Hypoglycemia
• Elevated hepatic transaminases and hyperbilirubinemia
• Lactic acidosis
• Hypoglycemia
• Liver histology
• Steatosis
• Cirrhosis
• Steatosis
• Cirrhosis
• Mitochondrial DNA analysis in liver and muscle [
• Mitochondrial DNA content:
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
• Multiple mtDNA deletions have been occasionally described in muscle and liver.
• Mitochondrial DNA content:
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
• Multiple mtDNA deletions have been occasionally described in muscle and liver.
• Electron transport chain (ETC) assays in liver and muscle tissue of affected individuals typically show decreased activity of multiple complexes with complex I having reduced activity in 80% of affected individuals [
• Note: Neither mtDNA analysis nor ETC assays are required to make the diagnosis of
• Elevated hepatic transaminases and hyperbilirubinemia
• Lactic acidosis
• Hypoglycemia
• Steatosis
• Cirrhosis
• Mitochondrial DNA content:
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
• Multiple mtDNA deletions have been occasionally described in muscle and liver.
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
• For an introduction to multigene panels click
• Exome array (when clinically available) may be considered if exome sequencing is not diagnostic, particularly when evidence supports autosomal dominant inheritance.
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Hepatic
Liver dysfunction or failure
Cholestasis and steatosis
Hepatomegaly
Neurologic
Developmental delay
Hypotonia
Microcephaly
Motor and sensory peripheral neuropathy
Gastrointestinal
Gastrointestinal dysmotility
Feeding difficulties
Failure to thrive
White matter abnormalities
Brain stem signal abnormalities
Basal ganglia signal abnormalities
Serum testing
Elevated hepatic transaminases and hyperbilirubinemia
Lactic acidosis
Hypoglycemia
Liver histology
Steatosis
Cirrhosis
Mitochondrial DNA analysis in liver and muscle [
Mitochondrial DNA content:
Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
Multiple mtDNA deletions have been occasionally described in muscle and liver.
Electron transport chain (ETC) assays in liver and muscle tissue of affected individuals typically show decreased activity of multiple complexes with complex I having reduced activity in 80% of affected individuals [
Note: Neither mtDNA analysis nor ETC assays are required to make the diagnosis of
• Hepatic
• Liver dysfunction or failure
• Cholestasis and steatosis
• Hepatomegaly
• Liver dysfunction or failure
• Cholestasis and steatosis
• Hepatomegaly
• Neurologic
• Developmental delay
• Hypotonia
• Microcephaly
• Motor and sensory peripheral neuropathy
• Developmental delay
• Hypotonia
• Microcephaly
• Motor and sensory peripheral neuropathy
• Gastrointestinal
• Gastrointestinal dysmotility
• Feeding difficulties
• Failure to thrive
• Gastrointestinal dysmotility
• Feeding difficulties
• Failure to thrive
• Liver dysfunction or failure
• Cholestasis and steatosis
• Hepatomegaly
• Developmental delay
• Hypotonia
• Microcephaly
• Motor and sensory peripheral neuropathy
• Gastrointestinal dysmotility
• Feeding difficulties
• Failure to thrive
• White matter abnormalities
• Brain stem signal abnormalities
• Basal ganglia signal abnormalities
• Serum testing
• Elevated hepatic transaminases and hyperbilirubinemia
• Lactic acidosis
• Hypoglycemia
• Elevated hepatic transaminases and hyperbilirubinemia
• Lactic acidosis
• Hypoglycemia
• Liver histology
• Steatosis
• Cirrhosis
• Steatosis
• Cirrhosis
• Mitochondrial DNA analysis in liver and muscle [
• Mitochondrial DNA content:
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
• Multiple mtDNA deletions have been occasionally described in muscle and liver.
• Mitochondrial DNA content:
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
• Multiple mtDNA deletions have been occasionally described in muscle and liver.
• Electron transport chain (ETC) assays in liver and muscle tissue of affected individuals typically show decreased activity of multiple complexes with complex I having reduced activity in 80% of affected individuals [
• Note: Neither mtDNA analysis nor ETC assays are required to make the diagnosis of
• Elevated hepatic transaminases and hyperbilirubinemia
• Lactic acidosis
• Hypoglycemia
• Steatosis
• Cirrhosis
• Mitochondrial DNA content:
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
• Multiple mtDNA deletions have been occasionally described in muscle and liver.
• Is typically reduced in liver tissue (<20% of that found in tissue- and age-matched controls);
• Can also be reduced in muscle tissue (typically <30% of that found in tissue- and age-matched controls).
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
Exome array (when clinically available) may be considered if exome sequencing is not diagnostic, particularly when evidence supports autosomal dominant inheritance.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Affected individuals of Navajo descent are commonly homozygotes for the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
• Exome array (when clinically available) may be considered if exome sequencing is not diagnostic, particularly when evidence supports autosomal dominant inheritance.
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
The vast majority of affected individuals (96/100) presented with an early-onset encephalohepatopathic (hepatocerebral) disease affecting mainly the nervous system and liver; mtDNA depletion is typically identified, particularly in liver. A later-onset neuromyopathic disease characterized by myopathy and neuropathy and associated with multiple mtDNA deletions in muscles has also rarely been described (4/100 affected individuals) [
Clinical manifestations include hepatic and neurologic findings summarized in
Clinical Manifestations of
Liver dysfunction typically presents as elevated transaminases, jaundice, hyperbilirubinemia, and coagulopathy.
Liver disease progresses to liver failure typically during infancy and early childhood.
Identified between ages seven and 11 years [
The neurologic manifestations can be overlooked or underestimated in children with early onset of severe hepatic involvement.
Some affected individuals present with psychomotor delays during early infancy, while others have normal development early in life followed by loss of motor and cognitive abilities later in infancy or early childhood.
Peripheral neuropathy typically manifests in early childhood with muscle weakness and wasting, decreased reflexes, and loss of sensation in the hands and feet.
Diffuse white matter abnormalities may resemble leukodystrophy or hypomyelination.
Some children have normal growth, especially early in the course of the disease.
May present as gastroesophageal reflux, recurrent vomiting, and/or diarrhea.
Lactic acidosis is a biochemical finding with mild to moderate elevation of lactate (3-9 mmol/L).
Hypoglycemia typically presents during the first six months of life and can be associated with lethargy, apnea, and/or seizures.
Outcome of Children with
Death most commonly occurred in the post-transplantation period due to sepsis, respiratory failure, or multiorgan failure.
The majority died during infancy (52/65; 80%); some died during early childhood (1-5 years) (10/65; 15%), adolescence (2/65; 3%), or early adulthood (1/65; 2%).
The oldest reported affected individual is 25 years old [
One individual presented during childhood, two during adolescence, and one during adulthood.
All four individuals had myopathy and peripheral neuropathy.
Liver manifestations were absent in two individuals, while the other two had milder liver involvement but without liver failure.
Development was normal in all affected individuals.
One individual had ptosis and ophthalmoplegia.
Mitochondrial DNA was assessed in muscle tissue in two individuals and showed normal mtDNA content with multiple mtDNA deletions [
No clear genotype-phenotype correlation exists. However, a trend for longer survival can be observed in individuals with biallelic pathogenic missense variants compared to individuals with biallelic null (nonsense, frameshift, deletions, and splice site) variants or individuals compound heterozygous for missense and null variants. In particular, individuals homozygous for
Navajo neurohepatopathy (NNH) was originally described as a distinct condition among Navajo children in the southwestern United States, but it is now clear that NNH is part of the
Encephalohepatopathic
The prevalence of
• One individual presented during childhood, two during adolescence, and one during adulthood.
• All four individuals had myopathy and peripheral neuropathy.
• Liver manifestations were absent in two individuals, while the other two had milder liver involvement but without liver failure.
• Development was normal in all affected individuals.
• One individual had ptosis and ophthalmoplegia.
• Mitochondrial DNA was assessed in muscle tissue in two individuals and showed normal mtDNA content with multiple mtDNA deletions [
## Clinical Description
The vast majority of affected individuals (96/100) presented with an early-onset encephalohepatopathic (hepatocerebral) disease affecting mainly the nervous system and liver; mtDNA depletion is typically identified, particularly in liver. A later-onset neuromyopathic disease characterized by myopathy and neuropathy and associated with multiple mtDNA deletions in muscles has also rarely been described (4/100 affected individuals) [
Clinical manifestations include hepatic and neurologic findings summarized in
Clinical Manifestations of
Liver dysfunction typically presents as elevated transaminases, jaundice, hyperbilirubinemia, and coagulopathy.
Liver disease progresses to liver failure typically during infancy and early childhood.
Identified between ages seven and 11 years [
The neurologic manifestations can be overlooked or underestimated in children with early onset of severe hepatic involvement.
Some affected individuals present with psychomotor delays during early infancy, while others have normal development early in life followed by loss of motor and cognitive abilities later in infancy or early childhood.
Peripheral neuropathy typically manifests in early childhood with muscle weakness and wasting, decreased reflexes, and loss of sensation in the hands and feet.
Diffuse white matter abnormalities may resemble leukodystrophy or hypomyelination.
Some children have normal growth, especially early in the course of the disease.
May present as gastroesophageal reflux, recurrent vomiting, and/or diarrhea.
Lactic acidosis is a biochemical finding with mild to moderate elevation of lactate (3-9 mmol/L).
Hypoglycemia typically presents during the first six months of life and can be associated with lethargy, apnea, and/or seizures.
Outcome of Children with
Death most commonly occurred in the post-transplantation period due to sepsis, respiratory failure, or multiorgan failure.
The majority died during infancy (52/65; 80%); some died during early childhood (1-5 years) (10/65; 15%), adolescence (2/65; 3%), or early adulthood (1/65; 2%).
The oldest reported affected individual is 25 years old [
One individual presented during childhood, two during adolescence, and one during adulthood.
All four individuals had myopathy and peripheral neuropathy.
Liver manifestations were absent in two individuals, while the other two had milder liver involvement but without liver failure.
Development was normal in all affected individuals.
One individual had ptosis and ophthalmoplegia.
Mitochondrial DNA was assessed in muscle tissue in two individuals and showed normal mtDNA content with multiple mtDNA deletions [
• One individual presented during childhood, two during adolescence, and one during adulthood.
• All four individuals had myopathy and peripheral neuropathy.
• Liver manifestations were absent in two individuals, while the other two had milder liver involvement but without liver failure.
• Development was normal in all affected individuals.
• One individual had ptosis and ophthalmoplegia.
• Mitochondrial DNA was assessed in muscle tissue in two individuals and showed normal mtDNA content with multiple mtDNA deletions [
## Genotype-Phenotype Correlations
No clear genotype-phenotype correlation exists. However, a trend for longer survival can be observed in individuals with biallelic pathogenic missense variants compared to individuals with biallelic null (nonsense, frameshift, deletions, and splice site) variants or individuals compound heterozygous for missense and null variants. In particular, individuals homozygous for
## Nomenclature
Navajo neurohepatopathy (NNH) was originally described as a distinct condition among Navajo children in the southwestern United States, but it is now clear that NNH is part of the
Encephalohepatopathic
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Mitochondrial DNA Maintenance Defects Presenting with Encephalohepatopathy
DD
Hypotonia
Liver dysfunction/failure
FTT
Lactic acidosis
DD
Hypotonia
Nystagmus
Liver dysfunction/failure
Lactic acidosis
DD
Psychomotor regression
Epilepsy
Liver dysfunction/failure
Hearing impairment
IUGR
Hypoglycemia
Liver dysfunction/failure
DD
Hypotonia
Liver dysfunction/failure
Lactic acidosis
AR = autosomal recessive; DD = developmental delay; FTT = failure to thrive; IUGR = intrauterine growth restriction; MOI = mode of inheritance
In addition, pathogenic variants in
Infantile liver failure is also a feature of the disorders caused by pathogenic variants in
Mitochondrial DNA Maintenance Defects Presenting with Myopathy
Hypotonia
HCM
Cataracts
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Exercise intolerance / easy fatigability
HCM
Hypotonia
HCM
Hypotonia
Loss of acquired motor skills
AD = autosomal dominant; AR = autosomal recessive; HCM = hypertrophic cardiomyopathy; MOI = mode of inheritance
• DD
• Hypotonia
• Liver dysfunction/failure
• FTT
• Lactic acidosis
• DD
• Hypotonia
• Nystagmus
• Liver dysfunction/failure
• Lactic acidosis
• DD
• Psychomotor regression
• Epilepsy
• Liver dysfunction/failure
• Hearing impairment
• IUGR
• Hypoglycemia
• Liver dysfunction/failure
• DD
• Hypotonia
• Liver dysfunction/failure
• Lactic acidosis
• Hypotonia
• HCM
• Cataracts
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Exercise intolerance / easy fatigability
• HCM
• Hypotonia
• HCM
• Hypotonia
• Loss of acquired motor skills
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
CNS = central nervous system
Management should involve a multidisciplinary team including specialists in hepatology, neurology, nutrition, clinical genetics, and child development.
Treatment of Manifestations in Individuals with
Note: Liver transplantation is controversial (see
Cornstarch may slow but not stop the progression of liver disease [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Nutritional deficiencies (e.g., of fat-soluble vitamins) can be prevented by ensuring adequate intake and frequent assessment by a dietitian experienced in managing children with liver disease.
No clinical guidelines for surveillance are available.
The following evaluations are suggested, with frequency varying according to the severity of the condition:
Recommended Surveillance for Individuals with
EEG = electroencephalogram; MRI = magnetic resonance imaging; NCV = nerve conduction velocity
Liver transaminases (ALT and AST), GGT, albumin, total and direct bilirubin, and coagulation profile (PT and PTT)
Prolonged fasting can lead to hypoglycemia and should be avoided.
See
Search
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
CNS = central nervous system
## Treatment of Manifestations
Management should involve a multidisciplinary team including specialists in hepatology, neurology, nutrition, clinical genetics, and child development.
Treatment of Manifestations in Individuals with
Note: Liver transplantation is controversial (see
Cornstarch may slow but not stop the progression of liver disease [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Prevention of Secondary Complications
Nutritional deficiencies (e.g., of fat-soluble vitamins) can be prevented by ensuring adequate intake and frequent assessment by a dietitian experienced in managing children with liver disease.
## Surveillance
No clinical guidelines for surveillance are available.
The following evaluations are suggested, with frequency varying according to the severity of the condition:
Recommended Surveillance for Individuals with
EEG = electroencephalogram; MRI = magnetic resonance imaging; NCV = nerve conduction velocity
Liver transaminases (ALT and AST), GGT, albumin, total and direct bilirubin, and coagulation profile (PT and PTT)
## Agents/Circumstances to Avoid
Prolonged fasting can lead to hypoglycemia and should be avoided.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
United Kingdom
United Kingdom
•
•
•
• Canada
•
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
MPV17-Related Hepatocerebral Mitochondrial DNA Maintenance Defect: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MPV17-Related Hepatocerebral Mitochondrial DNA Maintenance Defect (
Variants listed in the table have been provided by the authors.
Recently, it was reported that MPV17 loss caused mitochondrial deoxynucleotide insufficiency [
## Chapter Notes
17 May 2018 (ma) Comprehensive update posted live
17 May 2012 (me) Review posted live
27 February 2012 (aeh) Original submission
• 17 May 2018 (ma) Comprehensive update posted live
• 17 May 2012 (me) Review posted live
• 27 February 2012 (aeh) Original submission
## Revision History
17 May 2018 (ma) Comprehensive update posted live
17 May 2012 (me) Review posted live
27 February 2012 (aeh) Original submission
• 17 May 2018 (ma) Comprehensive update posted live
• 17 May 2012 (me) Review posted live
• 27 February 2012 (aeh) Original submission
## References
## Literature Cited
|
[
"F Al-Jasmi, HS Penefsky, A-K Souid. The phosphorescence oxygen analyzer as a screening tool for disorders with impaired lymphocyte bioenergetics.. Mol Genet Metab. 2011;104:529-36",
"A AlSaman, H Tomoum, F Invernizzi, M Zeviani. Hepatocerebral form of mitochondrial DNA depletion syndrome due to mutation in MPV17 gene.. Saudi J Gastroenterol. 2012;18:285-9",
"S Bijarnia-Mahay, N Mohan, D Goyal, IC Verma. Mitochondrial DNA depletion syndrome causing liver failure.. Indian Pediatr. 2014;51:666-8",
"CP Bitting, JA Hanson. Navajo neurohepatopathy: a case report and literature review emphasizing clinicopathologic diagnosis.. Acta Gastroenterol Belg. 2016;79:463-9",
"EL Blakely, A Butterworth, RDM Hadden, I Bodi, L He, R McFarland, RW Taylor. MPV17 mutation causes neuropathy and leukoencephalopathy with multiple mtDNA deletions in muscle.. Neuromuscul Disord. 2012;22:587-91",
"Y-R Choi, YB Hong, S-C Jung, JH Lee, YJ Kim, HJ Park, J Lee, H Koo, J-S Lee, DH Jwa, N Jung, S-Y Woo, S-B Kim, KW Chung, B-O Choi. A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy.. BMC Neurol. 2015;15:179",
"I Dalla Rosa, Y Cámara, R Durigon, CF Moss, S Vidoni, G Akman, L Hunt, MA Johnson, S Grocott, L Wang, DR Thorburn, M Hirano, J Poulton, RW Taylor, G Elgar, R Martí, P Voshol, IJ Holt, A Spinazzola. MPV17 loss causes deoxynucleotide insufficiency and slow DNA replication in mitochondria.. PLoS Genet. 2016;12",
"AW El-Hattab, F-Y Li, E Schmitt, S Zhang, WJ Craigen, L-JC Wong. MPV17-associated hepatocerebral mitochondrial DNA depletion syndrome: new patients and novel mutations.. Mol Genet Metab. 2010;99:300-8",
"AW El-Hattab, J Wang, H Dai, M Almannai, C Staufner, M Alfadhel, MJ Gambello, P Prasun, S Raza, HJ Lyons, M Afqi, MAM Saleh, EA Faqeih, HI Alzaidan, A Alshenqiti, LA Flore, J Hertecant, S Sacharow, DS Barbouth, K Murayama, AA Shah, HC Lin, LC Wong. MPV17-related mitochondrial DNA maintenance defect: new cases and review of clinical, biochemical, and molecular aspects.. Hum Mutat. 2018;39:461-70",
"C Garone, JC Rubio, SE Calvo, A Naini, K Tanji, S Dimauro, VK Mootha, M Hirano. MPV17 mutations causing adult-onset multisystemic disorder with multiple mitochondrial DNA deletions.. Arch Neurol. 2012;69:1648-51",
"S Kaji, K Murayama, I Nagata, H Nagasaka, M Takayanagi, A Ohtake, H Iwasa, M Nishiyama, Y Okazaki, H Harashima, T Eitoku, M Yamamoto, H Matsushita, K Kitamoto, S Sakata, T Katayama, S Sugimoto, Y Fujimoto, J Murakami, S Kanzaki, K Shiraki. Fluctuating liver functions in siblings with MPV17 mutations and possible improvement associated with dietary and pharmaceutical treatments targeting respiratory chain complex II.. Mol Genet Metab. 2009;97:292-6",
"CL Karadimas, TH Vu, SA Holve, P Chronopoulou, C Quinzii, SD Johnsen, J Kurth, E Eggers, L Palenzuela, K Tanji, E Bonilla, DC De Vivo, S DiMauro, M Hirano. Navajo neurohepatopathy is caused by a mutation in the MPV17 gene.. Am J Hum Genet. 2006;79:544-8",
"J Kim, E Kang, Y Kim, J-M Kim, BH Lee, K Murayama, G-H Kim, IH Choi, KM Kim, H-W Yoo. MPV17 mutations in patients with hepatocerebral mitochondrial DNA depletion syndrome.. Mol Genet Metab Rep. 2016;8:74-6",
"S Löllgen, H Weiher. The role of the Mpv17 protein mutations of which cause mitochondrial DNA depletion syndrome (MDDS): lessons from homologs in different species.. Biol Chem. 2015;396:13-25",
"P McKiernan, S Ball, S Santra, K Foster, C Fratter, J Poulton, K Craig, R McFarland, S Rahman, I Hargreaves, G Gupte, K Sharif, RW Taylor. Incidence of primary mitochondrial disease in children younger than 2 years presenting with acute liver failure.. J Pediatr Gastroenterol Nutr. 2016;63:592-7",
"BA Mendelsohn, N Mehta, B Hameed, M Pekmezci, S Packman, J Ralph. Adult-onset fatal neurohepatopathy in a woman caused by MPV17 mutation.. JIMD Rep. 2014;13:37-41",
"AN Merkle, DR Nascene, AM McKinney. MR imaging findings in the reticular formation in siblings with MPV17-related mitochondrial depletion syndrome.. AJNR Am J Neuroradiol. 2012;33:E34-5",
"A Navarro-Sastre, E Martín-Hernández, Y Campos, E Quintana, E Medina, RS de Las Heras, M Lluch, A Muñoz, P del Hoyo, R Martín, L Gort, P Briones, A Ribes. Lethal hepatopathy and leukodystrophy caused by a novel mutation in MPV17 gene: description of an alternative MPV17 spliced form.. Mol Genet Metab. 2008;94:234-9",
"C Nogueira, CFM de Souza, A Husny, TGJ Derks, FM Santorelli, L Vilarinho. MPV17: fatal hepatocerebral presentation in a Brazilian infant.. Mol Genet Metab. 2012;107:764",
"R Parini, F Furlan, L Notarangelo, A Spinazzola, G Uziel, P Strisciuglio, D Concolino, C Corbetta, G Nebbia, F Menni, G Rossi, M Maggioni, M. Zeviani. Glucose metabolism and diet-based prevention of liver dysfunction in MPV17 mutant patients.. J Hepatol. 2009;50:215-21",
"D Piekutowska-Abramczuk, M Pronicki, K Strawa, A Karkucińska-Więckowska, T Szymańska-Dębińska, A Fidziańska, MR Więckowski, D Jurkiewicz, E Ciara, I Jankowska, J Sykut-Cegielska, M Krajewska-Walasek, R Płoski, E Pronicka. Novel c.191C>G (p.Pro64Arg) MPV17 mutation identified in two pairs of unrelated Polish siblings with mitochondrial hepatoencephalopathy.. Clin Genet. 2014;85:573-7",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"AA Sarkhy, A Al-Sunaid, A Abdullah, M AlFadhel, W Eiyad. A novel MPV17 gene mutation in a Saudi infant causing fatal progressive liver failure.. Ann Saudi Med. 2014;34:175-8",
"A Spinazzola, R Santer, OH Akman, K Tsiakas, H Schaefer, X Ding, CL Karadimas, S Shanske, J Ganesh, S Di Mauro, M Zeviani. Hepatocerebral form of mitochondrial DNA depletion syndrome: novel MPV17 mutations.. Arch Neurol. 2008;65:1108-13",
"A Spinazzola, C Viscomi, E Fernandez-Vizarra, F Carrara, P D'Adamo, S Calvo, RM Marsano, C Donnini, H Weiher, P Strisciuglio, R Parini, E Sarzi, A Chan, S DiMauro, A Rötig, P Gasparini, I Ferrero, VK Mootha, V Tiranti, M Zeviani. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.. Nat Genet. 2006;38:570-5",
"J Uusimaa, J Evans, C Smith, A Butterworth, K Craig, N Ashley, C Liao, J Carver, A Diot, L Macleod, I Hargreaves, A Al-Hussaini, E Faqeih, A Asery, M Al Balwi, W Eyaid, A Al-Sunaid, D Kelly, I van Mourik, S Ball, J Jarvis, A Mulay, N Hadzic, M Samyn, A Baker, S Rahman, H Stewart, AA Morris, A Seller, C Fratter, RW Taylor, J Poulton. Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene.. Eur J Hum Genet. 2014;22:184-91",
"S Vilarinho, M Choi, D Jain, A Malhotra, S Kulkarni, D Pashankar, U Phatak, M Patel, A Bale, S Mane, RP Lifton, PK Mistry. Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology.. J Hepatol. 2014;61:1056-63",
"L-JC Wong, N Brunetti-Pierri, Q Zhang, N Yazigi, KE Bove, BB Dahms, MA Puchowicz, I Gonzalez-Gomez, ES Schmitt, CK Truong, CL Hoppel, P-C Chou, J Wang, EE Baldwin, D Adams, N Leslie, RG Boles, DS Kerr, WJ Craigen. Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy.. Hepatology. 2007;46:1218-27"
] |
17/5/2012
|
17/5/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mss
|
mss
|
[
"Nucleotide exchange factor SIL1",
"SIL1",
"Marinesco-Sjögren Syndrome"
] |
Marinesco-Sjögren Syndrome
|
Anna-Kaisa Anttonen
|
Summary Marinesco-Sjögren syndrome (MSS) is characterized by cerebellar ataxia with cerebellar atrophy, dysarthria, nystagmus, early-onset (not necessarily congenital) cataracts, myopathy, muscle weakness, and hypotonia. Additional features may include psychomotor delay, hypergonadotropic hypogonadism, short stature, and various skeletal abnormalities. Children with MSS usually present with muscular hypotonia in early infancy; distal and proximal muscular weakness is noticed during the first decade of life. Later, cerebellar findings of truncal ataxia, dysdiadochokinesia, nystagmus, and dysarthria become apparent. Motor function worsens progressively for some years, then stabilizes at an unpredictable age and degree of severity. Cataracts can develop rapidly and typically require lens extraction in the first decade of life. Although many adults have severe disabilities, life span in MSS appears to be near normal. The diagnosis of MSS is established in an individual with typical clinical findings and/or biallelic pathogenic variants in MSS is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an MSS-related pathogenic variant. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for Marinesco-Sjögren syndrome (MSS) have been published.
MSS
Cerebellar ataxia, dysarthria, and nystagmus
Early-onset (not necessarily congenital) cataracts
Muscle weakness and hypotonia
Psychomotor delay
Hypergonadotropic hypogonadism (i.e., primary gonadal failure)
Short stature
Skeletal abnormalities (scoliosis; shortening of metacarpals, metatarsals, and phalanges; coxa valga; pes planovalgus; and pectus carinatum)
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the clinical, imaging, and laboratory findings suggest the diagnosis of MSS, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry (see
For an introduction to multigene panels click
When the diagnosis of MSS is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Marinesco-Sjögren Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Approximately 40% of individuals with characteristic findings of Marinesco-Sjögren syndrome do not have identifiable pathogenic variants in
• Cerebellar ataxia, dysarthria, and nystagmus
• Early-onset (not necessarily congenital) cataracts
• Muscle weakness and hypotonia
• Psychomotor delay
• Hypergonadotropic hypogonadism (i.e., primary gonadal failure)
• Short stature
• Skeletal abnormalities (scoliosis; shortening of metacarpals, metatarsals, and phalanges; coxa valga; pes planovalgus; and pectus carinatum)
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry (see
• For an introduction to multigene panels click
## Suggestive Findings
MSS
Cerebellar ataxia, dysarthria, and nystagmus
Early-onset (not necessarily congenital) cataracts
Muscle weakness and hypotonia
Psychomotor delay
Hypergonadotropic hypogonadism (i.e., primary gonadal failure)
Short stature
Skeletal abnormalities (scoliosis; shortening of metacarpals, metatarsals, and phalanges; coxa valga; pes planovalgus; and pectus carinatum)
• Cerebellar ataxia, dysarthria, and nystagmus
• Early-onset (not necessarily congenital) cataracts
• Muscle weakness and hypotonia
• Psychomotor delay
• Hypergonadotropic hypogonadism (i.e., primary gonadal failure)
• Short stature
• Skeletal abnormalities (scoliosis; shortening of metacarpals, metatarsals, and phalanges; coxa valga; pes planovalgus; and pectus carinatum)
## Establishing the Diagnosis
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the clinical, imaging, and laboratory findings suggest the diagnosis of MSS, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry (see
For an introduction to multigene panels click
When the diagnosis of MSS is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Marinesco-Sjögren Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Approximately 40% of individuals with characteristic findings of Marinesco-Sjögren syndrome do not have identifiable pathogenic variants in
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry (see
• For an introduction to multigene panels click
## Option 1
When the clinical, imaging, and laboratory findings suggest the diagnosis of MSS, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry (see
For an introduction to multigene panels click
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry (see
• For an introduction to multigene panels click
## Option 2
When the diagnosis of MSS is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Marinesco-Sjögren Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Approximately 40% of individuals with characteristic findings of Marinesco-Sjögren syndrome do not have identifiable pathogenic variants in
## Clinical Characteristics
Marinesco-Sjögren syndrome (MSS) is characterized by cerebellar ataxia, dysarthria, nystagmus, early-onset cataracts, hypotonia, and muscle weakness. Additional features may include psychomotor delay, hypergonadotropic hypogonadism, short stature, and skeletal abnormalities. To date, at least 140 individuals have been identified with biallelic pathogenic variants in
Marinesco-Sjögren Syndrome: Frequency of Select Features
Based on
No genotype-phenotype correlations have been reported to date. It should be noted that the severity of intellectual disability and myopathy vary widely among Finnish individuals with MSS, all of whom are homozygous for the same
Previously used terms for Marinesco-Sjögren syndrome:
Garland-Moorhouse syndrome
Marinesco-Garland syndrome
Hereditary oligophrenic cerebello-lental degeneration
Prevalence is not known. The carrier frequency in Finland has been reported to be approximately 1:96, compared to an estimated worldwide carrier frequency of 1:700 [
• Garland-Moorhouse syndrome
• Marinesco-Garland syndrome
• Hereditary oligophrenic cerebello-lental degeneration
## Clinical Description
Marinesco-Sjögren syndrome (MSS) is characterized by cerebellar ataxia, dysarthria, nystagmus, early-onset cataracts, hypotonia, and muscle weakness. Additional features may include psychomotor delay, hypergonadotropic hypogonadism, short stature, and skeletal abnormalities. To date, at least 140 individuals have been identified with biallelic pathogenic variants in
Marinesco-Sjögren Syndrome: Frequency of Select Features
Based on
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been reported to date. It should be noted that the severity of intellectual disability and myopathy vary widely among Finnish individuals with MSS, all of whom are homozygous for the same
## Nomenclature
Previously used terms for Marinesco-Sjögren syndrome:
Garland-Moorhouse syndrome
Marinesco-Garland syndrome
Hereditary oligophrenic cerebello-lental degeneration
• Garland-Moorhouse syndrome
• Marinesco-Garland syndrome
• Hereditary oligophrenic cerebello-lental degeneration
## Prevalence
Prevalence is not known. The carrier frequency in Finland has been reported to be approximately 1:96, compared to an estimated worldwide carrier frequency of 1:700 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic disorders with features overlapping those of Marinesco-Sjögren syndrome (MSS) are listed in
Disorders to Consider in the Differential Diagnosis of Marinesco-Sjögren Syndrome
Myopathy
Cerebellar atrophy & ataxia
Encephalopathy, seizures, dementia, migraine, & stroke-like episodes often present
↑ plasma/CSF lactate concentration
Cardiomyopathy
Cataracts
DD
Short stature
Hypogonadism
Hypo- or demyelinating neuropathy & postinfectious rhabdomyolysis
Absence of cerebellar atrophy & myopathy
Ataxia by early childhood
Normal early psychomotor development; mild progressive cognitive decline accompanies other progressive CNS findings
Bilateral cataracts later in disease course
Lower-limb spasticity
Axonal peripheral neuropathy
Significantly ↑ concentrations of glucosylceramide in both erythrocytes & plasma
Myopathy, muscle weakness, & hypotonia
Cataracts
Strabismus
Short stature
Normal findings on brain MRI, absence of cerebellar atrophy
Absence of ataxia
Cataracts
Ataxia
Dementia (or psychosis)
Cataracts & ataxia later in onset than in MSS
Absence of manifestations in childhood & cerebellar atrophy
Congenital ataxia (predominantly truncal) resulting in delayed ambulation
Cerebellar atrophy
Moderate-to-profound ID
Dysarthria
Strabismus
Non-progressive clinical course
Absence of progressive myopathy & ↑ serum CK concentration
AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; CNS = central nervous system; CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; Mat = maternal; MOI = mode of inheritance; MSS = Marinesco-Sjögren syndrome
To date,
• Myopathy
• Cerebellar atrophy & ataxia
• Encephalopathy, seizures, dementia, migraine, & stroke-like episodes often present
• ↑ plasma/CSF lactate concentration
• Cardiomyopathy
• Cataracts
• DD
• Short stature
• Hypogonadism
• Hypo- or demyelinating neuropathy & postinfectious rhabdomyolysis
• Absence of cerebellar atrophy & myopathy
• Ataxia by early childhood
• Normal early psychomotor development; mild progressive cognitive decline accompanies other progressive CNS findings
• Bilateral cataracts later in disease course
• Lower-limb spasticity
• Axonal peripheral neuropathy
• Significantly ↑ concentrations of glucosylceramide in both erythrocytes & plasma
• Myopathy, muscle weakness, & hypotonia
• Cataracts
• Strabismus
• Short stature
• Normal findings on brain MRI, absence of cerebellar atrophy
• Absence of ataxia
• Cataracts
• Ataxia
• Dementia (or psychosis)
• Cataracts & ataxia later in onset than in MSS
• Absence of manifestations in childhood & cerebellar atrophy
• Congenital ataxia (predominantly truncal) resulting in delayed ambulation
• Cerebellar atrophy
• Moderate-to-profound ID
• Dysarthria
• Strabismus
• Non-progressive clinical course
• Absence of progressive myopathy & ↑ serum CK concentration
## Management
No clinical practice guidelines for Marinesco-Sjögren syndrome (MSS) have been published. In the absence of published guidelines, the following recommendations are based on the author's personal experience managing individuals with this disorder.
To establish the extent of disease and needs in an individual diagnosed with MSS, the evaluations summarized in
Marinesco-Sjögren Syndrome: Recommended Evaluations Following Initial Diagnosis
Developmental assessment
Assessment of intellectual abilities in older children, particularly before school age
To incl adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assessment of height, weight, & head circumference
Assessment for feeding issues
Community or
Social work involvement for parental support
Home nursing referral
MOI = mode of inheritance; MSS = Marinesco-Sjögren syndrome; PT = physical therapy; OT = occupational therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Marinesco-Sjögren Syndrome: Treatment of Manifestations
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Marinesco-Sjögren Syndrome: Recommended Surveillance
After counseling it is possible to clarify the genetic status of apparently asymptomatic at-risk sibs of an affected individual in order to initiate surveillance. Evaluations can include:
Molecular genetic testing if the pathogenic variants in the family are known;
Brain MRI or muscle biopsy to help identify features of MSS if the pathogenic variants in the family are not known.
See
Search
• Developmental assessment
• Assessment of intellectual abilities in older children, particularly before school age
• To incl adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assessment of height, weight, & head circumference
• Assessment for feeding issues
• Community or
• Social work involvement for parental support
• Home nursing referral
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Molecular genetic testing if the pathogenic variants in the family are known;
• Brain MRI or muscle biopsy to help identify features of MSS if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with MSS, the evaluations summarized in
Marinesco-Sjögren Syndrome: Recommended Evaluations Following Initial Diagnosis
Developmental assessment
Assessment of intellectual abilities in older children, particularly before school age
To incl adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assessment of height, weight, & head circumference
Assessment for feeding issues
Community or
Social work involvement for parental support
Home nursing referral
MOI = mode of inheritance; MSS = Marinesco-Sjögren syndrome; PT = physical therapy; OT = occupational therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Developmental assessment
• Assessment of intellectual abilities in older children, particularly before school age
• To incl adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assessment of height, weight, & head circumference
• Assessment for feeding issues
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Marinesco-Sjögren Syndrome: Treatment of Manifestations
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Marinesco-Sjögren Syndrome: Recommended Surveillance
## Evaluation of Relatives at Risk
After counseling it is possible to clarify the genetic status of apparently asymptomatic at-risk sibs of an affected individual in order to initiate surveillance. Evaluations can include:
Molecular genetic testing if the pathogenic variants in the family are known;
Brain MRI or muscle biopsy to help identify features of MSS if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Brain MRI or muscle biopsy to help identify features of MSS if the pathogenic variants in the family are not known.
## Therapies Under Investigation
Search
## Genetic Counseling
Marinesco-Sjögren syndrome (MSS) is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for an MSS-related pathogenic variant.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Intrafamilial variability is observed in MSS; manifestations of the disorder may vary among affected sibs.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with MSS, particularly if both partners are of the same ancestry. A
If biallelic
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an MSS-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Intrafamilial variability is observed in MSS; manifestations of the disorder may vary among affected sibs.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with MSS, particularly if both partners are of the same ancestry. A
## Mode of Inheritance
Marinesco-Sjögren syndrome (MSS) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an MSS-related pathogenic variant.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Intrafamilial variability is observed in MSS; manifestations of the disorder may vary among affected sibs.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for an MSS-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Intrafamilial variability is observed in MSS; manifestations of the disorder may vary among affected sibs.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with MSS, particularly if both partners are of the same ancestry. A
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with MSS, particularly if both partners are of the same ancestry. A
## Prenatal Testing and Preimplantation Genetic Testing
If biallelic
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Marinesco-Sjogren Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Marinesco-Sjogren Syndrome (
Most of the MSS-associated
In transiently transfected COS-1 cells, an MSS-associated missense
Variants listed in the table have been provided by the author.
## Molecular Pathogenesis
Most of the MSS-associated
In transiently transfected COS-1 cells, an MSS-associated missense
Variants listed in the table have been provided by the author.
## Chapter Notes
Dr Anttonen is actively involved in clinical research regarding individuals with Marinesco-Sjögren syndrome (MSS) and would be happy to communicate with persons who have any questions regarding the diagnosis of MSS or other considerations.
Anna-Kaisa Anttonen, MD, PhD (2006-present)Anna-Elina Lehesjoki, MD, PhD; University of Helsinki (2006-2019)
3 October 2024 (sw) Comprehensive update posted live
10 January 2019 (ha) Comprehensive update posted live
7 September 2010 (me) Comprehensive update posted live
29 November 2006 (me) Review posted live
6 July 2006 (ael) Original submission
• 3 October 2024 (sw) Comprehensive update posted live
• 10 January 2019 (ha) Comprehensive update posted live
• 7 September 2010 (me) Comprehensive update posted live
• 29 November 2006 (me) Review posted live
• 6 July 2006 (ael) Original submission
## Author Notes
Dr Anttonen is actively involved in clinical research regarding individuals with Marinesco-Sjögren syndrome (MSS) and would be happy to communicate with persons who have any questions regarding the diagnosis of MSS or other considerations.
## Author History
Anna-Kaisa Anttonen, MD, PhD (2006-present)Anna-Elina Lehesjoki, MD, PhD; University of Helsinki (2006-2019)
## Revision History
3 October 2024 (sw) Comprehensive update posted live
10 January 2019 (ha) Comprehensive update posted live
7 September 2010 (me) Comprehensive update posted live
29 November 2006 (me) Review posted live
6 July 2006 (ael) Original submission
• 3 October 2024 (sw) Comprehensive update posted live
• 10 January 2019 (ha) Comprehensive update posted live
• 7 September 2010 (me) Comprehensive update posted live
• 29 November 2006 (me) Review posted live
• 6 July 2006 (ael) Original submission
## References
## Literature Cited
|
[] |
29/11/2006
|
3/10/2024
|
7/10/2008
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mstn
|
mstn
|
[
"Growth/differentiation factor 8",
"MSTN",
"Myostatin-Related Muscle Hypertrophy"
] |
Myostatin-Related Muscle Hypertrophy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Kathryn R Wagner, Julie S Cohen
|
Summary Myostatin-related muscle hypertrophy is characterized by reduced subcutaneous fat pad thickness and increased muscle size in individuals with normal or increased muscle strength. Both heterozygotes and homozygotes for a causative variant in Skeletal muscle size in an individual with myostatin-related muscle hypertrophy is measured by ultrasound examination, DEXA, or MRI. Subcutaneous fat pad thickness is measured by ultrasound or with a caliper. Myostatin-related muscle hypertrophy is not known to cause medical complications. The phenotypes associated with myostatin-related muscle hypertrophy are inherited in an incomplete autosomal dominant manner. At conception, the sibs of a child with homozygous myostatin-related muscle hypertrophy have a 25% chance of having homozygous myostatin-related muscle hypertrophy, a 50% chance of having one
|
## Diagnosis
The diagnosis of myostatin-related muscle hypertrophy is established by clinical findings of reduced subcutaneous fat pad thickness and increased muscle size in individuals with normal or increased muscle strength and an
Skeletal muscle size can be measured by ultrasound, DEXA, or MRI. It is expected to be several deviations above normal for age- and sex-matched controls.
Subcutaneous fat pad thickness can be measured by ultrasound or with a caliper at various standard locations for which normal values exist.
Creatine kinase (CK) serum concentration is expected to be normal.
Molecular Genetic Testing Used in Myostatin-Related Muscle Hypertrophy
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.. For issues to consider in interpretation of sequence analysis results, click
The only
## Clinical Diagnosis
The diagnosis of myostatin-related muscle hypertrophy is established by clinical findings of reduced subcutaneous fat pad thickness and increased muscle size in individuals with normal or increased muscle strength and an
## Testing
Skeletal muscle size can be measured by ultrasound, DEXA, or MRI. It is expected to be several deviations above normal for age- and sex-matched controls.
Subcutaneous fat pad thickness can be measured by ultrasound or with a caliper at various standard locations for which normal values exist.
Creatine kinase (CK) serum concentration is expected to be normal.
Molecular Genetic Testing Used in Myostatin-Related Muscle Hypertrophy
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.. For issues to consider in interpretation of sequence analysis results, click
The only
## Molecular Genetic Testing
Molecular Genetic Testing Used in Myostatin-Related Muscle Hypertrophy
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.. For issues to consider in interpretation of sequence analysis results, click
The only
## Testing Strategy
## Clinical Characteristics
Clinical manifestations of myostatin-related muscle hypertrophy appear to be dependent on the amount of myostatin protein present. Therefore both heterozygotes and homozygotes can exhibit muscle hypertrophy.
He initially displayed stimulus-induced myoclonus that subsided after two months. The relationship between myoclonus and the
Ultrasonography revealed normal muscle echogenicity and cross-sectional diameter of quadriceps muscle 7.2 SD above the mean.
No information is currently available as only one myostatin-related muscle hypertrophy-causing variant in
In a multigenerational family segregating a 3.4-Mb deletion of chromosome 2q32.1q32.3 including
Penetrance is unknown.
Anticipation is not known to occur.
Prevalence is unknown.
## Clinical Description
Clinical manifestations of myostatin-related muscle hypertrophy appear to be dependent on the amount of myostatin protein present. Therefore both heterozygotes and homozygotes can exhibit muscle hypertrophy.
He initially displayed stimulus-induced myoclonus that subsided after two months. The relationship between myoclonus and the
Ultrasonography revealed normal muscle echogenicity and cross-sectional diameter of quadriceps muscle 7.2 SD above the mean.
## Genotype-Phenotype Correlations
No information is currently available as only one myostatin-related muscle hypertrophy-causing variant in
In a multigenerational family segregating a 3.4-Mb deletion of chromosome 2q32.1q32.3 including
## Penetrance
Penetrance is unknown.
## Anticipation
Anticipation is not known to occur.
## Prevalence
Prevalence is unknown.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The
Duchenne and Becker muscular dystrophy (see
Limb-girdle muscular dystrophy 1C (caveolinopathy)
Limb-girdle muscular dystrophies 2C, 2D, 2E (sarcoglycanopthies)
Channelopathies such as
The
• Duchenne and Becker muscular dystrophy (see
• Limb-girdle muscular dystrophy 1C (caveolinopathy)
• Limb-girdle muscular dystrophies 2C, 2D, 2E (sarcoglycanopthies)
• Channelopathies such as
## Management
Myostatin-related muscle hypertrophy is not currently known to cause any medical complications.
See
Search
## Treatment of Manifestations
Myostatin-related muscle hypertrophy is not currently known to cause any medical complications.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The phenotypes associated with myostatin-related muscle hypertrophy are inherited in an incomplete autosomal dominant manner.
The parents of a child with homozygous myostatin-related muscle hypertrophy are obligate heterozygotes and therefore have one
Heterozygotes may have increased muscle mass.
At conception, each sib of a child with homozygous myostatin-related muscle hypertrophy has a 25% chance of having homozygous myostatin-related muscle hypertrophy, a 50% chance of having one
Heterozygotes may have increased muscle mass.
Individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with an
Recommendations for the evaluation of parents of a proband with an apparent
Note: Although individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with increased muscle mass, the family history may appear to be negative because of incomplete penetrance or failure to recognize the condition in family members.
The chance that the sibs of the proband will inherit the
If a parent of the proband has increased muscle mass, the chance that the sibs will inherit the
• The parents of a child with homozygous myostatin-related muscle hypertrophy are obligate heterozygotes and therefore have one
• Heterozygotes may have increased muscle mass.
• At conception, each sib of a child with homozygous myostatin-related muscle hypertrophy has a 25% chance of having homozygous myostatin-related muscle hypertrophy, a 50% chance of having one
• Heterozygotes may have increased muscle mass.
• Individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with an
• Recommendations for the evaluation of parents of a proband with an apparent
• The chance that the sibs of the proband will inherit the
• If a parent of the proband has increased muscle mass, the chance that the sibs will inherit the
## Mode of Inheritance
The phenotypes associated with myostatin-related muscle hypertrophy are inherited in an incomplete autosomal dominant manner.
## Risk to Family Members
The parents of a child with homozygous myostatin-related muscle hypertrophy are obligate heterozygotes and therefore have one
Heterozygotes may have increased muscle mass.
At conception, each sib of a child with homozygous myostatin-related muscle hypertrophy has a 25% chance of having homozygous myostatin-related muscle hypertrophy, a 50% chance of having one
Heterozygotes may have increased muscle mass.
Individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with an
Recommendations for the evaluation of parents of a proband with an apparent
Note: Although individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with increased muscle mass, the family history may appear to be negative because of incomplete penetrance or failure to recognize the condition in family members.
The chance that the sibs of the proband will inherit the
If a parent of the proband has increased muscle mass, the chance that the sibs will inherit the
• The parents of a child with homozygous myostatin-related muscle hypertrophy are obligate heterozygotes and therefore have one
• Heterozygotes may have increased muscle mass.
• At conception, each sib of a child with homozygous myostatin-related muscle hypertrophy has a 25% chance of having homozygous myostatin-related muscle hypertrophy, a 50% chance of having one
• Heterozygotes may have increased muscle mass.
• Individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with an
• Recommendations for the evaluation of parents of a proband with an apparent
• The chance that the sibs of the proband will inherit the
• If a parent of the proband has increased muscle mass, the chance that the sibs will inherit the
## Related Genetic Counseling Issues
## Resources
No specific resources for Myostatin-Related Muscle Hypertrophy have been identified by
## Molecular Genetics
Myostatin-Related Muscle Hypertrophy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Myostatin-Related Muscle Hypertrophy (
Selected
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Mice heterozygous for an
"Double-muscled" cattle previously linked to the muscular hypertrophy (mh) locus on chromosome 2 have also been found to have pathogenic variants in the gene for myostatin [
• Mice heterozygous for an
• "Double-muscled" cattle previously linked to the muscular hypertrophy (mh) locus on chromosome 2 have also been found to have pathogenic variants in the gene for myostatin [
## References
## Literature Cited
## Chapter Notes
Julie S Cohen, ScM, CGC (2013-present)Nicole Johnson, ScM, CGC; Johns Hopkins School of Medicine (2005-2009)Kathryn R Wagner, MD, PhD (2005-present)
18 April 2019 (ma) Chapter retired: extremely rare
3 July 2013 (me) Comprehensive update posted live
30 April 2009 (me) Comprehensive update posted live
4 October 2005 (me) Review posted live
14 February 2005 (kw) Original submission
• 18 April 2019 (ma) Chapter retired: extremely rare
• 3 July 2013 (me) Comprehensive update posted live
• 30 April 2009 (me) Comprehensive update posted live
• 4 October 2005 (me) Review posted live
• 14 February 2005 (kw) Original submission
## Author History
Julie S Cohen, ScM, CGC (2013-present)Nicole Johnson, ScM, CGC; Johns Hopkins School of Medicine (2005-2009)Kathryn R Wagner, MD, PhD (2005-present)
## Revision History
18 April 2019 (ma) Chapter retired: extremely rare
3 July 2013 (me) Comprehensive update posted live
30 April 2009 (me) Comprehensive update posted live
4 October 2005 (me) Review posted live
14 February 2005 (kw) Original submission
• 18 April 2019 (ma) Chapter retired: extremely rare
• 3 July 2013 (me) Comprehensive update posted live
• 30 April 2009 (me) Comprehensive update posted live
• 4 October 2005 (me) Review posted live
• 14 February 2005 (kw) Original submission
|
[
"RE Ferrell, V Conte, EC Lawrence, SM Roth, JM Hagberg, BF Hurley. Frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes.. Genomics 1999;62:203-7",
"L Grobet, LJ Martin, D Poncelet, D Pirottin, B Brouwers, J Riquet, A Schoeberlein, S Dunner, F Ménissier, J Massabanda, R Fries, R Hanset, M Georges. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle.. Nat Genet 1997;17:71-4",
"R Kambadur, M Sharma, TP Smith, JJ Bass. Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle.. Genome Res 1997;7:910-6",
"AC McPherron, AM Lawler, SJ Lee. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.. Nature 1997;387:83-90",
"J Meienberg, M Rohrbach, S Neuenschwander, K Spanaus, C Giunta, S Alonso, E Arnold, C Henggeler, S Regenass, A Patrignani, S Azzarello-Burri, B Steiner, AO Nygren, T Carrel, B Steinmann, G Mátyás. Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency.. Eur J Hum Genet. 2010;18:1315-21",
"HH Schmidt, J Genschel, P Baier, M Schmidt, J Ockenga, UJ Tietge, M Pröpsting, C Büttner, MP Manns, H Lochs, G Brabant. Dyslipemia in familial partial lipodystrophy caused by an R482W mutation in the LMNA gene.. J Clin Endocrinol Metab 2001;86:2289-95",
"M Schuelke, KR Wagner, LE Stolz, C Hübner, T Riebel, W Kömen, T Braun, JF Tobin, SJ Lee. Myostatin mutation associated with gross muscle hypertrophy in a child.. N Engl J Med 2004;350:2682-8"
] |
5/10/2005
|
3/7/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
msud
|
msud
|
[
"BCKD Deficiency",
"Branched-Chain Ketoacid Dehydrogenase Deficiency",
"Maple Syrup Disease",
"MSUD",
"BCKD Deficiency",
"Branched-Chain Ketoacid Dehydrogenase Deficiency",
"MSUD",
"Maple Syrup Disease",
"2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial",
"2-oxoisovalerate dehydrogenase subunit beta, mitochondrial",
"Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial",
"BCKDHA",
"BCKDHB",
"DBT",
"Maple Syrup Urine Disease"
] |
Maple Syrup Urine Disease
|
Kevin A Strauss, Erik G Puffenberger, Vincent J Carson
|
Summary Maple syrup urine disease (MSUD) is categorized as classic (severe), intermediate, or intermittent. Neonates with classic MSUD are born asymptomatic but without treatment follow a predictable course: Individuals with intermediate MSUD have partial branched-chain alpha-ketoacid dehydrogenase deficiency that manifests only intermittently or responds to dietary thiamine therapy; these individuals can experience severe metabolic intoxication and encephalopathy in the face of sufficient catabolic stress. In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed neonatal manifestations of MSUD remain asymptomatic with continued treatment adherence. Suggestive biochemical findings on NBS include whole-blood concentration ratios of (leucine + isoleucine) to alanine and phenylalanine that are above the cutoff values for the particular screening lab. Follow-up plasma amino acid analysis typically demonstrates elevated concentrations of BCAAs and alloisoleucine. The diagnosis of MSUD is confirmed by identification of biallelic pathogenic variants in MSUD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.
|
## Diagnosis
Maple syrup urine disease (MSUD) is caused by decreased activity of the branched-chain alpha-ketoacid dehydrogenase complex (BCKD), the second enzymatic step in the degradative pathway of the branched-chain amino acids (BCAAs), which includes leucine, isoleucine, and valine.
NBS for MSUD is primarily based on quantification of the ratios of (leucine + isoleucine) to alanine and phenylalanine concentrations on dry blood spots.
A positive screening value (i.e., those above the cutoff reported by the screening laboratory) require follow-up biochemical testing with quantitative plasma amino acid and alloisoleucine analyses. If either is abnormal, treatment (see
Note: Individual states set standards for positive or suspected positive screens.
Because leucine-isoleucine and hydroxyproline cannot be differentiated by mass spectrometry, neonates with isolated hydroxyprolinemia will screen positive for MSUD, but confirmatory amino acid analysis will show only increased hydroxyproline (a false positive newborn screening result).
Neonates and infants suspected of having MSUD should never be challenged with higher than normal protein intake during the diagnostic process (see
Supportive clinical and laboratory findings can include the following.
Untreated infant:
Maple syrup odor in cerumen, the first clinical sign of MSUD, is detectable 12 hours after birth.
Signs of deepening encephalopathy including lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" are evident by age four to five days.
Coma and central respiratory failure may occur by age seven to ten days, sometimes before newborn screening results are available.
Untreated older individuals with milder variants of MSUD:
Anorexia
Poor growth
Irritability
Developmental delays later in infancy or childhood
Acute hyperleucinemia, ketonuria, and encephalopathy if stressed by fasting, dehydration, or infectious illness
Elevated plasma concentrations of BCAAs and alloisoleucine
Urinary excretion of BCKDs and branched-chain alpha-ketoacids (BCKAs) in infants older than 48-72 hours on an unrestricted diet
Ketonuria detected by standard urine test strips
Ketonuria in a newborn should always prompt investigation for metabolic disorders.
Absence of hypoglycemia and hyperammonemia
The diagnosis of MSUD in a proband with suggestive metabolic/biochemical findings
Note: (1) In vitro measurements of BCKD activity do not correlate with measurements of in vivo leucine oxidation [
Sequence analysis detects missense, nonsense, and splice site variants and small intragenic deletions/insertions. Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.
For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic click
Molecular Genetic Testing Used in Maple Syrup Urine Disease
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
Inactivating variants of
Defects of
• NBS for MSUD is primarily based on quantification of the ratios of (leucine + isoleucine) to alanine and phenylalanine concentrations on dry blood spots.
• A positive screening value (i.e., those above the cutoff reported by the screening laboratory) require follow-up biochemical testing with quantitative plasma amino acid and alloisoleucine analyses. If either is abnormal, treatment (see
• Note: Individual states set standards for positive or suspected positive screens.
• Because leucine-isoleucine and hydroxyproline cannot be differentiated by mass spectrometry, neonates with isolated hydroxyprolinemia will screen positive for MSUD, but confirmatory amino acid analysis will show only increased hydroxyproline (a false positive newborn screening result).
• Neonates and infants suspected of having MSUD should never be challenged with higher than normal protein intake during the diagnostic process (see
• Untreated infant:
• Maple syrup odor in cerumen, the first clinical sign of MSUD, is detectable 12 hours after birth.
• Signs of deepening encephalopathy including lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" are evident by age four to five days.
• Coma and central respiratory failure may occur by age seven to ten days, sometimes before newborn screening results are available.
• Maple syrup odor in cerumen, the first clinical sign of MSUD, is detectable 12 hours after birth.
• Signs of deepening encephalopathy including lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" are evident by age four to five days.
• Coma and central respiratory failure may occur by age seven to ten days, sometimes before newborn screening results are available.
• Untreated older individuals with milder variants of MSUD:
• Anorexia
• Poor growth
• Irritability
• Developmental delays later in infancy or childhood
• Acute hyperleucinemia, ketonuria, and encephalopathy if stressed by fasting, dehydration, or infectious illness
• Anorexia
• Poor growth
• Irritability
• Developmental delays later in infancy or childhood
• Acute hyperleucinemia, ketonuria, and encephalopathy if stressed by fasting, dehydration, or infectious illness
• Maple syrup odor in cerumen, the first clinical sign of MSUD, is detectable 12 hours after birth.
• Signs of deepening encephalopathy including lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" are evident by age four to five days.
• Coma and central respiratory failure may occur by age seven to ten days, sometimes before newborn screening results are available.
• Anorexia
• Poor growth
• Irritability
• Developmental delays later in infancy or childhood
• Acute hyperleucinemia, ketonuria, and encephalopathy if stressed by fasting, dehydration, or infectious illness
• Elevated plasma concentrations of BCAAs and alloisoleucine
• Urinary excretion of BCKDs and branched-chain alpha-ketoacids (BCKAs) in infants older than 48-72 hours on an unrestricted diet
• Ketonuria detected by standard urine test strips
• Ketonuria in a newborn should always prompt investigation for metabolic disorders.
• Absence of hypoglycemia and hyperammonemia
• Sequence analysis detects missense, nonsense, and splice site variants and small intragenic deletions/insertions. Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.
• For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
## Establishing the Diagnosis
The diagnosis of MSUD in a proband with suggestive metabolic/biochemical findings
Note: (1) In vitro measurements of BCKD activity do not correlate with measurements of in vivo leucine oxidation [
Sequence analysis detects missense, nonsense, and splice site variants and small intragenic deletions/insertions. Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.
For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic click
Molecular Genetic Testing Used in Maple Syrup Urine Disease
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
Inactivating variants of
Defects of
• Sequence analysis detects missense, nonsense, and splice site variants and small intragenic deletions/insertions. Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.
• For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
## Molecular Genetic Testing Approaches
Sequence analysis detects missense, nonsense, and splice site variants and small intragenic deletions/insertions. Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.
For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic click
Molecular Genetic Testing Used in Maple Syrup Urine Disease
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
Inactivating variants of
Defects of
• Sequence analysis detects missense, nonsense, and splice site variants and small intragenic deletions/insertions. Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.
• For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
## Clinical Characteristics
Traditionally, the metabolic phenotype of maple syrup urine disease (MSUD) is termed classic or intermediate on the basis of residual branched-chain alpha-ketoacid dehydrogenase (BCKD) enzyme activity. Rarely, affected individuals have partial BCKD enzyme deficiency that manifests only intermittently or responds to dietary thiamine therapy (see
Clinical Phenotypes of Maple Syrup Urine Disease
Maple syrup odor of cerumen
Poor feeding
Irritability, lethargy
Opisthotonus
Focal dystonia
"Fencing," "bicycling"
Obtundation, coma
Central respiratory failure
↑ BCAAs in plasma
↑ plasma alloisoleucine
↑ BCKAs in urine
Ketonuria
Maple syrup odor of cerumen
Poor growth
Poor feeding
Irritability
Developmental delays
Encephalopathy during illness
Normal early growth & development
Episodic decompensations that can be severe
Normal BCAAs when well
Similar to classic biochemical profile during illness
BCAAs = branched-chain amino acids; BCKAs = branched-chain alpha-ketoacids
All infants with classic MSUD present during the neonatal period. For other forms, age of presentation depends on several variables, including dietary protein and calorie intake, growth rate, number and severity of infectious illnesses, and rarely, dietary thiamine intake.
Biochemical signs should always be interpreted in the context of dietary leucine tolerance and prevailing clinical circumstances. Dietary leucine tolerance (in mg/kg/day) is defined as the steady-state leucine intake that permits normal growth and maintains plasma leucine concentration within the normal range.
The authors do not rely on tissue measurements of decarboxylation activity but classify affected individuals based on their leucine tolerance and metabolic response to illness. Decarboxylation data are from
Metabolic considerations in establishing MSUD phenotype:
Maple syrup odor is evident in cerumen soon after birth and in urine by age five to seven days. In untreated neonates, ketonuria, irritability, and poor feeding occur within 48 hours of delivery. Lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" are evident by age four to five days and are followed by coma and central respiratory failure. Preemptive detection of affected newborns, before they exhibit neurologic signs of MSUD, significantly reduces lifetime risk of intellectual disability, mental illness, and global functional impairment [
Following the neonatal period, acute metabolic intoxication (leucinosis) and neurologic deterioration can develop rapidly at any age as a result of net protein degradation precipitated by infection, surgery, injury, or psychological stress (see
Each episode of acute leucinosis is associated with a risk for cerebral edema (see
Transient periods of MSUD encephalopathy appear fully reversible, provided no global or focal ischemic brain damage occurs. In contrast, prolonged amino acid imbalances, particularly if they occur during the early years of brain development, lead to structural and functional neurologic abnormalities that have morbid long-term psychomotor consequences [
Neonatal screening and sophisticated enteral and parenteral treatment protocols (see
Lifetime Relative Risk of Each Finding Based on Condition at the Time of Diagnosis
The relative risk in this table compares the likelihood of developing the finding if the affected individual was ill at the time of diagnosis versus if the affected individual was well at the time of diagnosis.
Similar principles govern the acute and chronic management of classic and intermediate forms of MSUD (see
Children with the intermittent form of MSUD have normal growth and intellectual development throughout infancy and early childhood. When they are well, they generally tolerate a normal leucine intake, and plasma amino acid and urine organic acid profiles are normal or show only mild elevations of BCAAs. During infections or other physiologic stress, they can develop the clinical and biochemical features of classic MSUD, in rare cases culminating in coma and death [
It is not known with certainty if individuals with true thiamine-responsive MSUD exist. In general, such putative individuals have residual ex vivo BCKD enzyme activity of up to 40% normal and are not ill in the neonatal period, but present later in life with a clinical course similar to intermediate MSUD. To date, no person with "thiamine-responsive" MSUD has been treated solely with thiamine. Rather, they are treated with a combination of thiamine (doses ranging from 10 to 1,000 mg/day) and dietary BCAA restriction, making the in vivo contribution of thiamine impossible to discern [
BCKD has four subunit components (E1a, E1b, E2, and E3). Pathogenic variants in both alleles encoding any subunit can result in decreased activity of the enzyme complex and the accumulation of BCAAs and corresponding BCKAs in tissues and plasma [
For more information on the pathophysiology of MSUD click
The severity of the MSUD metabolic phenotype is determined by the amount of residual BCKD enzyme activity relative to dietary BCAA excess and the large demands for BCAA oxidation that accompany fasting, illness, or other catabolic stresses [
Biochemical derangement caused by biallelic pathogenic variants in
Note:
MSUD is rare in most populations, with incidence estimates of 1:185,000 live births [
As a result of a founder variant (
• Maple syrup odor of cerumen
• Poor feeding
• Irritability, lethargy
• Opisthotonus
• Focal dystonia
• "Fencing," "bicycling"
• Obtundation, coma
• Central respiratory failure
• ↑ BCAAs in plasma
• ↑ plasma alloisoleucine
• ↑ BCKAs in urine
• Ketonuria
• Maple syrup odor of cerumen
• Poor growth
• Poor feeding
• Irritability
• Developmental delays
• Encephalopathy during illness
• Normal early growth & development
• Episodic decompensations that can be severe
• Normal BCAAs when well
• Similar to classic biochemical profile during illness
## Clinical Description
Traditionally, the metabolic phenotype of maple syrup urine disease (MSUD) is termed classic or intermediate on the basis of residual branched-chain alpha-ketoacid dehydrogenase (BCKD) enzyme activity. Rarely, affected individuals have partial BCKD enzyme deficiency that manifests only intermittently or responds to dietary thiamine therapy (see
Clinical Phenotypes of Maple Syrup Urine Disease
Maple syrup odor of cerumen
Poor feeding
Irritability, lethargy
Opisthotonus
Focal dystonia
"Fencing," "bicycling"
Obtundation, coma
Central respiratory failure
↑ BCAAs in plasma
↑ plasma alloisoleucine
↑ BCKAs in urine
Ketonuria
Maple syrup odor of cerumen
Poor growth
Poor feeding
Irritability
Developmental delays
Encephalopathy during illness
Normal early growth & development
Episodic decompensations that can be severe
Normal BCAAs when well
Similar to classic biochemical profile during illness
BCAAs = branched-chain amino acids; BCKAs = branched-chain alpha-ketoacids
All infants with classic MSUD present during the neonatal period. For other forms, age of presentation depends on several variables, including dietary protein and calorie intake, growth rate, number and severity of infectious illnesses, and rarely, dietary thiamine intake.
Biochemical signs should always be interpreted in the context of dietary leucine tolerance and prevailing clinical circumstances. Dietary leucine tolerance (in mg/kg/day) is defined as the steady-state leucine intake that permits normal growth and maintains plasma leucine concentration within the normal range.
The authors do not rely on tissue measurements of decarboxylation activity but classify affected individuals based on their leucine tolerance and metabolic response to illness. Decarboxylation data are from
Metabolic considerations in establishing MSUD phenotype:
Maple syrup odor is evident in cerumen soon after birth and in urine by age five to seven days. In untreated neonates, ketonuria, irritability, and poor feeding occur within 48 hours of delivery. Lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" are evident by age four to five days and are followed by coma and central respiratory failure. Preemptive detection of affected newborns, before they exhibit neurologic signs of MSUD, significantly reduces lifetime risk of intellectual disability, mental illness, and global functional impairment [
Following the neonatal period, acute metabolic intoxication (leucinosis) and neurologic deterioration can develop rapidly at any age as a result of net protein degradation precipitated by infection, surgery, injury, or psychological stress (see
Each episode of acute leucinosis is associated with a risk for cerebral edema (see
Transient periods of MSUD encephalopathy appear fully reversible, provided no global or focal ischemic brain damage occurs. In contrast, prolonged amino acid imbalances, particularly if they occur during the early years of brain development, lead to structural and functional neurologic abnormalities that have morbid long-term psychomotor consequences [
Neonatal screening and sophisticated enteral and parenteral treatment protocols (see
Lifetime Relative Risk of Each Finding Based on Condition at the Time of Diagnosis
The relative risk in this table compares the likelihood of developing the finding if the affected individual was ill at the time of diagnosis versus if the affected individual was well at the time of diagnosis.
Similar principles govern the acute and chronic management of classic and intermediate forms of MSUD (see
Children with the intermittent form of MSUD have normal growth and intellectual development throughout infancy and early childhood. When they are well, they generally tolerate a normal leucine intake, and plasma amino acid and urine organic acid profiles are normal or show only mild elevations of BCAAs. During infections or other physiologic stress, they can develop the clinical and biochemical features of classic MSUD, in rare cases culminating in coma and death [
It is not known with certainty if individuals with true thiamine-responsive MSUD exist. In general, such putative individuals have residual ex vivo BCKD enzyme activity of up to 40% normal and are not ill in the neonatal period, but present later in life with a clinical course similar to intermediate MSUD. To date, no person with "thiamine-responsive" MSUD has been treated solely with thiamine. Rather, they are treated with a combination of thiamine (doses ranging from 10 to 1,000 mg/day) and dietary BCAA restriction, making the in vivo contribution of thiamine impossible to discern [
• Maple syrup odor of cerumen
• Poor feeding
• Irritability, lethargy
• Opisthotonus
• Focal dystonia
• "Fencing," "bicycling"
• Obtundation, coma
• Central respiratory failure
• ↑ BCAAs in plasma
• ↑ plasma alloisoleucine
• ↑ BCKAs in urine
• Ketonuria
• Maple syrup odor of cerumen
• Poor growth
• Poor feeding
• Irritability
• Developmental delays
• Encephalopathy during illness
• Normal early growth & development
• Episodic decompensations that can be severe
• Normal BCAAs when well
• Similar to classic biochemical profile during illness
## Classic MSUD Phenotype
Maple syrup odor is evident in cerumen soon after birth and in urine by age five to seven days. In untreated neonates, ketonuria, irritability, and poor feeding occur within 48 hours of delivery. Lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" are evident by age four to five days and are followed by coma and central respiratory failure. Preemptive detection of affected newborns, before they exhibit neurologic signs of MSUD, significantly reduces lifetime risk of intellectual disability, mental illness, and global functional impairment [
Following the neonatal period, acute metabolic intoxication (leucinosis) and neurologic deterioration can develop rapidly at any age as a result of net protein degradation precipitated by infection, surgery, injury, or psychological stress (see
Each episode of acute leucinosis is associated with a risk for cerebral edema (see
Transient periods of MSUD encephalopathy appear fully reversible, provided no global or focal ischemic brain damage occurs. In contrast, prolonged amino acid imbalances, particularly if they occur during the early years of brain development, lead to structural and functional neurologic abnormalities that have morbid long-term psychomotor consequences [
Neonatal screening and sophisticated enteral and parenteral treatment protocols (see
Lifetime Relative Risk of Each Finding Based on Condition at the Time of Diagnosis
The relative risk in this table compares the likelihood of developing the finding if the affected individual was ill at the time of diagnosis versus if the affected individual was well at the time of diagnosis.
## Intermediate MSUD
Similar principles govern the acute and chronic management of classic and intermediate forms of MSUD (see
## Intermittent MSUD
Children with the intermittent form of MSUD have normal growth and intellectual development throughout infancy and early childhood. When they are well, they generally tolerate a normal leucine intake, and plasma amino acid and urine organic acid profiles are normal or show only mild elevations of BCAAs. During infections or other physiologic stress, they can develop the clinical and biochemical features of classic MSUD, in rare cases culminating in coma and death [
## Thiamine-Responsive MSUD
It is not known with certainty if individuals with true thiamine-responsive MSUD exist. In general, such putative individuals have residual ex vivo BCKD enzyme activity of up to 40% normal and are not ill in the neonatal period, but present later in life with a clinical course similar to intermediate MSUD. To date, no person with "thiamine-responsive" MSUD has been treated solely with thiamine. Rather, they are treated with a combination of thiamine (doses ranging from 10 to 1,000 mg/day) and dietary BCAA restriction, making the in vivo contribution of thiamine impossible to discern [
## Pathophysiology
BCKD has four subunit components (E1a, E1b, E2, and E3). Pathogenic variants in both alleles encoding any subunit can result in decreased activity of the enzyme complex and the accumulation of BCAAs and corresponding BCKAs in tissues and plasma [
For more information on the pathophysiology of MSUD click
## Genotype-Phenotype Correlations
The severity of the MSUD metabolic phenotype is determined by the amount of residual BCKD enzyme activity relative to dietary BCAA excess and the large demands for BCAA oxidation that accompany fasting, illness, or other catabolic stresses [
## Nomenclature
Biochemical derangement caused by biallelic pathogenic variants in
Note:
## Prevalence
MSUD is rare in most populations, with incidence estimates of 1:185,000 live births [
As a result of a founder variant (
## Genetically Related (Allelic) Disorders
No other phenotypes are known to be associated with germline pathogenic variants in
## Differential Diagnosis
Entities to exclude in the encephalopathic neonate include birth asphyxia, hypoglycemia, status epilepticus, kernicterus, meningitis, and encephalitis. The few inborn errors of metabolism that present with neonatal encephalopathy include the following:
Hyperketosis syndromes (e.g., beta-ketothiolase deficiency [OMIM
Urea cycle defects (See
Among these, MSUD is unique for the sweet odor of cerumen and a positive urine dinitrophenylhydrazine test. Laboratory testing that includes quantitative plasma amino acids, plasma or whole-blood alloisoleucine, serum acylcarnitines, urine organic acids, plasma ammonia concentration, and serum lactate concentration distinguishes among these possibilities. In particular, quantitative analysis of plasma amino acids is generally sufficient to diagnosis MSUD expeditiously.
4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone), which is thought to be responsible for the characteristic odor of MSUD [
Note: Pathogenic variants in
• Hyperketosis syndromes (e.g., beta-ketothiolase deficiency [OMIM
• Urea cycle defects (See
## Management
When maple syrup urine disease (MSUD) is suspected during the diagnostic evaluation (i.e., due to elevated concentration of leucine, isoleucine, valine, and/or alloisoleucine), metabolic treatment should be initiated immediately.
Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach to care with oversight and expertise from a specialized metabolic center. Consensus nutritional guidelines have been published [
To establish the extent of disease and needs in an individual following initial diagnosis of MSUD, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of Maple Syrup Urine Disease
Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended).
Consider a short hospitalization at a center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis & risks for acute encephalopathic crises to caregivers).
Determine whether patient has classic or intermediate MSUD through assessment of concentration ratios among the BCAAs & between leucine & other essential & nonessential amino acids.
ADHD = attention-deficit/hyperactivity disorder; BCAAs = branched-chain amino acids (leucine, isoleucine, and valine); OT = occupational therapist; PT = physical therapist
After a new diagnosis of MSUD in an infant or child, the closest hospital and local pediatrician should also be informed.
The following plasma concentration ratios are the most representative of amino acid regulation: leucine:isoleucine, leucine:valine, leucine:tyrosine, leucine:phenylalanine, leucine:glutamate, and leucine:alanine (mol:mol) [
In MSUD, plasma leucine concentration has the strongest reciprocal relationship to plasma alanine and glutamine concentrations (Spearman correlation coefficient -0.86 and -0.62, respectively; p<0.0001; see
Severe branched-chain alpha-ketoacid dehydrogenase (BCKD) deficiency (classic MSUD) affects amino acid homeostasis at multiple levels and causes frequent and variable disturbances of plasma amino acid concentration ratios.
In milder intermediate forms of MSUD, plasma BCAAs may be chronically elevated while plasma amino acid concentration ratios tend to be preserved.
Plasma amino values between ages four and 26 months from a child with classic MSUD show a strong reciprocal relationship between leucine (gray diamonds) and alanine (white circles) (Spearman correlation coefficient = -0.86; p<0.0001).
Republished with permission from
All children with MSUD and feeding difficulties require supervision of a specialist metabolic dietitian with experience in managing the diet of those with MSUD.
The main principles of treatment are age-appropriate tolerance of leucine, isoleucine, and valine, with stable plasma branched-chain amino acid (BCAA) concentrations and BCAA concentration ratios, while avoiding deficiencies of essential amino acids, fatty acids, and micronutrients (see
Routine Daily Treatment in Individuals with Maple Syrup Urine Disease
Breast milk or regular infant formula can be used as a natural protein source.
For infants w/classic MSUD, breast milk should be expressed & quantified.
Record of BCAA supplement intake maintained by parents
Dried blood spots by overnight mail for monitoring of amino acid concentrations (See
Children: 20-40 mg/kg/day
Adults:10-15 mg/kg/day
In persons w/classic MSUD (0%-2% enzyme activity)
See
Isoleucine supplements can periodically be suspended based on plasma amino acid monitoring, but continuous valine supplementation is recommended.
Continuous valine fortification is directly related to long-term intellectual outcome.
Adequate provision of information & education to parents, patients, & caregivers
For information on treatment during illness or acute decompensation, see
PT
Aggressive rehab therapy
BCAAs = branched-chain amino acids (leucine, isoleucine, and valine); PT = physical therapy
The dietary requirement for BCAAs varies as a function of age, growth rate, calorie intake, illness, and residual in vivo branched-chain alpha-ketoacid dehydrogenase (BCKD) enzyme activity.
For asymptomatic individuals; see
For rapidly growing infants, monitoring weekly or twice weekly is recommended.
Valine has a low affinity for the blood-brain barrier LAT1 transporter, which makes it especially vulnerable to competitive inhibition by leucine.
Which may include ADHD, depression, or anxiety
Leucine (A), energy (B), and total protein (C) intakes of 15 stable Mennonite infants with classic MSUD on dietary management
Republished with permission from
Mean and 25th to 75th Percentile Range Nutrient Intakes (per kg-day) by Age Group
Data derived from Mennonite children from birth to age 4 years with classic MSUD
Emergency Outpatient Treatment in Individuals with Maple Syrup Urine Disease
Trial of outpatient treatment at home for ≤12 hrs w/periodic measurement of urine BCKAs using DNPH strips
Reassessment (~ every 2 hrs) for clinical changes
BCAA = branched-chain amino acid; BCKAs = branched-chain alpha-ketoacids; DNPH = dinitrophenylhydrazine
Fever <38.5°C (101°F), enteral or gastrostomy tube feeding tolerated without recurrent vomiting or diarrhea, and absence of neurologic symptoms (altered consciousness, irritability, hypotonia)
High-calorie BCAA-free "sick day" formulas
Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features discussed with the designated center of expertise for inherited metabolic diseases
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma) should be managed symptomatically and with generous caloric support in a hospital setting (see
Acute Inpatient Treatment in Individuals with Maple Syrup Urine Disease
Hospitals admitting patients w/MSUD encephalopathy should have an established mechanism for procuring MSUD parenteral amino acid solutions devoid of BCAAs.
For patients of any age who can tolerate enteral feeding (even if intubated), continuous nasogastric delivery (30-60 mL/hr) of a BCAA-free MSUD formula (0.7-1.2 kcal/mL) supplemented w/1% liquid solutions of isoleucine & valine can meet protein goals while providing addl calories.
Peritoneal dialysis & venovenous hemofiltration are less effective & more dangerous than short courses of continuous hemodialysis.
When hemodialysis is used to treat MSUD it must be coupled w/effective nutritional management to constrain catabolic response & prevent recurrent clinical intoxication.
Superficial & invasive
Persons w/MSUD are vulnerable to bacterial or fungal infection from central venous catheters
Stop all enteral feeding & measure serum concentrations of lipase & amylase.
Supportive treatment w/BCAA-free parenteral nutrition solutions
BCAAs = branch-chain amino acids (leucine, isoleucine, and valine); EER = estimated energy expenditure
Establish central venous access; where regional expertise allows, the authors recommend placement of a peripheral intravenous central catheter (PICC) or other form of central line for treatment of metabolic intoxication.
Parenteral MSUD amino acid solutions are the preferred protein source for individuals with MSUD who have severe metabolic encephalopathy; however, such parenteral solutions are available from a very limited number of specialty pharmacies and often prove difficult to procure in a timely manner.
Nutritional therapy alone can effectively reduce even extremely elevated plasma concentrations of leucine in persons with MSUD of any age and under a wide variety of clinical circumstances [
A combined approach to therapy, using hemodialysis with simultaneous anabolic nutritional therapy was shown to be highly effective in one neonate with classic MSUD [
Dialysis without simultaneous management of the underlying disturbance of protein turnover is analogous to treating diabetic ketoacidosis with invasive removal of glucose and ketones rather than insulin infusion. In both conditions, effective treatment depends not only on lowering concentrations of pathologic metabolites, but also on controlling the underlying metabolic derangement (in this case ongoing protein degradation due to catabolism).
Most commonly associated with high intravenous fluid, glucose, and insulin infusions.
The most commonly encountered biochemical complications of treatment are hyperglycemia, hypoglyemia, hyponatremia, hypokalemia, and hypophosphatemia.
During episodes of acute encephalopathy, individuals with MSUD are typically too unstable for magnetic resonance imaging. Cranial CT scan is used to evaluate for major indices of cerebral edema, such as decreased volume of cerebral ventricles and basal fluid spaces, or reduced gray-white discrimination (see
Signs and symptoms typically include epigastric or mid-back pain, anorexia, and/or vomiting, developing in two to three days into treatment of a metabolic decompensation.
During acute metabolic crisis, newborns, infants, and children with MSUD can develop acute focal or generalized dystonic posturing attributed to an increased plasma leucine:tyrosine concentration ratio, restricted brain tyrosine uptake, and reduced cerebral dopamine synthesis [
Prevention of Primary Manifestations in Individuals with Maple Syrup Urine Disease
Effective for classic MSUD, w/removal of dietary restrictions & complete protection from decompensations during illness
Post transplantation, plasma leucine, isoleucine, & valine concentrations typically normalize w/in 6 hrs & chronically remain ~2x the reference mean on an unrestricted diet.
Disease-free survival & graft survival are high, 100% in a series of 93 patients transplanted at University Pittsburgh Medical Center between 2003 & 2019.
Risks assoc w/surgery & immunosuppression are similar to those in other pediatric liver transplant populations & may incl EBV-assoc post-transplantation lymphoproliferative disease.
Liver transplantation does not reverse cognitive disability or psychiatric illness in patients w/MSUD but may arrest progression of neurocognitive impairment & prevent life-threatening cerebral edema assoc w/metabolic crisis.
BCAA = branched-chain amino acid; EBV = Epstein-Barr virus
The existence of "thiamine-responsive" branched-chain alpha-ketoacid dehydrogenase (BCKD) mutants is controversial.
Any trauma care or surgical procedures should be approached in consultation with a metabolic specialist.
Recommended Surveillance for Individuals with Maple Syrup Urine Disease
For rapidly growing infants, monitoring 1x or 2x/wk
Weekly in children, adolescents, & adults
See
The frequency of amino acid monitoring varies by age, metabolic stability, adherence, and regional clinical practice.
The frequency of amino acid monitoring correlates directly with metabolic control [
The Denver Developmental Screening Test II or a comparable tool is useful for monitoring development of infants and young children with MSUD.
School-age children, adolescents, and adults should have neurocognitive testing if indicated by school performance or behavior problems [
Plasma leucine concentration: 150-300 µmol/L with an age-appropriate intake
Plasma isoleucine concentration approximately equal to plasma leucine concentration
Plasma valine concentration at least twofold plasma leucine concentration
Indices of calcium, magnesium, zinc, folate, selenium, and omega-3 essential fatty acid sufficiency
Early diagnosis of at-risk sibs of an affected individual may allow asymptomatic infants to be managed out of the hospital by experienced providers.
Newborn at-risk sibs who have not undergone prenatal testing can be tested in one of two ways:
Plasma amino acid analysis of a sample obtained at approximately 24 hours of life. In some laboratories, samples obtained earlier can yield false negative results.
If the pathogenic variants have been identified in the family, a cord blood sample can be used for molecular genetic testing.
Before confirmatory molecular testing is complete, at-risk neonates can be managed with an MSUD prescription diet if serial plasma amino acid profiles provide evidence of MSUD.
See
With the advent of newborn screening and preventive care, more women with MSUD are surviving to child-bearing age. Successful delivery of a healthy baby is possible for women with classic MSUD [
Elevated maternal leucine plasma concentration, like elevated maternal phenylalanine plasma concentration, is likely teratogenic. If a woman with MSUD is planning a pregnancy, metabolic control should be maintained in a rigorous fashion preceding and throughout gestation. Keeping the maternal plasma levels of the branched-chain amino acids between 100 and 300 μmol/L is compatible with delivery of a normal infant [
During the development of the placenta and fetus, maternal BCAA and protein requirements increase, and frequent monitoring of plasma amino acid concentrations and fetal growth may be necessary to avoid essential amino acid deficiencies [
The postpartum period is dangerous for the affected mother. Catabolic stress of labor, involutional changes of the uterus, and internal sequestration of blood are potential sources of metabolic decompensation [
Search
• Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended).
• Consider a short hospitalization at a center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis & risks for acute encephalopathic crises to caregivers).
• Determine whether patient has classic or intermediate MSUD through assessment of concentration ratios among the BCAAs & between leucine & other essential & nonessential amino acids.
• Breast milk or regular infant formula can be used as a natural protein source.
• For infants w/classic MSUD, breast milk should be expressed & quantified.
• Record of BCAA supplement intake maintained by parents
• Dried blood spots by overnight mail for monitoring of amino acid concentrations (See
• Children: 20-40 mg/kg/day
• Adults:10-15 mg/kg/day
• In persons w/classic MSUD (0%-2% enzyme activity)
• See
• Isoleucine supplements can periodically be suspended based on plasma amino acid monitoring, but continuous valine supplementation is recommended.
• Continuous valine fortification is directly related to long-term intellectual outcome.
• Adequate provision of information & education to parents, patients, & caregivers
• For information on treatment during illness or acute decompensation, see
• PT
• Aggressive rehab therapy
• Trial of outpatient treatment at home for ≤12 hrs w/periodic measurement of urine BCKAs using DNPH strips
• Reassessment (~ every 2 hrs) for clinical changes
• Hospitals admitting patients w/MSUD encephalopathy should have an established mechanism for procuring MSUD parenteral amino acid solutions devoid of BCAAs.
• For patients of any age who can tolerate enteral feeding (even if intubated), continuous nasogastric delivery (30-60 mL/hr) of a BCAA-free MSUD formula (0.7-1.2 kcal/mL) supplemented w/1% liquid solutions of isoleucine & valine can meet protein goals while providing addl calories.
• Peritoneal dialysis & venovenous hemofiltration are less effective & more dangerous than short courses of continuous hemodialysis.
• When hemodialysis is used to treat MSUD it must be coupled w/effective nutritional management to constrain catabolic response & prevent recurrent clinical intoxication.
• Superficial & invasive
• Persons w/MSUD are vulnerable to bacterial or fungal infection from central venous catheters
• Stop all enteral feeding & measure serum concentrations of lipase & amylase.
• Supportive treatment w/BCAA-free parenteral nutrition solutions
• Effective for classic MSUD, w/removal of dietary restrictions & complete protection from decompensations during illness
• Post transplantation, plasma leucine, isoleucine, & valine concentrations typically normalize w/in 6 hrs & chronically remain ~2x the reference mean on an unrestricted diet.
• Disease-free survival & graft survival are high, 100% in a series of 93 patients transplanted at University Pittsburgh Medical Center between 2003 & 2019.
• Risks assoc w/surgery & immunosuppression are similar to those in other pediatric liver transplant populations & may incl EBV-assoc post-transplantation lymphoproliferative disease.
• Liver transplantation does not reverse cognitive disability or psychiatric illness in patients w/MSUD but may arrest progression of neurocognitive impairment & prevent life-threatening cerebral edema assoc w/metabolic crisis.
• For rapidly growing infants, monitoring 1x or 2x/wk
• Weekly in children, adolescents, & adults
• Plasma leucine concentration: 150-300 µmol/L with an age-appropriate intake
• Plasma isoleucine concentration approximately equal to plasma leucine concentration
• Plasma valine concentration at least twofold plasma leucine concentration
• Indices of calcium, magnesium, zinc, folate, selenium, and omega-3 essential fatty acid sufficiency
• Plasma amino acid analysis of a sample obtained at approximately 24 hours of life. In some laboratories, samples obtained earlier can yield false negative results.
• If the pathogenic variants have been identified in the family, a cord blood sample can be used for molecular genetic testing.
## Evaluations Following Initial Diagnosis
When maple syrup urine disease (MSUD) is suspected during the diagnostic evaluation (i.e., due to elevated concentration of leucine, isoleucine, valine, and/or alloisoleucine), metabolic treatment should be initiated immediately.
Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach to care with oversight and expertise from a specialized metabolic center. Consensus nutritional guidelines have been published [
To establish the extent of disease and needs in an individual following initial diagnosis of MSUD, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of Maple Syrup Urine Disease
Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended).
Consider a short hospitalization at a center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis & risks for acute encephalopathic crises to caregivers).
Determine whether patient has classic or intermediate MSUD through assessment of concentration ratios among the BCAAs & between leucine & other essential & nonessential amino acids.
ADHD = attention-deficit/hyperactivity disorder; BCAAs = branched-chain amino acids (leucine, isoleucine, and valine); OT = occupational therapist; PT = physical therapist
After a new diagnosis of MSUD in an infant or child, the closest hospital and local pediatrician should also be informed.
The following plasma concentration ratios are the most representative of amino acid regulation: leucine:isoleucine, leucine:valine, leucine:tyrosine, leucine:phenylalanine, leucine:glutamate, and leucine:alanine (mol:mol) [
In MSUD, plasma leucine concentration has the strongest reciprocal relationship to plasma alanine and glutamine concentrations (Spearman correlation coefficient -0.86 and -0.62, respectively; p<0.0001; see
Severe branched-chain alpha-ketoacid dehydrogenase (BCKD) deficiency (classic MSUD) affects amino acid homeostasis at multiple levels and causes frequent and variable disturbances of plasma amino acid concentration ratios.
In milder intermediate forms of MSUD, plasma BCAAs may be chronically elevated while plasma amino acid concentration ratios tend to be preserved.
Plasma amino values between ages four and 26 months from a child with classic MSUD show a strong reciprocal relationship between leucine (gray diamonds) and alanine (white circles) (Spearman correlation coefficient = -0.86; p<0.0001).
Republished with permission from
• Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended).
• Consider a short hospitalization at a center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis & risks for acute encephalopathic crises to caregivers).
• Determine whether patient has classic or intermediate MSUD through assessment of concentration ratios among the BCAAs & between leucine & other essential & nonessential amino acids.
## Treatment of Manifestations
All children with MSUD and feeding difficulties require supervision of a specialist metabolic dietitian with experience in managing the diet of those with MSUD.
The main principles of treatment are age-appropriate tolerance of leucine, isoleucine, and valine, with stable plasma branched-chain amino acid (BCAA) concentrations and BCAA concentration ratios, while avoiding deficiencies of essential amino acids, fatty acids, and micronutrients (see
Routine Daily Treatment in Individuals with Maple Syrup Urine Disease
Breast milk or regular infant formula can be used as a natural protein source.
For infants w/classic MSUD, breast milk should be expressed & quantified.
Record of BCAA supplement intake maintained by parents
Dried blood spots by overnight mail for monitoring of amino acid concentrations (See
Children: 20-40 mg/kg/day
Adults:10-15 mg/kg/day
In persons w/classic MSUD (0%-2% enzyme activity)
See
Isoleucine supplements can periodically be suspended based on plasma amino acid monitoring, but continuous valine supplementation is recommended.
Continuous valine fortification is directly related to long-term intellectual outcome.
Adequate provision of information & education to parents, patients, & caregivers
For information on treatment during illness or acute decompensation, see
PT
Aggressive rehab therapy
BCAAs = branched-chain amino acids (leucine, isoleucine, and valine); PT = physical therapy
The dietary requirement for BCAAs varies as a function of age, growth rate, calorie intake, illness, and residual in vivo branched-chain alpha-ketoacid dehydrogenase (BCKD) enzyme activity.
For asymptomatic individuals; see
For rapidly growing infants, monitoring weekly or twice weekly is recommended.
Valine has a low affinity for the blood-brain barrier LAT1 transporter, which makes it especially vulnerable to competitive inhibition by leucine.
Which may include ADHD, depression, or anxiety
Leucine (A), energy (B), and total protein (C) intakes of 15 stable Mennonite infants with classic MSUD on dietary management
Republished with permission from
Mean and 25th to 75th Percentile Range Nutrient Intakes (per kg-day) by Age Group
Data derived from Mennonite children from birth to age 4 years with classic MSUD
Emergency Outpatient Treatment in Individuals with Maple Syrup Urine Disease
Trial of outpatient treatment at home for ≤12 hrs w/periodic measurement of urine BCKAs using DNPH strips
Reassessment (~ every 2 hrs) for clinical changes
BCAA = branched-chain amino acid; BCKAs = branched-chain alpha-ketoacids; DNPH = dinitrophenylhydrazine
Fever <38.5°C (101°F), enteral or gastrostomy tube feeding tolerated without recurrent vomiting or diarrhea, and absence of neurologic symptoms (altered consciousness, irritability, hypotonia)
High-calorie BCAA-free "sick day" formulas
Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features discussed with the designated center of expertise for inherited metabolic diseases
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma) should be managed symptomatically and with generous caloric support in a hospital setting (see
Acute Inpatient Treatment in Individuals with Maple Syrup Urine Disease
Hospitals admitting patients w/MSUD encephalopathy should have an established mechanism for procuring MSUD parenteral amino acid solutions devoid of BCAAs.
For patients of any age who can tolerate enteral feeding (even if intubated), continuous nasogastric delivery (30-60 mL/hr) of a BCAA-free MSUD formula (0.7-1.2 kcal/mL) supplemented w/1% liquid solutions of isoleucine & valine can meet protein goals while providing addl calories.
Peritoneal dialysis & venovenous hemofiltration are less effective & more dangerous than short courses of continuous hemodialysis.
When hemodialysis is used to treat MSUD it must be coupled w/effective nutritional management to constrain catabolic response & prevent recurrent clinical intoxication.
Superficial & invasive
Persons w/MSUD are vulnerable to bacterial or fungal infection from central venous catheters
Stop all enteral feeding & measure serum concentrations of lipase & amylase.
Supportive treatment w/BCAA-free parenteral nutrition solutions
BCAAs = branch-chain amino acids (leucine, isoleucine, and valine); EER = estimated energy expenditure
Establish central venous access; where regional expertise allows, the authors recommend placement of a peripheral intravenous central catheter (PICC) or other form of central line for treatment of metabolic intoxication.
Parenteral MSUD amino acid solutions are the preferred protein source for individuals with MSUD who have severe metabolic encephalopathy; however, such parenteral solutions are available from a very limited number of specialty pharmacies and often prove difficult to procure in a timely manner.
Nutritional therapy alone can effectively reduce even extremely elevated plasma concentrations of leucine in persons with MSUD of any age and under a wide variety of clinical circumstances [
A combined approach to therapy, using hemodialysis with simultaneous anabolic nutritional therapy was shown to be highly effective in one neonate with classic MSUD [
Dialysis without simultaneous management of the underlying disturbance of protein turnover is analogous to treating diabetic ketoacidosis with invasive removal of glucose and ketones rather than insulin infusion. In both conditions, effective treatment depends not only on lowering concentrations of pathologic metabolites, but also on controlling the underlying metabolic derangement (in this case ongoing protein degradation due to catabolism).
Most commonly associated with high intravenous fluid, glucose, and insulin infusions.
The most commonly encountered biochemical complications of treatment are hyperglycemia, hypoglyemia, hyponatremia, hypokalemia, and hypophosphatemia.
During episodes of acute encephalopathy, individuals with MSUD are typically too unstable for magnetic resonance imaging. Cranial CT scan is used to evaluate for major indices of cerebral edema, such as decreased volume of cerebral ventricles and basal fluid spaces, or reduced gray-white discrimination (see
Signs and symptoms typically include epigastric or mid-back pain, anorexia, and/or vomiting, developing in two to three days into treatment of a metabolic decompensation.
During acute metabolic crisis, newborns, infants, and children with MSUD can develop acute focal or generalized dystonic posturing attributed to an increased plasma leucine:tyrosine concentration ratio, restricted brain tyrosine uptake, and reduced cerebral dopamine synthesis [
• Breast milk or regular infant formula can be used as a natural protein source.
• For infants w/classic MSUD, breast milk should be expressed & quantified.
• Record of BCAA supplement intake maintained by parents
• Dried blood spots by overnight mail for monitoring of amino acid concentrations (See
• Children: 20-40 mg/kg/day
• Adults:10-15 mg/kg/day
• In persons w/classic MSUD (0%-2% enzyme activity)
• See
• Isoleucine supplements can periodically be suspended based on plasma amino acid monitoring, but continuous valine supplementation is recommended.
• Continuous valine fortification is directly related to long-term intellectual outcome.
• Adequate provision of information & education to parents, patients, & caregivers
• For information on treatment during illness or acute decompensation, see
• PT
• Aggressive rehab therapy
• Trial of outpatient treatment at home for ≤12 hrs w/periodic measurement of urine BCKAs using DNPH strips
• Reassessment (~ every 2 hrs) for clinical changes
• Hospitals admitting patients w/MSUD encephalopathy should have an established mechanism for procuring MSUD parenteral amino acid solutions devoid of BCAAs.
• For patients of any age who can tolerate enteral feeding (even if intubated), continuous nasogastric delivery (30-60 mL/hr) of a BCAA-free MSUD formula (0.7-1.2 kcal/mL) supplemented w/1% liquid solutions of isoleucine & valine can meet protein goals while providing addl calories.
• Peritoneal dialysis & venovenous hemofiltration are less effective & more dangerous than short courses of continuous hemodialysis.
• When hemodialysis is used to treat MSUD it must be coupled w/effective nutritional management to constrain catabolic response & prevent recurrent clinical intoxication.
• Superficial & invasive
• Persons w/MSUD are vulnerable to bacterial or fungal infection from central venous catheters
• Stop all enteral feeding & measure serum concentrations of lipase & amylase.
• Supportive treatment w/BCAA-free parenteral nutrition solutions
## Prevention of Primary Manifestations
Prevention of Primary Manifestations in Individuals with Maple Syrup Urine Disease
Effective for classic MSUD, w/removal of dietary restrictions & complete protection from decompensations during illness
Post transplantation, plasma leucine, isoleucine, & valine concentrations typically normalize w/in 6 hrs & chronically remain ~2x the reference mean on an unrestricted diet.
Disease-free survival & graft survival are high, 100% in a series of 93 patients transplanted at University Pittsburgh Medical Center between 2003 & 2019.
Risks assoc w/surgery & immunosuppression are similar to those in other pediatric liver transplant populations & may incl EBV-assoc post-transplantation lymphoproliferative disease.
Liver transplantation does not reverse cognitive disability or psychiatric illness in patients w/MSUD but may arrest progression of neurocognitive impairment & prevent life-threatening cerebral edema assoc w/metabolic crisis.
BCAA = branched-chain amino acid; EBV = Epstein-Barr virus
The existence of "thiamine-responsive" branched-chain alpha-ketoacid dehydrogenase (BCKD) mutants is controversial.
• Effective for classic MSUD, w/removal of dietary restrictions & complete protection from decompensations during illness
• Post transplantation, plasma leucine, isoleucine, & valine concentrations typically normalize w/in 6 hrs & chronically remain ~2x the reference mean on an unrestricted diet.
• Disease-free survival & graft survival are high, 100% in a series of 93 patients transplanted at University Pittsburgh Medical Center between 2003 & 2019.
• Risks assoc w/surgery & immunosuppression are similar to those in other pediatric liver transplant populations & may incl EBV-assoc post-transplantation lymphoproliferative disease.
• Liver transplantation does not reverse cognitive disability or psychiatric illness in patients w/MSUD but may arrest progression of neurocognitive impairment & prevent life-threatening cerebral edema assoc w/metabolic crisis.
## Prevention of Secondary Complications
Any trauma care or surgical procedures should be approached in consultation with a metabolic specialist.
## Surveillance
Recommended Surveillance for Individuals with Maple Syrup Urine Disease
For rapidly growing infants, monitoring 1x or 2x/wk
Weekly in children, adolescents, & adults
See
The frequency of amino acid monitoring varies by age, metabolic stability, adherence, and regional clinical practice.
The frequency of amino acid monitoring correlates directly with metabolic control [
The Denver Developmental Screening Test II or a comparable tool is useful for monitoring development of infants and young children with MSUD.
School-age children, adolescents, and adults should have neurocognitive testing if indicated by school performance or behavior problems [
Plasma leucine concentration: 150-300 µmol/L with an age-appropriate intake
Plasma isoleucine concentration approximately equal to plasma leucine concentration
Plasma valine concentration at least twofold plasma leucine concentration
Indices of calcium, magnesium, zinc, folate, selenium, and omega-3 essential fatty acid sufficiency
• For rapidly growing infants, monitoring 1x or 2x/wk
• Weekly in children, adolescents, & adults
• Plasma leucine concentration: 150-300 µmol/L with an age-appropriate intake
• Plasma isoleucine concentration approximately equal to plasma leucine concentration
• Plasma valine concentration at least twofold plasma leucine concentration
• Indices of calcium, magnesium, zinc, folate, selenium, and omega-3 essential fatty acid sufficiency
## Evaluation of Relatives at Risk
Early diagnosis of at-risk sibs of an affected individual may allow asymptomatic infants to be managed out of the hospital by experienced providers.
Newborn at-risk sibs who have not undergone prenatal testing can be tested in one of two ways:
Plasma amino acid analysis of a sample obtained at approximately 24 hours of life. In some laboratories, samples obtained earlier can yield false negative results.
If the pathogenic variants have been identified in the family, a cord blood sample can be used for molecular genetic testing.
Before confirmatory molecular testing is complete, at-risk neonates can be managed with an MSUD prescription diet if serial plasma amino acid profiles provide evidence of MSUD.
See
• Plasma amino acid analysis of a sample obtained at approximately 24 hours of life. In some laboratories, samples obtained earlier can yield false negative results.
• If the pathogenic variants have been identified in the family, a cord blood sample can be used for molecular genetic testing.
## Pregnancy Management
With the advent of newborn screening and preventive care, more women with MSUD are surviving to child-bearing age. Successful delivery of a healthy baby is possible for women with classic MSUD [
Elevated maternal leucine plasma concentration, like elevated maternal phenylalanine plasma concentration, is likely teratogenic. If a woman with MSUD is planning a pregnancy, metabolic control should be maintained in a rigorous fashion preceding and throughout gestation. Keeping the maternal plasma levels of the branched-chain amino acids between 100 and 300 μmol/L is compatible with delivery of a normal infant [
During the development of the placenta and fetus, maternal BCAA and protein requirements increase, and frequent monitoring of plasma amino acid concentrations and fetal growth may be necessary to avoid essential amino acid deficiencies [
The postpartum period is dangerous for the affected mother. Catabolic stress of labor, involutional changes of the uterus, and internal sequestration of blood are potential sources of metabolic decompensation [
## Therapies Under Investigation
Search
## Genetic Counseling
Maple syrup urine disease (MSUD) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Maple syrup urine disease (MSUD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.
## Resources
TEMPLE (Tools Enabling Metabolic Parents LEarning)
United Kingdom
United Kingdom
Health Resources & Services Administration
•
• TEMPLE (Tools Enabling Metabolic Parents LEarning)
• United Kingdom
•
•
•
•
•
•
•
•
•
•
•
• United Kingdom
•
•
• Health Resources & Services Administration
•
•
•
•
•
## Molecular Genetics
Maple Syrup Urine Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Maple Syrup Urine Disease (
Maple syrup urine disease (MSUD) is caused by decreased activity of human branched-chain alpha-ketoacid dehydrogenase complex (BCKD), a multi-enzyme complex found in the mitochondria. It catalyzes the oxidative decarboxylation of the branched-chain ketoacids (alpha-ketoisocaproate, alpha-keto-beta-methyl valerate, and alpha-ketoisovalerate) in the second step in the degradative pathway of the branched-chain amino acids (BCAAs; leucine, isoleucine, and valine).
BCKD has four subunit components (E1a, E1b, E2, and E3). Biallelic pathogenic variants in one of the four unlinked genes encoding any subunit can result in decreased activity of the enzyme complex and the accumulation of BCAAs and corresponding branched-chain alpha-ketoacids (BCKAs) in tissues and plasma [
Biochemical derangements caused by pathogenic variants in the genes encoding BCKA decarboxylase (E1) alpha subunit (MSUD type 1A), BCKA decarboxylase (E1) beta subunit (MSUD type 1B), and dihydrolipoyl transacylase (E2) subunit (MSUD type 2) are indistinguishable biochemically.
Note: The E3 subunit (lipoamide dehydrogenase encoded by
The BCKD complex consists of three catalytic components:
The E1 decarboxylase, which is a heterotetramer of alpha and beta subunits (alpha2, beta2)
The E2 transacylase, which is a homo-24-mer
The E3 dehydrogenase, which is a homodimer
The complete functional BCKD complex contains a cubic E2 core surrounded by the following:
Twelve E1 components
Six E3 components
A single kinase
BCKD colocalizes with BCAA transaminases in mitochondria of diverse tissues and is regulated by a kinase-phosphatase pair. In humans, skeletal muscle is the major site for both transamination and oxidation of BCAAs. The liver and kidney each mediate an estimated 10%-15% of whole-body BCAA transamination-oxidation [
Maple Syrup Urine Disease: Gene-Specific Laboratory Considerations
Genes from
Deletions may be mediated by nonallelic homologous recombination between repetitive elements. However, these elements are not more abundant in
As described in the Human Gene Mutation Database [
Maple Syrup Urine Disease: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes from
Variant designation that does not conform to current naming conventions
• The E1 decarboxylase, which is a heterotetramer of alpha and beta subunits (alpha2, beta2)
• The E2 transacylase, which is a homo-24-mer
• The E3 dehydrogenase, which is a homodimer
• Twelve E1 components
• Six E3 components
• A single kinase
## Molecular Pathogenesis
Maple syrup urine disease (MSUD) is caused by decreased activity of human branched-chain alpha-ketoacid dehydrogenase complex (BCKD), a multi-enzyme complex found in the mitochondria. It catalyzes the oxidative decarboxylation of the branched-chain ketoacids (alpha-ketoisocaproate, alpha-keto-beta-methyl valerate, and alpha-ketoisovalerate) in the second step in the degradative pathway of the branched-chain amino acids (BCAAs; leucine, isoleucine, and valine).
BCKD has four subunit components (E1a, E1b, E2, and E3). Biallelic pathogenic variants in one of the four unlinked genes encoding any subunit can result in decreased activity of the enzyme complex and the accumulation of BCAAs and corresponding branched-chain alpha-ketoacids (BCKAs) in tissues and plasma [
Biochemical derangements caused by pathogenic variants in the genes encoding BCKA decarboxylase (E1) alpha subunit (MSUD type 1A), BCKA decarboxylase (E1) beta subunit (MSUD type 1B), and dihydrolipoyl transacylase (E2) subunit (MSUD type 2) are indistinguishable biochemically.
Note: The E3 subunit (lipoamide dehydrogenase encoded by
The BCKD complex consists of three catalytic components:
The E1 decarboxylase, which is a heterotetramer of alpha and beta subunits (alpha2, beta2)
The E2 transacylase, which is a homo-24-mer
The E3 dehydrogenase, which is a homodimer
The complete functional BCKD complex contains a cubic E2 core surrounded by the following:
Twelve E1 components
Six E3 components
A single kinase
BCKD colocalizes with BCAA transaminases in mitochondria of diverse tissues and is regulated by a kinase-phosphatase pair. In humans, skeletal muscle is the major site for both transamination and oxidation of BCAAs. The liver and kidney each mediate an estimated 10%-15% of whole-body BCAA transamination-oxidation [
Maple Syrup Urine Disease: Gene-Specific Laboratory Considerations
Genes from
Deletions may be mediated by nonallelic homologous recombination between repetitive elements. However, these elements are not more abundant in
As described in the Human Gene Mutation Database [
Maple Syrup Urine Disease: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes from
Variant designation that does not conform to current naming conventions
• The E1 decarboxylase, which is a heterotetramer of alpha and beta subunits (alpha2, beta2)
• The E2 transacylase, which is a homo-24-mer
• The E3 dehydrogenase, which is a homodimer
• Twelve E1 components
• Six E3 components
• A single kinase
## Chapter Notes
D Holmes Morton, MD; Clinic for Special Children (2006-2020)Erik G Puffenberger, PhD (2006-present)Kevin A Strauss, MD (2006-present)Vincent J Carson, MD (2020-present)
23 April 2020 (ma) Comprehensive update posted live
9 May 2013 (me) Comprehensive update posted live
15 December 2009 (me) Comprehensive update posted live
30 January 2006 (me) Review posted live
22 November 2004 (ep) Original submission
• 23 April 2020 (ma) Comprehensive update posted live
• 9 May 2013 (me) Comprehensive update posted live
• 15 December 2009 (me) Comprehensive update posted live
• 30 January 2006 (me) Review posted live
• 22 November 2004 (ep) Original submission
## Author History
D Holmes Morton, MD; Clinic for Special Children (2006-2020)Erik G Puffenberger, PhD (2006-present)Kevin A Strauss, MD (2006-present)Vincent J Carson, MD (2020-present)
## Revision History
23 April 2020 (ma) Comprehensive update posted live
9 May 2013 (me) Comprehensive update posted live
15 December 2009 (me) Comprehensive update posted live
30 January 2006 (me) Review posted live
22 November 2004 (ep) Original submission
• 23 April 2020 (ma) Comprehensive update posted live
• 9 May 2013 (me) Comprehensive update posted live
• 15 December 2009 (me) Comprehensive update posted live
• 30 January 2006 (me) Review posted live
• 22 November 2004 (ep) Original submission
## References
Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A, Singh RH. Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Available
Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, Morton DH. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Available
Strauss KA, Wardley B, Robinson D, Hendrickson C, Rider NL, Puffenberger EG, Shellmer D, Moser AB, Morton DH. Classical maple syrup urine disease and brain development: principles of management and formula design. Mol Genet Metab. 99:333-45. Available
• Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A, Singh RH. Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Available
• Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, Morton DH. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Available
• Strauss KA, Wardley B, Robinson D, Hendrickson C, Rider NL, Puffenberger EG, Shellmer D, Moser AB, Morton DH. Classical maple syrup urine disease and brain development: principles of management and formula design. Mol Genet Metab. 99:333-45. Available
## Published Guidelines / Consensus Statements
Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A, Singh RH. Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Available
Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, Morton DH. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Available
Strauss KA, Wardley B, Robinson D, Hendrickson C, Rider NL, Puffenberger EG, Shellmer D, Moser AB, Morton DH. Classical maple syrup urine disease and brain development: principles of management and formula design. Mol Genet Metab. 99:333-45. Available
• Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A, Singh RH. Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Available
• Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, Morton DH. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Available
• Strauss KA, Wardley B, Robinson D, Hendrickson C, Rider NL, Puffenberger EG, Shellmer D, Moser AB, Morton DH. Classical maple syrup urine disease and brain development: principles of management and formula design. Mol Genet Metab. 99:333-45. Available
## Literature Cited
Serial plasma leucine measurements over a 62-day NICU course in a Mennonite newborn with trisomy 21 and classic MSUD. Plasma leucine levels rise predictably as a result of net protein catabolism provoked by a variety of physiologic stresses, including intravenous line sepsis, congestive heart failure, and ventricular septal defect repair. Each catabolic illness is treated with parenteral MSUD solution, high calorie intake, and supplemental isoleucine and valine to restore the anabolic state.
Republished with permission from
A. Coronal T
B. Comparable coronal slice from a healthy age-matched individual
C. Comparable axial CT image of the brain of an individual with MSUD during crisis. Note indices of cerebral edema: apposition of cerebral tissue to the inner skull table, decreased volume of cerebral ventricles and basal fluid spaces, and reduced gray-white discrimination.
D. Comparable axial CT image of a normal brain
|
[] |
30/1/2006
|
23/4/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
msx2
|
msx2
|
[
"Symmetric Parietal Foramina",
"Symmetric Parietal Foramina",
"Homeobox protein aristaless-like 4",
"Homeobox protein MSX-2",
"ALX4",
"MSX2",
"Enlarged Parietal Foramina"
] |
Enlarged Parietal Foramina
|
Lampros A Mavrogiannis, Andrew OM Wilkie
|
Summary Enlarged parietal foramina are characteristic symmetric, paired radiolucencies of the parietal bones, located close to the intersection of the sagittal and lambdoid sutures, caused by deficient ossification around the parietal notch. Enlarged parietal foramina are usually asymptomatic. Meningeal, cortical, and vascular malformations of the posterior fossa occasionally accompany the bone defects and may predispose to epilepsy. In a minority of individuals, headaches, vomiting, or intense local pain are sometimes associated with the defects, especially on application of mild pressure to the unprotected cerebral cortex. The diagnosis of enlarged parietal foramina is established in a proband with characteristic clinical and imaging findings and a heterozygous pathogenic variant in Enlarged parietal foramina are inherited in an autosomal dominant manner. Most individuals diagnosed with enlarged parietal foramina have an affected parent. The proportion of individuals with enlarged parietal foramina caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for enlarged parietal foramina have been published. In practice, confounding with minute parietal foramina, which are normal anatomic variations, is very unlikely given the size, location, and natural history of the defects, as well as the positive family history.
Enlarged parietal foramina
The diagnosis of enlarged parietal foramina
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and imaging findings suggest the diagnosis of enlarged parietal foramina, a
For an introduction to multigene panels click
When the diagnosis of enlarged parietal foramina is not considered because an individual has atypical clinical and/or imaging findings,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Enlarged Parietal Foramina
NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Excluding syndromic cases, sequence-level changes comprise the majority of pathogenic variants [
Very limited evidence from a single source for additional genetic heterogeneity exists (OMIM
## Suggestive Findings
Enlarged parietal foramina
## Establishing the Diagnosis
The diagnosis of enlarged parietal foramina
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and imaging findings suggest the diagnosis of enlarged parietal foramina, a
For an introduction to multigene panels click
When the diagnosis of enlarged parietal foramina is not considered because an individual has atypical clinical and/or imaging findings,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Enlarged Parietal Foramina
NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Excluding syndromic cases, sequence-level changes comprise the majority of pathogenic variants [
Very limited evidence from a single source for additional genetic heterogeneity exists (OMIM
## Option 1
When the phenotypic and imaging findings suggest the diagnosis of enlarged parietal foramina, a
For an introduction to multigene panels click
## Option 2
When the diagnosis of enlarged parietal foramina is not considered because an individual has atypical clinical and/or imaging findings,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Enlarged Parietal Foramina
NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Excluding syndromic cases, sequence-level changes comprise the majority of pathogenic variants [
Very limited evidence from a single source for additional genetic heterogeneity exists (OMIM
## Clinical Characteristics
Isolated enlarged parietal foramina caused by a heterozygous
Cranium bifidum tends to resolve into distinct enlarged parietal foramina over the first few years of life through the midline ossification of a central bridge of bone bisecting the defect [
Meningeal, cortical, and vascular malformations of the posterior fossa occasionally accompany the bone defects and may predispose to epilepsy [
In a minority of individuals, headaches, vomiting, or intense local pain are sometimes associated with the defects, especially on application of mild pressure to the unprotected cerebral cortex [
Scalp defects have been reported [
A risk from direct trauma exists and skull fracture has been reported [
Features of the frontonasal dysplasia spectrum, ranging from almost inconspicuous to clearly apparent, may manifest in individuals with heterozygous
With respect to the skull defects, no significant phenotypic differences exist between enlarged parietal foramina caused by
Penetrance for
Enlarged parietal foramina have been referred to using the obsolete eponymous label "Catlin mark." Other terms that may be encountered are "foramina parietalia permagna," "fenestrae parietales symmetricae," and "giant parietal foramina."
The prevalence of enlarged parietal foramina is in the range of 1:15,000 to 1:50,000 according to old surveys [
## Clinical Description
Isolated enlarged parietal foramina caused by a heterozygous
Cranium bifidum tends to resolve into distinct enlarged parietal foramina over the first few years of life through the midline ossification of a central bridge of bone bisecting the defect [
Meningeal, cortical, and vascular malformations of the posterior fossa occasionally accompany the bone defects and may predispose to epilepsy [
In a minority of individuals, headaches, vomiting, or intense local pain are sometimes associated with the defects, especially on application of mild pressure to the unprotected cerebral cortex [
Scalp defects have been reported [
A risk from direct trauma exists and skull fracture has been reported [
Features of the frontonasal dysplasia spectrum, ranging from almost inconspicuous to clearly apparent, may manifest in individuals with heterozygous
## Phenotype Correlations by Gene
With respect to the skull defects, no significant phenotypic differences exist between enlarged parietal foramina caused by
## Genotype-Phenotype Correlations
## Penetrance
Penetrance for
## Nomenclature
Enlarged parietal foramina have been referred to using the obsolete eponymous label "Catlin mark." Other terms that may be encountered are "foramina parietalia permagna," "fenestrae parietales symmetricae," and "giant parietal foramina."
## Prevalence
The prevalence of enlarged parietal foramina is in the range of 1:15,000 to 1:50,000 according to old surveys [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Allelic Disorders
Median facial malformations of frontonasal dysplasia type w/enlarged parietal foramina
Craniosynostosis, alopecia, cryptorchidism, brain abnormalities, intellectual disability
Typically associated w/biallelic pathogenic variants; has been reported predominantly in consanguineous families.
Enlarged parietal foramina
Hypoplastic clavicles
Reported in a single family
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
• Median facial malformations of frontonasal dysplasia type w/enlarged parietal foramina
• Craniosynostosis, alopecia, cryptorchidism, brain abnormalities, intellectual disability
• Typically associated w/biallelic pathogenic variants; has been reported predominantly in consanguineous families.
• Enlarged parietal foramina
• Hypoplastic clavicles
• Reported in a single family
## Differential Diagnosis
Isolated enlarged parietal foramina need to be distinguished from syndromic associations, including those described in
Syndromes with Enlarged Parietal Foramina to Consider in the Differential Diagnosis of Isolated Enlarged Parietal Foramina
Craniosynostosis, predominantly coronal synostosis
Wide fontanelles & enlarged parietal foramina
Hypoplasia of clavicles
Imperforate anus.
Genitourinary malformations
Skin eruptions
Craniosynostosis syndrome characterized by coronal synostosis, facial asymmetry, strabismus, ptosis, & distinctive appearance of ears
Syndactyly of digits 2 & 3 of hand variably present
Enlarged parietal foramina are less common manifestation
Gross defect of skull vault, frontonasal dysplasia, & facial dysostosis
Dominant-negative
Craniosynostosis, usually affecting coronal sutures
Intellectual disability
Bony defects of metopic, sagittal, or lambdoid sutures & enlarged parietal foramina
Severe frontonasal dysplasia
Cranium bifidum / enlarged parietal foramina
Brain abnormalities & intellectual disability
Limb defects
Cryptorchidism in males
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Overlap may be observed between the mild end of the
• Craniosynostosis, predominantly coronal synostosis
• Wide fontanelles & enlarged parietal foramina
• Hypoplasia of clavicles
• Imperforate anus.
• Genitourinary malformations
• Skin eruptions
• Craniosynostosis syndrome characterized by coronal synostosis, facial asymmetry, strabismus, ptosis, & distinctive appearance of ears
• Syndactyly of digits 2 & 3 of hand variably present
• Enlarged parietal foramina are less common manifestation
• Gross defect of skull vault, frontonasal dysplasia, & facial dysostosis
• Dominant-negative
• Craniosynostosis, usually affecting coronal sutures
• Intellectual disability
• Bony defects of metopic, sagittal, or lambdoid sutures & enlarged parietal foramina
• Severe frontonasal dysplasia
• Cranium bifidum / enlarged parietal foramina
• Brain abnormalities & intellectual disability
• Limb defects
• Cryptorchidism in males
## Management
No clinical practice guidelines for enlarged parietal foramina have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder, together with review of the literature.
To establish the extent of disease and needs of an individual diagnosed with enlarged parietal foramina, the evaluations summarized in
Enlarged Parietal Foramina: Recommended Evaluations Following Initial Diagnosis
Skull radiographs
Skull 3D CT w/bone windows
Assess for seizures.
Brain imaging using CT or MRI as needed to assess for meningeal, cortical, & vascular malformations of posterior fossa
MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Enlarged Parietal Foramina: Treatment of Manifestations
Mgmt is generally conservative.
Note: When large skull defects are identified prenatally, consideration should be given to planning of delivery (e.g., review of indications to use scalp electrodes, forceps, &/or vacuum extraction). Elective cesarean section may ↓ theoretic risk for traumatic birth injury.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
ASM = anti-seizure medication
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Enlarged Parietal Foramina: Recommended Surveillance
Contact sports should be avoided if a midline bony defect persists.
See
Search
• Skull radiographs
• Skull 3D CT w/bone windows
• Assess for seizures.
• Brain imaging using CT or MRI as needed to assess for meningeal, cortical, & vascular malformations of posterior fossa
• Mgmt is generally conservative.
• Note: When large skull defects are identified prenatally, consideration should be given to planning of delivery (e.g., review of indications to use scalp electrodes, forceps, &/or vacuum extraction). Elective cesarean section may ↓ theoretic risk for traumatic birth injury.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with enlarged parietal foramina, the evaluations summarized in
Enlarged Parietal Foramina: Recommended Evaluations Following Initial Diagnosis
Skull radiographs
Skull 3D CT w/bone windows
Assess for seizures.
Brain imaging using CT or MRI as needed to assess for meningeal, cortical, & vascular malformations of posterior fossa
MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Skull radiographs
• Skull 3D CT w/bone windows
• Assess for seizures.
• Brain imaging using CT or MRI as needed to assess for meningeal, cortical, & vascular malformations of posterior fossa
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Enlarged Parietal Foramina: Treatment of Manifestations
Mgmt is generally conservative.
Note: When large skull defects are identified prenatally, consideration should be given to planning of delivery (e.g., review of indications to use scalp electrodes, forceps, &/or vacuum extraction). Elective cesarean section may ↓ theoretic risk for traumatic birth injury.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
ASM = anti-seizure medication
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
• Mgmt is generally conservative.
• Note: When large skull defects are identified prenatally, consideration should be given to planning of delivery (e.g., review of indications to use scalp electrodes, forceps, &/or vacuum extraction). Elective cesarean section may ↓ theoretic risk for traumatic birth injury.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Enlarged Parietal Foramina: Recommended Surveillance
## Agents/Circumstances to Avoid
Contact sports should be avoided if a midline bony defect persists.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Isolated enlarged parietal foramina are inherited in an autosomal dominant manner.
Most individuals diagnosed with enlarged parietal foramina have an affected parent.
Some individuals diagnosed with enlarged parietal foramina may have the disorder as the result of a
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or reduced, age-related penetrance. Therefore,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
Recommendations for the evaluation of parents of a proband may also include physical examination and skull radiography.
If a parent of the proband is affected and/or is known to have the
If the proband has a known
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for enlarged parietal foramina because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
When enlarged parietal foramina are ascertained in families with a background of consanguinity or endogamy, the risk for severe multiple malformations from homozygous
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with enlarged parietal foramina have an affected parent.
• Some individuals diagnosed with enlarged parietal foramina may have the disorder as the result of a
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or reduced, age-related penetrance. Therefore,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• Recommendations for the evaluation of parents of a proband may also include physical examination and skull radiography.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or is known to have the
• If the proband has a known
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for enlarged parietal foramina because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• When enlarged parietal foramina are ascertained in families with a background of consanguinity or endogamy, the risk for severe multiple malformations from homozygous
## Mode of Inheritance
Isolated enlarged parietal foramina are inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with enlarged parietal foramina have an affected parent.
Some individuals diagnosed with enlarged parietal foramina may have the disorder as the result of a
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or reduced, age-related penetrance. Therefore,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
Recommendations for the evaluation of parents of a proband may also include physical examination and skull radiography.
If a parent of the proband is affected and/or is known to have the
If the proband has a known
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for enlarged parietal foramina because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
• Most individuals diagnosed with enlarged parietal foramina have an affected parent.
• Some individuals diagnosed with enlarged parietal foramina may have the disorder as the result of a
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or reduced, age-related penetrance. Therefore,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• Recommendations for the evaluation of parents of a proband may also include physical examination and skull radiography.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or is known to have the
• If the proband has a known
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for enlarged parietal foramina because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
When enlarged parietal foramina are ascertained in families with a background of consanguinity or endogamy, the risk for severe multiple malformations from homozygous
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• When enlarged parietal foramina are ascertained in families with a background of consanguinity or endogamy, the risk for severe multiple malformations from homozygous
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
Enlarged Parietal Foramina: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Enlarged Parietal Foramina (
## Molecular Pathogenesis
## Chapter Notes
Prof Andrew Wilkie (
We are grateful to Tracy Lester and Helen Lord at the Oxford Medical Genetics Laboratories for collating and providing clinical testing service data.
26 June 2025 (sw) Comprehensive update posted live
27 November 2019 (bp) Comprehensive update posted live
8 November 2012 (me) Comprehensive update posted live
30 March 2010 (me) Comprehensive update posted live
25 May 2006 (me) Comprehensive update posted live
30 March 2004 (ca/me) Review posted live
13 January 2004 (aw) Original submission
• 26 June 2025 (sw) Comprehensive update posted live
• 27 November 2019 (bp) Comprehensive update posted live
• 8 November 2012 (me) Comprehensive update posted live
• 30 March 2010 (me) Comprehensive update posted live
• 25 May 2006 (me) Comprehensive update posted live
• 30 March 2004 (ca/me) Review posted live
• 13 January 2004 (aw) Original submission
## Author Notes
Prof Andrew Wilkie (
## Acknowledgments
We are grateful to Tracy Lester and Helen Lord at the Oxford Medical Genetics Laboratories for collating and providing clinical testing service data.
## Revision History
26 June 2025 (sw) Comprehensive update posted live
27 November 2019 (bp) Comprehensive update posted live
8 November 2012 (me) Comprehensive update posted live
30 March 2010 (me) Comprehensive update posted live
25 May 2006 (me) Comprehensive update posted live
30 March 2004 (ca/me) Review posted live
13 January 2004 (aw) Original submission
• 26 June 2025 (sw) Comprehensive update posted live
• 27 November 2019 (bp) Comprehensive update posted live
• 8 November 2012 (me) Comprehensive update posted live
• 30 March 2010 (me) Comprehensive update posted live
• 25 May 2006 (me) Comprehensive update posted live
• 30 March 2004 (ca/me) Review posted live
• 13 January 2004 (aw) Original submission
## References
## Literature Cited
|
[] |
30/3/2004
|
26/6/2025
|
26/5/2004
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
mt-deafness
|
mt-deafness
|
[
"Not applicable",
"MT-RNR1",
"MT-TS1",
"Nonsyndromic Hearing Loss and Deafness, Mitochondrial"
] |
Nonsyndromic Hearing Loss and Deafness, Mitochondrial
|
Shin-ichi Usami, Shin-ya Nishio
|
Summary Mitochondrial nonsyndromic hearing loss and deafness is characterized by sensorineural hearing loss (SNHL) of variable onset and severity. Pathogenic variants in Pathogenic variants in The diagnosis of mitochondrial nonsyndromic hearing loss and deafness is established in a proband with hearing loss and identification of a pathogenic variant in Mitochondrial nonsyndromic hearing loss and deafness is caused by pathogenic variants in mitochondrial DNA (mtDNA) and is transmitted by maternal inheritance. The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have hearing loss. All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the mtDNA pathogenic variant in the family is known. Because of mitotic segregation, the mtDNA pathogenic variant load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues. Furthermore, the presence of the mtDNA pathogenic variant does not predict the age of onset or severity of hearing loss.
|
## Diagnosis
Mitochondrial nonsyndromic hearing loss and deafness
Moderate-to-profound hearing loss
Hearing loss graded by level of severity:
Mild (26-40 dB)
Moderate (41-55 dB)
Moderately severe (56-70 dB)
Severe (71-90 dB)
Profound (90 dB)
Hearing is assessed by a variety of methods; see
Mild-to-moderate high-frequency hearing loss
No other systemic findings on history or physical examination
A family history of hearing loss suggestive of maternal inheritance (i.e., no transmission through a male)
Onset of hearing loss following administration of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin
The diagnosis of mitochondrial nonsyndromic hearing loss and deafness
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetics of Mitochondrial Nonsyndromic Hearing Loss and Deafness: Most Common Genetic Causes
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Molecular Genetics of Mitochondrial Nonsyndromic Hearing Loss and Deafness: Less Common Genetic Causes
Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <1% of mitochondrial nonsyndromic hearing loss and deafness).
See
Mitochondrial gene variants for nonsyndromic deafness and hearing loss in this table are limited to variants classified as "Confirmed" or "Reported" in the
• Moderate-to-profound hearing loss
• Hearing loss graded by level of severity:
• Mild (26-40 dB)
• Moderate (41-55 dB)
• Moderately severe (56-70 dB)
• Severe (71-90 dB)
• Profound (90 dB)
• Hearing is assessed by a variety of methods; see
• Mild (26-40 dB)
• Moderate (41-55 dB)
• Moderately severe (56-70 dB)
• Severe (71-90 dB)
• Profound (90 dB)
• Mild-to-moderate high-frequency hearing loss
• No other systemic findings on history or physical examination
• A family history of hearing loss suggestive of maternal inheritance (i.e., no transmission through a male)
• Onset of hearing loss following administration of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin
• Mild (26-40 dB)
• Moderate (41-55 dB)
• Moderately severe (56-70 dB)
• Severe (71-90 dB)
• Profound (90 dB)
• For an introduction to multigene panels click
## Suggestive Findings
Mitochondrial nonsyndromic hearing loss and deafness
Moderate-to-profound hearing loss
Hearing loss graded by level of severity:
Mild (26-40 dB)
Moderate (41-55 dB)
Moderately severe (56-70 dB)
Severe (71-90 dB)
Profound (90 dB)
Hearing is assessed by a variety of methods; see
Mild-to-moderate high-frequency hearing loss
No other systemic findings on history or physical examination
A family history of hearing loss suggestive of maternal inheritance (i.e., no transmission through a male)
Onset of hearing loss following administration of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin
• Moderate-to-profound hearing loss
• Hearing loss graded by level of severity:
• Mild (26-40 dB)
• Moderate (41-55 dB)
• Moderately severe (56-70 dB)
• Severe (71-90 dB)
• Profound (90 dB)
• Hearing is assessed by a variety of methods; see
• Mild (26-40 dB)
• Moderate (41-55 dB)
• Moderately severe (56-70 dB)
• Severe (71-90 dB)
• Profound (90 dB)
• Mild-to-moderate high-frequency hearing loss
• No other systemic findings on history or physical examination
• A family history of hearing loss suggestive of maternal inheritance (i.e., no transmission through a male)
• Onset of hearing loss following administration of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin
• Mild (26-40 dB)
• Moderate (41-55 dB)
• Moderately severe (56-70 dB)
• Severe (71-90 dB)
• Profound (90 dB)
## Establishing the Diagnosis
The diagnosis of mitochondrial nonsyndromic hearing loss and deafness
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetics of Mitochondrial Nonsyndromic Hearing Loss and Deafness: Most Common Genetic Causes
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Molecular Genetics of Mitochondrial Nonsyndromic Hearing Loss and Deafness: Less Common Genetic Causes
Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <1% of mitochondrial nonsyndromic hearing loss and deafness).
See
Mitochondrial gene variants for nonsyndromic deafness and hearing loss in this table are limited to variants classified as "Confirmed" or "Reported" in the
• For an introduction to multigene panels click
## Clinical Characteristics
Hearing loss is bilateral and severe to profound [
Aminoglycoside ototoxicity secondary to the presence of a predisposing mtDNA pathogenic variant appears to be related to the administration of aminoglycosides (independent of dose) in contrast to "dose-related" aminoglycoside ototoxicity, which is related to the dose and/or plasma concentration of aminoglycosides in individuals who do not have a predisposing mtDNA pathogenic variant.
Vestibular symptoms are uncommon [
The severity, onset age, and audiometric configuration of
Many individuals with progressive hearing loss commonly experience episodes of tinnitus, but vestibular symptoms are rare in these individuals. A small percentage of individuals with the
Onset of SNHL caused by the
The
The
In addition, this pathogenic variant was co-identified with
See
Most
The penetrance for hearing loss in individuals with the
The averaged penetrance of eight Chinese families harboring the
Variants
Note: It has been suggested that penetrance for hearing loss is lower in some families from China [
The prevalence of mitochondrial nonsyndromic hearing loss and deafness has been well studied for
In a prospective study in the Tianjin Province in China in which 58,000 newborns were screened with both audiologic and genetic methods,
The prevalence of the
Prevalence of
0.14%-0.7% of general population
1.9%-11% of persons w/NSHL
1.4% of persons w/early-onset HL
2% of persons w/late-onset HL
4.3% of maternally inherited HL
2/703 (0.3%) neonates in the NICU
3/1,473 (0.2%) general population
0.8% of individuals w/adult-onset HL
0.3%-0.9% of persons w/NSHL
HL = hearing loss; LBW = low birth weight; NICU = neonatal intensive care unit; NSHL = nonsyndromic hearing loss
The prevalence of
Prevalence of
0.014%, 0.029%, & 0.25% of general population
0.18%-0.64% of persons w/HL
HL = hearing loss
The prevalence of the
The prevalence of pathogenic variant
The prevalence of
• Most
• The penetrance for hearing loss in individuals with the
• The averaged penetrance of eight Chinese families harboring the
• Variants
• 0.14%-0.7% of general population
• 1.9%-11% of persons w/NSHL
• 1.4% of persons w/early-onset HL
• 2% of persons w/late-onset HL
• 4.3% of maternally inherited HL
• 2/703 (0.3%) neonates in the NICU
• 3/1,473 (0.2%) general population
• 0.8% of individuals w/adult-onset HL
• 0.3%-0.9% of persons w/NSHL
• 0.014%, 0.029%, & 0.25% of general population
• 0.18%-0.64% of persons w/HL
## Clinical Description
Hearing loss is bilateral and severe to profound [
Aminoglycoside ototoxicity secondary to the presence of a predisposing mtDNA pathogenic variant appears to be related to the administration of aminoglycosides (independent of dose) in contrast to "dose-related" aminoglycoside ototoxicity, which is related to the dose and/or plasma concentration of aminoglycosides in individuals who do not have a predisposing mtDNA pathogenic variant.
Vestibular symptoms are uncommon [
The severity, onset age, and audiometric configuration of
Many individuals with progressive hearing loss commonly experience episodes of tinnitus, but vestibular symptoms are rare in these individuals. A small percentage of individuals with the
Onset of SNHL caused by the
The
The
In addition, this pathogenic variant was co-identified with
Hearing loss is bilateral and severe to profound [
Aminoglycoside ototoxicity secondary to the presence of a predisposing mtDNA pathogenic variant appears to be related to the administration of aminoglycosides (independent of dose) in contrast to "dose-related" aminoglycoside ototoxicity, which is related to the dose and/or plasma concentration of aminoglycosides in individuals who do not have a predisposing mtDNA pathogenic variant.
Vestibular symptoms are uncommon [
The severity, onset age, and audiometric configuration of
Many individuals with progressive hearing loss commonly experience episodes of tinnitus, but vestibular symptoms are rare in these individuals. A small percentage of individuals with the
Onset of SNHL caused by the
The
## Other Forms of Mitochondrial Gene-Related Hearing Loss
The
In addition, this pathogenic variant was co-identified with
## Phenotype Correlations by Gene
See
## Genotype-Phenotype Correlations
## Penetrance
Most
The penetrance for hearing loss in individuals with the
The averaged penetrance of eight Chinese families harboring the
Variants
Note: It has been suggested that penetrance for hearing loss is lower in some families from China [
• Most
• The penetrance for hearing loss in individuals with the
• The averaged penetrance of eight Chinese families harboring the
• Variants
## Prevalence
The prevalence of mitochondrial nonsyndromic hearing loss and deafness has been well studied for
In a prospective study in the Tianjin Province in China in which 58,000 newborns were screened with both audiologic and genetic methods,
The prevalence of the
Prevalence of
0.14%-0.7% of general population
1.9%-11% of persons w/NSHL
1.4% of persons w/early-onset HL
2% of persons w/late-onset HL
4.3% of maternally inherited HL
2/703 (0.3%) neonates in the NICU
3/1,473 (0.2%) general population
0.8% of individuals w/adult-onset HL
0.3%-0.9% of persons w/NSHL
HL = hearing loss; LBW = low birth weight; NICU = neonatal intensive care unit; NSHL = nonsyndromic hearing loss
The prevalence of
Prevalence of
0.014%, 0.029%, & 0.25% of general population
0.18%-0.64% of persons w/HL
HL = hearing loss
The prevalence of the
The prevalence of pathogenic variant
The prevalence of
• 0.14%-0.7% of general population
• 1.9%-11% of persons w/NSHL
• 1.4% of persons w/early-onset HL
• 2% of persons w/late-onset HL
• 4.3% of maternally inherited HL
• 2/703 (0.3%) neonates in the NICU
• 3/1,473 (0.2%) general population
• 0.8% of individuals w/adult-onset HL
• 0.3%-0.9% of persons w/NSHL
• 0.014%, 0.029%, & 0.25% of general population
• 0.18%-0.64% of persons w/HL
## Genetically Related (Allelic) Disorders
Mitochondrial DNA pathogenic variants are responsible for a heterogeneous group of inherited diseases (see
## Differential Diagnosis
Other genetic causes of nonsyndromic hearing loss and deafness need to be considered (see
Maternally inherited diabetes mellitus and deafness (MIDD) is also caused by the
## Management
To establish the extent of hearing loss and needs in an individual diagnosed with mitochondrial nonsyndromic hearing loss and deafness, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Complete auditory assessment (See
Examination of the skin for evidence of keratoderma
Consultation with a clinical geneticist and/or genetic counselor
Treatment includes the following:
Appropriate rehabilitation including hearing aids, speech therapy, culturally appropriate language training, and evaluation for eligibility for cochlear implantation [
Electric acoustic stimulation (EAS) for individuals with mitochondrial hearing loss with residual hearing in the lower frequencies [
Enrollment in educational programs appropriate for the hearing impaired
For mild keratoderma, use of lotions and emollients; for severe keratoderma, dermatologic evaluation
In the US, aminoglycoside use is most common in the neonatal intensive care unit; however, the therapeutic imperative of treatment with antibiotics in a neonatal intensive care unit setting does not always lend itself to pre-treatment screening by molecular genetic testing.
In a commentary by
In the Tianjin Province in China, screening of 58,000 newborns by audiometry and molecular genetic testing determined that 1.8% of newborns had a pathogenic mitochondrial DNA variant and only one newborn had hearing loss [
The following are appropriate:
Annual audiometric assessment to evaluate stability or progression of hearing loss
Annual examination by a physician to assess for related clinical findings (e.g., palmoplantar keratosis)
Aminoglycosides and noise exposure should be avoided, particularly in individuals with normal hearing who have the
In a family in which the mtDNA pathogenic variant is known, prospective molecular genetic testing of at-risk maternal relatives allows early detection of those who have inherited the mtDNA pathogenic variant and would benefit from:
Avoiding aminoglycosides to prevent onset of hearing loss
Appropriate early support and management
See
Use of aminoglycoside antibiotics during pregnancy in a mother who has the
Of note, if the mother has the
Search
• Complete auditory assessment (See
• Examination of the skin for evidence of keratoderma
• Consultation with a clinical geneticist and/or genetic counselor
• Appropriate rehabilitation including hearing aids, speech therapy, culturally appropriate language training, and evaluation for eligibility for cochlear implantation [
• Electric acoustic stimulation (EAS) for individuals with mitochondrial hearing loss with residual hearing in the lower frequencies [
• Enrollment in educational programs appropriate for the hearing impaired
• For mild keratoderma, use of lotions and emollients; for severe keratoderma, dermatologic evaluation
• In a commentary by
• In the Tianjin Province in China, screening of 58,000 newborns by audiometry and molecular genetic testing determined that 1.8% of newborns had a pathogenic mitochondrial DNA variant and only one newborn had hearing loss [
• Annual audiometric assessment to evaluate stability or progression of hearing loss
• Annual examination by a physician to assess for related clinical findings (e.g., palmoplantar keratosis)
• Avoiding aminoglycosides to prevent onset of hearing loss
• Appropriate early support and management
## Evaluations Following Initial Diagnosis
To establish the extent of hearing loss and needs in an individual diagnosed with mitochondrial nonsyndromic hearing loss and deafness, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Complete auditory assessment (See
Examination of the skin for evidence of keratoderma
Consultation with a clinical geneticist and/or genetic counselor
• Complete auditory assessment (See
• Examination of the skin for evidence of keratoderma
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Treatment includes the following:
Appropriate rehabilitation including hearing aids, speech therapy, culturally appropriate language training, and evaluation for eligibility for cochlear implantation [
Electric acoustic stimulation (EAS) for individuals with mitochondrial hearing loss with residual hearing in the lower frequencies [
Enrollment in educational programs appropriate for the hearing impaired
For mild keratoderma, use of lotions and emollients; for severe keratoderma, dermatologic evaluation
• Appropriate rehabilitation including hearing aids, speech therapy, culturally appropriate language training, and evaluation for eligibility for cochlear implantation [
• Electric acoustic stimulation (EAS) for individuals with mitochondrial hearing loss with residual hearing in the lower frequencies [
• Enrollment in educational programs appropriate for the hearing impaired
• For mild keratoderma, use of lotions and emollients; for severe keratoderma, dermatologic evaluation
## Prevention of Primary Manifestations
In the US, aminoglycoside use is most common in the neonatal intensive care unit; however, the therapeutic imperative of treatment with antibiotics in a neonatal intensive care unit setting does not always lend itself to pre-treatment screening by molecular genetic testing.
In a commentary by
In the Tianjin Province in China, screening of 58,000 newborns by audiometry and molecular genetic testing determined that 1.8% of newborns had a pathogenic mitochondrial DNA variant and only one newborn had hearing loss [
• In a commentary by
• In the Tianjin Province in China, screening of 58,000 newborns by audiometry and molecular genetic testing determined that 1.8% of newborns had a pathogenic mitochondrial DNA variant and only one newborn had hearing loss [
## Surveillance
The following are appropriate:
Annual audiometric assessment to evaluate stability or progression of hearing loss
Annual examination by a physician to assess for related clinical findings (e.g., palmoplantar keratosis)
• Annual audiometric assessment to evaluate stability or progression of hearing loss
• Annual examination by a physician to assess for related clinical findings (e.g., palmoplantar keratosis)
## Agents/Circumstances to Avoid
Aminoglycosides and noise exposure should be avoided, particularly in individuals with normal hearing who have the
## Evaluation of Relatives at Risk
In a family in which the mtDNA pathogenic variant is known, prospective molecular genetic testing of at-risk maternal relatives allows early detection of those who have inherited the mtDNA pathogenic variant and would benefit from:
Avoiding aminoglycosides to prevent onset of hearing loss
Appropriate early support and management
See
• Avoiding aminoglycosides to prevent onset of hearing loss
• Appropriate early support and management
## Pregnancy Management
Use of aminoglycoside antibiotics during pregnancy in a mother who has the
Of note, if the mother has the
## Therapies Under Investigation
Search
## Genetic Counseling
Mitochondrial nonsyndromic hearing loss and deafness is caused by pathogenic variants in mitochondrial DNA (mtDNA) and is transmitted by maternal inheritance.
The father of a proband is not at risk of having the mtDNA pathogenic variant.
The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have hearing loss.
Up to 85% of individuals with mitochondrial nonsyndromic hearing loss have no known family history of hearing loss. The explanation for apparently simplex cases may be the absence of a comprehensive and/or reliable family history or, in rare cases, a
The risk to the sibs depends on the genetic load of the mitochondrial pathogenic variant in the mother (e.g., a mother heteroplasmic for a mtDNA pathogenic variant may transmit a low level of mutated mtDNA to her offspring, thus conferring a lower disease risk than a mother homoplasmic for a mtDNA pathogenic variant).
If the mother has the mtDNA pathogenic variant, all sibs will inherit the variant; however, the risk of hearing loss depends on (a) the mutational load (see
All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant.
Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant.
See Management,
Many culturally deaf individuals view medical advances in hearing loss as a threat to the existence of their culture; it is important to acknowledge this point of view. The counseling session provides an opportunity to educate the individual regarding the etiology and natural history of the hearing loss and to discuss appropriate resources for services and information; such counseling is generally well received. Issues of prevention, cochlear implants, reproduction, and family planning should be dealt with in a culturally sensitive manner [
The following points are noteworthy:
Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter.
Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented."
Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning.
The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided.
The optimal time for the determination of genetic status and discussion of prenatal testing availability is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are deaf or have a family history of deafness.
Once a mtDNA nonsyndromic hearing loss and deafness-causing variant has been identified in the mother, prenatal testing is possible; however, it is typically not performed.
If the mother is homoplasmic for a pathogenic variant, genetic testing is not needed to predict that the fetus inherited the variant (based on the maternally inherited pattern); therefore, the results of prenatal testing for mitochondrial nonsyndromic hearing loss and deafness do not provide additional information.
If the mtDNA pathogenic variant is identified in the fetal tissue sampled:
The mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues because of mitotic segregation.
The presence of the mtDNA pathogenic variant does not predict the occurrence, age of onset, or severity of hearing loss.
If the mtDNA variant is not identified in the fetal tissue sampled, the pathogenic variant is likely present in fetal tissue not sampled.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of a proband is not at risk of having the mtDNA pathogenic variant.
• The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have hearing loss.
• Up to 85% of individuals with mitochondrial nonsyndromic hearing loss have no known family history of hearing loss. The explanation for apparently simplex cases may be the absence of a comprehensive and/or reliable family history or, in rare cases, a
• The risk to the sibs depends on the genetic load of the mitochondrial pathogenic variant in the mother (e.g., a mother heteroplasmic for a mtDNA pathogenic variant may transmit a low level of mutated mtDNA to her offspring, thus conferring a lower disease risk than a mother homoplasmic for a mtDNA pathogenic variant).
• If the mother has the mtDNA pathogenic variant, all sibs will inherit the variant; however, the risk of hearing loss depends on (a) the mutational load (see
• All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant.
• Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant.
• Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter.
• Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented."
• Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning.
• The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided.
• The optimal time for the determination of genetic status and discussion of prenatal testing availability is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are deaf or have a family history of deafness.
• The mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues because of mitotic segregation.
• The presence of the mtDNA pathogenic variant does not predict the occurrence, age of onset, or severity of hearing loss.
## Mode of Inheritance
Mitochondrial nonsyndromic hearing loss and deafness is caused by pathogenic variants in mitochondrial DNA (mtDNA) and is transmitted by maternal inheritance.
## Risk to Family Members
The father of a proband is not at risk of having the mtDNA pathogenic variant.
The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have hearing loss.
Up to 85% of individuals with mitochondrial nonsyndromic hearing loss have no known family history of hearing loss. The explanation for apparently simplex cases may be the absence of a comprehensive and/or reliable family history or, in rare cases, a
The risk to the sibs depends on the genetic load of the mitochondrial pathogenic variant in the mother (e.g., a mother heteroplasmic for a mtDNA pathogenic variant may transmit a low level of mutated mtDNA to her offspring, thus conferring a lower disease risk than a mother homoplasmic for a mtDNA pathogenic variant).
If the mother has the mtDNA pathogenic variant, all sibs will inherit the variant; however, the risk of hearing loss depends on (a) the mutational load (see
All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant.
Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant.
• The father of a proband is not at risk of having the mtDNA pathogenic variant.
• The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have hearing loss.
• Up to 85% of individuals with mitochondrial nonsyndromic hearing loss have no known family history of hearing loss. The explanation for apparently simplex cases may be the absence of a comprehensive and/or reliable family history or, in rare cases, a
• The risk to the sibs depends on the genetic load of the mitochondrial pathogenic variant in the mother (e.g., a mother heteroplasmic for a mtDNA pathogenic variant may transmit a low level of mutated mtDNA to her offspring, thus conferring a lower disease risk than a mother homoplasmic for a mtDNA pathogenic variant).
• If the mother has the mtDNA pathogenic variant, all sibs will inherit the variant; however, the risk of hearing loss depends on (a) the mutational load (see
• All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant.
• Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant.
## Related Genetic Counseling Issues
See Management,
Many culturally deaf individuals view medical advances in hearing loss as a threat to the existence of their culture; it is important to acknowledge this point of view. The counseling session provides an opportunity to educate the individual regarding the etiology and natural history of the hearing loss and to discuss appropriate resources for services and information; such counseling is generally well received. Issues of prevention, cochlear implants, reproduction, and family planning should be dealt with in a culturally sensitive manner [
The following points are noteworthy:
Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter.
Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented."
Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning.
The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided.
The optimal time for the determination of genetic status and discussion of prenatal testing availability is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are deaf or have a family history of deafness.
• Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter.
• Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented."
• Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning.
• The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided.
• The optimal time for the determination of genetic status and discussion of prenatal testing availability is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are deaf or have a family history of deafness.
## Prenatal Testing
Once a mtDNA nonsyndromic hearing loss and deafness-causing variant has been identified in the mother, prenatal testing is possible; however, it is typically not performed.
If the mother is homoplasmic for a pathogenic variant, genetic testing is not needed to predict that the fetus inherited the variant (based on the maternally inherited pattern); therefore, the results of prenatal testing for mitochondrial nonsyndromic hearing loss and deafness do not provide additional information.
If the mtDNA pathogenic variant is identified in the fetal tissue sampled:
The mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues because of mitotic segregation.
The presence of the mtDNA pathogenic variant does not predict the occurrence, age of onset, or severity of hearing loss.
If the mtDNA variant is not identified in the fetal tissue sampled, the pathogenic variant is likely present in fetal tissue not sampled.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues because of mitotic segregation.
• The presence of the mtDNA pathogenic variant does not predict the occurrence, age of onset, or severity of hearing loss.
## Resources
Health Resources & Services Administration
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
• Health Resources & Services Administration
•
•
•
## Molecular Genetics
Nonsyndromic Hearing Loss and Deafness, Mitochondrial: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Nonsyndromic Hearing Loss and Deafness, Mitochondrial (
Variants
Variants listed in the table have been provided by the authors.
NA = not applicable.
Variant designation that does not conform to current naming conventions
Pathogenic variants m.1555A>G and m.1494C>T are located in the decoding center of the mitochondrial ribosome, and cause: (1) conformational change of stem-loop structure of aminoglycoside binding site of 12S rRNA similar to the bacterial type ribosome; (2) reduction of mitochondrial protein synthesis; and (3) mis-incorporation of amino acids with or without aminoglycoside exposure [
Many variants in
m.7445A>G [
m.7445A>C [
m.7445A>T [
m.7462C>T [
m.7471dupC (reported as m.7472insC) [
m.7505T>C [
m.7510T>C [
m.7511T>C [
These variants are identified as homoplasmic or heteroplasmic. (For details regarding heteroplasmy refer to
Variants listed in the table have been provided by the authors.
NA = not applicable
The two adjoining variants at positions m.7444 and m.7443 do not alter the cleavage or processing of the tRNA-Ser(UCN) in a similar fashion, therefore, they are unlikely to share this pathogenic mechanism. These three base pairs also encode the stop codon in MT-CO1 (mitochondrially encoded cytochrome
• m.7445A>G [
• m.7445A>C [
• m.7445A>T [
• m.7462C>T [
• m.7471dupC (reported as m.7472insC) [
• m.7505T>C [
• m.7510T>C [
• m.7511T>C [
## Chapter Notes
Shin-ya Nishio, PhD (2017-present)Arti Pandya, MD, MBA; Virginia Commonwealth University Health System (2004-2017)Shin-ichi Usami, MD, PhD (2017-present)
14 June 2018 (sw) Comprehensive update posted live
3 July 2014 (me) Comprehensive update posted live
21 April 2011 (me) Comprehensive update posted live
24 July 2007 (me) Comprehensive update posted live
22 October 2004 (me) Review posted live
13 August 2003 (ap) Original submission
• 14 June 2018 (sw) Comprehensive update posted live
• 3 July 2014 (me) Comprehensive update posted live
• 21 April 2011 (me) Comprehensive update posted live
• 24 July 2007 (me) Comprehensive update posted live
• 22 October 2004 (me) Review posted live
• 13 August 2003 (ap) Original submission
## Author History
Shin-ya Nishio, PhD (2017-present)Arti Pandya, MD, MBA; Virginia Commonwealth University Health System (2004-2017)Shin-ichi Usami, MD, PhD (2017-present)
## Revision History
14 June 2018 (sw) Comprehensive update posted live
3 July 2014 (me) Comprehensive update posted live
21 April 2011 (me) Comprehensive update posted live
24 July 2007 (me) Comprehensive update posted live
22 October 2004 (me) Review posted live
13 August 2003 (ap) Original submission
• 14 June 2018 (sw) Comprehensive update posted live
• 3 July 2014 (me) Comprehensive update posted live
• 21 April 2011 (me) Comprehensive update posted live
• 24 July 2007 (me) Comprehensive update posted live
• 22 October 2004 (me) Review posted live
• 13 August 2003 (ap) Original submission
## References
## Published Guidelines / Consensus Statements
## Literature Cited
|
[] |
22/10/2004
|
14/6/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mt-mpan
|
mt-mpan
|
[
"Neurodegeneration with Brain Iron Accumulation 4 (NBIA4)",
"Neurodegeneration with Brain Iron Accumulation 4 (NBIA4)",
"Protein C19orf12",
"C19orf12",
"Mitochondrial Membrane Protein-Associated Neurodegeneration"
] |
Mitochondrial Membrane Protein-Associated Neurodegeneration
|
Allison Gregory, Thomas Klopstock, Tomasz Kmiec, Penelope Hogarth, Susan J Hayflick
|
Summary Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia (which may be limited to the hands and feet or more generalized), neuropsychiatric abnormalities (emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity), and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence. Survival is usually well into adulthood. End-stage disease is characterized by severe dementia, spasticity, dystonia, and parkinsonism. The diagnosis of MPAN MPAN is inherited in an autosomal recessive or (less commonly) autosomal dominant manner. Once the
|
## Diagnosis
Mitochondrial membrane protein-associated neurodegeneration (MPAN)
Onset in childhood to early adulthood with slow progression and survival well into adulthood
Cognitive decline progressing to severe dementia
Prominent neuropsychiatric abnormalities including emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity
Optic atrophy
Dystonia, often of the hands and feet
Upper motor neuron signs (spasticity, hyperreflexia, Babinski sign)
Lower motor neuron signs (muscle weakness and atrophy, hyporeflexia, fasciculations)
Dysarthria
*Exceptions include (1) affected sisters homozygous for the pathogenic variant
Serial MRI studies show that iron accumulation and brain atrophy progress with the disease course.
On T
Generalized cortical atrophy and cerebellar atrophy [
T
Hydrocephalus has also been reported in one adult with MPAN and may be a rare finding [
Postmortem neuropathologic examination (see
The diagnosis of MPAN
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Onset in childhood to early adulthood with slow progression and survival well into adulthood
• Cognitive decline progressing to severe dementia
• Prominent neuropsychiatric abnormalities including emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity
• Optic atrophy
• Dystonia, often of the hands and feet
• Upper motor neuron signs (spasticity, hyperreflexia, Babinski sign)
• Lower motor neuron signs (muscle weakness and atrophy, hyporeflexia, fasciculations)
• Dysarthria
• Generalized cortical atrophy and cerebellar atrophy [
• T
• Hydrocephalus has also been reported in one adult with MPAN and may be a rare finding [
## Suggestive Findings
Mitochondrial membrane protein-associated neurodegeneration (MPAN)
Onset in childhood to early adulthood with slow progression and survival well into adulthood
Cognitive decline progressing to severe dementia
Prominent neuropsychiatric abnormalities including emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity
Optic atrophy
Dystonia, often of the hands and feet
Upper motor neuron signs (spasticity, hyperreflexia, Babinski sign)
Lower motor neuron signs (muscle weakness and atrophy, hyporeflexia, fasciculations)
Dysarthria
*Exceptions include (1) affected sisters homozygous for the pathogenic variant
Serial MRI studies show that iron accumulation and brain atrophy progress with the disease course.
On T
Generalized cortical atrophy and cerebellar atrophy [
T
Hydrocephalus has also been reported in one adult with MPAN and may be a rare finding [
Postmortem neuropathologic examination (see
• Onset in childhood to early adulthood with slow progression and survival well into adulthood
• Cognitive decline progressing to severe dementia
• Prominent neuropsychiatric abnormalities including emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity
• Optic atrophy
• Dystonia, often of the hands and feet
• Upper motor neuron signs (spasticity, hyperreflexia, Babinski sign)
• Lower motor neuron signs (muscle weakness and atrophy, hyporeflexia, fasciculations)
• Dysarthria
• Generalized cortical atrophy and cerebellar atrophy [
• T
• Hydrocephalus has also been reported in one adult with MPAN and may be a rare finding [
## Clinical findings
Onset in childhood to early adulthood with slow progression and survival well into adulthood
Cognitive decline progressing to severe dementia
Prominent neuropsychiatric abnormalities including emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity
Optic atrophy
Dystonia, often of the hands and feet
Upper motor neuron signs (spasticity, hyperreflexia, Babinski sign)
Lower motor neuron signs (muscle weakness and atrophy, hyporeflexia, fasciculations)
Dysarthria
• Onset in childhood to early adulthood with slow progression and survival well into adulthood
• Cognitive decline progressing to severe dementia
• Prominent neuropsychiatric abnormalities including emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity
• Optic atrophy
• Dystonia, often of the hands and feet
• Upper motor neuron signs (spasticity, hyperreflexia, Babinski sign)
• Lower motor neuron signs (muscle weakness and atrophy, hyporeflexia, fasciculations)
• Dysarthria
## Imaging findings
*Exceptions include (1) affected sisters homozygous for the pathogenic variant
Serial MRI studies show that iron accumulation and brain atrophy progress with the disease course.
On T
Generalized cortical atrophy and cerebellar atrophy [
T
Hydrocephalus has also been reported in one adult with MPAN and may be a rare finding [
• Generalized cortical atrophy and cerebellar atrophy [
• T
• Hydrocephalus has also been reported in one adult with MPAN and may be a rare finding [
## Neuropathology
Postmortem neuropathologic examination (see
## Establishing the Diagnosis
The diagnosis of MPAN
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia, neuropsychiatric abnormalities, and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence.
Onset of MPAN typically occurs in childhood (3-16 years, considered juvenile onset) to early adulthood (17-24 years, considered adult onset), but onset has been reported as late as age 55 years [
Individuals with MPAN learn to walk and are usually mobile into early adulthood [
Some individuals present with vision impairment associated with optic atrophy, which is more common in childhood-onset than adult-onset MPAN.
The progression of MPAN is usually slow with survival well into adulthood. However, rare individuals have had abrupt adult onset and rapid progression [
The terminal stages of MPAN are characterized by severe dementia, spasticity, dystonia, and parkinsonism. Affected individuals are no longer ambulatory; communication is limited due to dysarthria and cognitive decline. Weight loss and bowel and/or bladder incontinence are common. Persons with advanced disease may have stereotypic hand or head movements with alterations in consciousness that do not appear to be manifestations of seizures. Death typically occurs secondary to complications such as aspiration pneumonia.
Fewer than 200 affected individuals have been described to date; thus, the phenotypic spectrum of MPAN is likely to broaden as more affected individuals are described.
The phenotypes associated with autosomal recessive (AR) MPAN and autosomal dominant (AD) MPAN are indistinguishable [
Select Features of Mitochondrial Membrane Protein-Associated Neurodegeneration
LMN = lower motor neuron; UMN = upper motor neuron
The phenotypes of AR and AD MPAN are indistinguishable, both arising from loss of function of the C19orf12 protein.
The pathogenic variant
Note: Previous speculation that the variant
The prevalence of MPAN is roughly estimated at less than one in 1,000,000.
The prevalence may be higher in the Turkish population due to the
• The pathogenic variant
• Note: Previous speculation that the variant
## Clinical Description
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia, neuropsychiatric abnormalities, and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence.
Onset of MPAN typically occurs in childhood (3-16 years, considered juvenile onset) to early adulthood (17-24 years, considered adult onset), but onset has been reported as late as age 55 years [
Individuals with MPAN learn to walk and are usually mobile into early adulthood [
Some individuals present with vision impairment associated with optic atrophy, which is more common in childhood-onset than adult-onset MPAN.
The progression of MPAN is usually slow with survival well into adulthood. However, rare individuals have had abrupt adult onset and rapid progression [
The terminal stages of MPAN are characterized by severe dementia, spasticity, dystonia, and parkinsonism. Affected individuals are no longer ambulatory; communication is limited due to dysarthria and cognitive decline. Weight loss and bowel and/or bladder incontinence are common. Persons with advanced disease may have stereotypic hand or head movements with alterations in consciousness that do not appear to be manifestations of seizures. Death typically occurs secondary to complications such as aspiration pneumonia.
Fewer than 200 affected individuals have been described to date; thus, the phenotypic spectrum of MPAN is likely to broaden as more affected individuals are described.
The phenotypes associated with autosomal recessive (AR) MPAN and autosomal dominant (AD) MPAN are indistinguishable [
Select Features of Mitochondrial Membrane Protein-Associated Neurodegeneration
LMN = lower motor neuron; UMN = upper motor neuron
## Genotype-Phenotype Correlations
The phenotypes of AR and AD MPAN are indistinguishable, both arising from loss of function of the C19orf12 protein.
The pathogenic variant
Note: Previous speculation that the variant
• The pathogenic variant
• Note: Previous speculation that the variant
## Prevalence
The prevalence of MPAN is roughly estimated at less than one in 1,000,000.
The prevalence may be higher in the Turkish population due to the
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Note: Although a study had suggested that
## Differential Diagnosis
Neuronal loss, gliosis, widespread iron deposits, and eosinophilic spheroidal structures in the globus pallidus in MPAN are similar to the neuropathologic changes seen in PKAN. In MPAN, however, widespread Lewy bodies throughout the neocortex, deep gray matter, and midbrain are more prominent than the findings observed in PLAN and other forms of
Peripheral axonal spheroids, previously thought to be limited to PLAN, may be detected in skin or nerve biopsies of individuals with MPAN [
The high frequency of optic atrophy in MPAN helps distinguish it from other forms of NBIA, in which optic atrophy is more rare.
See
• Neuronal loss, gliosis, widespread iron deposits, and eosinophilic spheroidal structures in the globus pallidus in MPAN are similar to the neuropathologic changes seen in PKAN. In MPAN, however, widespread Lewy bodies throughout the neocortex, deep gray matter, and midbrain are more prominent than the findings observed in PLAN and other forms of
• Peripheral axonal spheroids, previously thought to be limited to PLAN, may be detected in skin or nerve biopsies of individuals with MPAN [
• The high frequency of optic atrophy in MPAN helps distinguish it from other forms of NBIA, in which optic atrophy is more rare.
## Management
To establish the extent of disease and needs in an individual diagnosed with mitochondrial membrane protein-associated neurodegeneration (MPAN), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mitochondrial Membrane Protein-Associated Neurodegeneration
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
BCVA
Refractive error
Color vision testing
Slit lamp exam
Dilated funduscopic exam
Community
Social work involvement for parental support;
Home nursing referral.
BCVA = best-corrected Snellen visual acuity; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations in Individuals with Mitochondrial Membrane Protein-Associated Neurodegeneration
Use of low vision aids
Work w/agencies for visually impaired
Consider nutritional & vitamin supplementation to meet dietary needs.
Gastric feeding tube as needed to minimize weight loss & ↓ risk of aspiration
Glycopyrrolate or transdermal scopolamine patch to ↓ volume of secretions
Consider tracheostomy.
ADL = activities of daily living; DD = developmental delay; ID = intellectual disability
Low vision aids such as magnifiers and closed circuit television may provide useful reading vision for individuals with reduced central acuity and constricted visual fields.
In the US, publicly funded agencies at the state level provide services for the blind or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Recommended Surveillance for Individuals with Mitochondrial Membrane Protein-Associated Neurodegeneration
Neurologic assessment for progression
Assess response to medications, side effects, &/or need for new medications or dosage adjustments.
When stable: annually
Others: may need at 3-6-mo intervals
Children: annually
Adults: every 1-3 yrs
ADL = activities of daily living; DD = developmental delay; ID = intellectual disability
See
Iron chelation using deferiprone has been investigated in a randomized, double-blind, placebo-controlled trial in a distinct NBIA disorder, PKAN [
Search
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• BCVA
• Refractive error
• Color vision testing
• Slit lamp exam
• Dilated funduscopic exam
• Community
• Social work involvement for parental support;
• Home nursing referral.
• Use of low vision aids
• Work w/agencies for visually impaired
• Consider nutritional & vitamin supplementation to meet dietary needs.
• Gastric feeding tube as needed to minimize weight loss & ↓ risk of aspiration
• Glycopyrrolate or transdermal scopolamine patch to ↓ volume of secretions
• Consider tracheostomy.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Neurologic assessment for progression
• Assess response to medications, side effects, &/or need for new medications or dosage adjustments.
• When stable: annually
• Others: may need at 3-6-mo intervals
• Children: annually
• Adults: every 1-3 yrs
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with mitochondrial membrane protein-associated neurodegeneration (MPAN), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Mitochondrial Membrane Protein-Associated Neurodegeneration
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
BCVA
Refractive error
Color vision testing
Slit lamp exam
Dilated funduscopic exam
Community
Social work involvement for parental support;
Home nursing referral.
BCVA = best-corrected Snellen visual acuity; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• BCVA
• Refractive error
• Color vision testing
• Slit lamp exam
• Dilated funduscopic exam
• Community
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Mitochondrial Membrane Protein-Associated Neurodegeneration
Use of low vision aids
Work w/agencies for visually impaired
Consider nutritional & vitamin supplementation to meet dietary needs.
Gastric feeding tube as needed to minimize weight loss & ↓ risk of aspiration
Glycopyrrolate or transdermal scopolamine patch to ↓ volume of secretions
Consider tracheostomy.
ADL = activities of daily living; DD = developmental delay; ID = intellectual disability
Low vision aids such as magnifiers and closed circuit television may provide useful reading vision for individuals with reduced central acuity and constricted visual fields.
In the US, publicly funded agencies at the state level provide services for the blind or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Use of low vision aids
• Work w/agencies for visually impaired
• Consider nutritional & vitamin supplementation to meet dietary needs.
• Gastric feeding tube as needed to minimize weight loss & ↓ risk of aspiration
• Glycopyrrolate or transdermal scopolamine patch to ↓ volume of secretions
• Consider tracheostomy.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Surveillance
Recommended Surveillance for Individuals with Mitochondrial Membrane Protein-Associated Neurodegeneration
Neurologic assessment for progression
Assess response to medications, side effects, &/or need for new medications or dosage adjustments.
When stable: annually
Others: may need at 3-6-mo intervals
Children: annually
Adults: every 1-3 yrs
ADL = activities of daily living; DD = developmental delay; ID = intellectual disability
• Neurologic assessment for progression
• Assess response to medications, side effects, &/or need for new medications or dosage adjustments.
• When stable: annually
• Others: may need at 3-6-mo intervals
• Children: annually
• Adults: every 1-3 yrs
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Iron chelation using deferiprone has been investigated in a randomized, double-blind, placebo-controlled trial in a distinct NBIA disorder, PKAN [
Search
## Genetic Counseling
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is inherited in an autosomal recessive or, less commonly, an autosomal dominant manner.
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the autosomal recessive
Rarely, individuals diagnosed with autosomal dominant MPAN have an affected parent.
More often, a proband with autosomal dominant MPAN has the disorder as a result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the
Because only two multigeneration families with inherited autosomal dominant MPAN have been reported to date, the risk for MPAN in individuals who inherit a
If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
Each child of an individual with autosomal dominant MPAN has a 50% risk of inheriting the pathogenic variant.
While physical and cognitive impairment in MPAN reduces the possibility of having children, some individuals with late-onset MPAN will reproduce before the onset of symptoms [
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers or affected.
Once the pathogenic
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Rarely, individuals diagnosed with autosomal dominant MPAN have an affected parent.
• More often, a proband with autosomal dominant MPAN has the disorder as a result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the
• Because only two multigeneration families with inherited autosomal dominant MPAN have been reported to date, the risk for MPAN in individuals who inherit a
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• Each child of an individual with autosomal dominant MPAN has a 50% risk of inheriting the pathogenic variant.
• While physical and cognitive impairment in MPAN reduces the possibility of having children, some individuals with late-onset MPAN will reproduce before the onset of symptoms [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers or affected.
## Mode of Inheritance
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is inherited in an autosomal recessive or, less commonly, an autosomal dominant manner.
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the autosomal recessive
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the autosomal recessive
## Autosomal Dominant Inheritance – Risk to Family Members
Rarely, individuals diagnosed with autosomal dominant MPAN have an affected parent.
More often, a proband with autosomal dominant MPAN has the disorder as a result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the
Because only two multigeneration families with inherited autosomal dominant MPAN have been reported to date, the risk for MPAN in individuals who inherit a
If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
Each child of an individual with autosomal dominant MPAN has a 50% risk of inheriting the pathogenic variant.
While physical and cognitive impairment in MPAN reduces the possibility of having children, some individuals with late-onset MPAN will reproduce before the onset of symptoms [
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Rarely, individuals diagnosed with autosomal dominant MPAN have an affected parent.
• More often, a proband with autosomal dominant MPAN has the disorder as a result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the
• Because only two multigeneration families with inherited autosomal dominant MPAN have been reported to date, the risk for MPAN in individuals who inherit a
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• Each child of an individual with autosomal dominant MPAN has a 50% risk of inheriting the pathogenic variant.
• While physical and cognitive impairment in MPAN reduces the possibility of having children, some individuals with late-onset MPAN will reproduce before the onset of symptoms [
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers or affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers or affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Center of Excellence for NBIA Clinical Care and Research
International Registry for NBIA and Related Disorders
Oregon Health & Science University
Germany
•
•
•
•
•
• Center of Excellence for NBIA Clinical Care and Research
• International Registry for NBIA and Related Disorders
• Oregon Health & Science University
•
•
• Germany
•
## Molecular Genetics
Mitochondrial Membrane Protein-Associated Neurodegeneration: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Mitochondrial Membrane Protein-Associated Neurodegeneration (
Association with the mitochondrial membrane and co-regulation with proteins of fatty acid biogenesis and branched chain amino acid degradation expression profiles suggest similarities to other proteins known to be defective in NBIA. C19orf12 is suspected of playing a role in lipid homeostasis [
Notable
Founder variant in Turkish population [
Mean age of onset is 25 yrs in persons homozygous for this variant [
See
Founder variant in Eastern European (Polish) population
Assoc w/juvenile onset [
Variants listed in the table have been provided by the authors.
• Founder variant in Turkish population [
• Mean age of onset is 25 yrs in persons homozygous for this variant [
• See
• Founder variant in Eastern European (Polish) population
• Assoc w/juvenile onset [
## Molecular Pathogenesis
Association with the mitochondrial membrane and co-regulation with proteins of fatty acid biogenesis and branched chain amino acid degradation expression profiles suggest similarities to other proteins known to be defective in NBIA. C19orf12 is suspected of playing a role in lipid homeostasis [
Notable
Founder variant in Turkish population [
Mean age of onset is 25 yrs in persons homozygous for this variant [
See
Founder variant in Eastern European (Polish) population
Assoc w/juvenile onset [
Variants listed in the table have been provided by the authors.
• Founder variant in Turkish population [
• Mean age of onset is 25 yrs in persons homozygous for this variant [
• See
• Founder variant in Eastern European (Polish) population
• Assoc w/juvenile onset [
## Chapter Notes
Investigators and clinicians at Oregon Health & Science University have studied the NBIA disorders, including MPAN, for more than 25 years. Our program includes an NBIA Center of Excellence committed to providing comprehensive care for patients with NBIA around the world (
For more information, please contact us:
The authors acknowledge funding from the European Commission Seventh Framework Programme (FP7/2007-2013, HEALTH-F2-2011, grant agreement No. 277984, TIRCON).
Allison Gregory, MS, CGC (2014-present)Monika Hartig, MD; Technische Universität München (2014-2021)Susan J Hayflick, MD (2014-present)Penelope Hogarth, MD (2014-present)Thomas Klopstock, MD (2021-present)Tomasz Kmiec, MD (2014-present)Holger Prokisch, PhD; Technische Universität München (2014-2021)
4 March 2021 (bp) Comprehensive update posted live
27 February 2014 (me) Review posted live
3 September 2013 (ag) Original submission
• 4 March 2021 (bp) Comprehensive update posted live
• 27 February 2014 (me) Review posted live
• 3 September 2013 (ag) Original submission
## Author Notes
Investigators and clinicians at Oregon Health & Science University have studied the NBIA disorders, including MPAN, for more than 25 years. Our program includes an NBIA Center of Excellence committed to providing comprehensive care for patients with NBIA around the world (
For more information, please contact us:
## Acknowledgments
The authors acknowledge funding from the European Commission Seventh Framework Programme (FP7/2007-2013, HEALTH-F2-2011, grant agreement No. 277984, TIRCON).
## Author History
Allison Gregory, MS, CGC (2014-present)Monika Hartig, MD; Technische Universität München (2014-2021)Susan J Hayflick, MD (2014-present)Penelope Hogarth, MD (2014-present)Thomas Klopstock, MD (2021-present)Tomasz Kmiec, MD (2014-present)Holger Prokisch, PhD; Technische Universität München (2014-2021)
## Revision History
4 March 2021 (bp) Comprehensive update posted live
27 February 2014 (me) Review posted live
3 September 2013 (ag) Original submission
• 4 March 2021 (bp) Comprehensive update posted live
• 27 February 2014 (me) Review posted live
• 3 September 2013 (ag) Original submission
## References
## Literature Cited
T
A. Typical eye-of-the-tiger sign seen in
B. Iron accumulation in globus pallidus without an eye-of-the-tiger sign, as observed in MPAN and other forms of
C. Isointense streaking of the medial medullary lamina between the hypointense signal regions in globus pallidus externa and interna, observed in most persons with MPAN; may be mistaken for an eye-of-the-tiger sign
|
[
"N Al Macki, I Rashdi. A novel deletion mutation of exon 2 of the C19orf12 gene in an Omani family with mitochondrial membrane protein-associated neurodegeneration (MPAN).. Oman Med J. 2017;32:66-8",
"E Bayram, E Peker, S Metzger, M Akbostanct. Myoclonus, hydrocephalus in mitochondrial protein-associated neurodegeneration.. Can J Neurol Sci. 2019;46:628-30",
"M Deschauer, C Gaul, C Behrmann, H Prokisch, S Zierz, TB Haack. C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.. J Neurol. 2012;259:2434-9",
"O Dogu, CE Krebs, H Kaleagasi, Z Demirtas, N Oksuz, RH Walker, C Paisán-Ruiz. Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration.. Clin Genet. 2013;84:350-5",
"M Gagliardi, G Annesi, G Lesca, E Broussolle, G Iannello, V Vaiti, A Gambardella, A. Quattrone. C19orf12 gene mutations in patients with neurodegeneration with brain iron accumulation.. Parkinsonism Relat Disord. 2015;21:813-6",
"E Gore, BS Appleby, ML Cohen, SD DeBrosse, JB Leverenz, BL Miller, SL Siedlak, X Zhu, AJ Lerner. Clinical and imaging characteristics of late onset mitochondrial membrane protein-associated neurodegeneration (MPAN).. Neurocase. 2016;22:476-83",
"A Gregory, M Lotia, SY Jeong, R Fox, D Zhen, L Sanford, J Hamada, A Jahic, C Beetz, A Freed, MA Kurian, T Cullup, MCM van der Weijden, V Nguyen, N Setthavongsack, D Garcia, V Krajbich, T Pham, R Woltjer, BP George, KQ Minks, AR Paciorkowski, P Hogarth, J Jankovic, SJ Hayflick. Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).. Mol Genet Genomic Med. 2019;7",
"M Hartig, H Prokisch, T Meitinger, T Klopstock. Mitochondrial membrane protein-associated neurodegeneration (MPAN).. Int Rev Neurobiol. 2013;110:73-84",
"MB Hartig, A Iuso, T Haack, T Kmiec, E Jurkiewicz, K Heim, S Roeber, V Tarabin, S Dusi, M Krajewska-Walasek, S Jozwiak, M Hempel, J Winkelmann, M Elstner, K Oexle, T Klopstock, W Mueller-Felber, T Gasser, C Trenkwalder, V Tiranti, H Kretzschmar, G Schmitz, TM Strom, T Meitinger, H Prokisch. Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.. Am J Hum Genet. 2011;89:543-50",
"P Hogarth, A Gregory, MC Kruer, L Sanford, W Wagoner, MR Natowicz, RT Egel, SH Subramony, JG Goldman, E Berry-Kravis, NC Foulds, SR Hammans, I Desguerre, D Rodriguez, C Wilson, A Diedrich, S Green, H Tran, L Reese, RL Woltjer, SJ Hayflick. New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN.. Neurology. 2013;80:268-75",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"J Kim, Y Liao, C Ionita, AE Bale, B Daras, G Ascadi. Mitochondrial membrate protein-associated neurodegeneration mimicking juvenile amyotrophic lateral sclerosis.. Pediatr Neurol. 2016;64:83-6",
"T Klopstock, F Tricta, L Neumayr, I Karin, G Zorzi, C Fradette, T Kmiec, B Buchner, HE Steele, R Horvath, PF Chinnery, A Basu, C Kupper, C Neuhofer, B Kalman, P Dusek, Z Yapici, I Wilson, F Zhao, F Zibordi, N Nardocci, C Aguilar, SJ Hayflick, M Spino, AM Blamire, P Hogarth, E Vichinsky. Safety and efficacy of deperiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study.. Lancet Neurol. 2019;18:631-42",
"MA Kurian, NV Morgan, L MacPherson, K Foster, D Peake, R Gupta, SG Philip, C Hendriksz, JE Morton, HM Kingston, EM Rosser, E Wassmer, P Gissen, ER Maher. Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN).. Neurology. 2008;70:1623-9",
"G Landouré, PP Zhu, CM Lourenço, JO Johnson, C Toro, KV Bricceno, C Rinaldi, KG Meilleur, M Sangaré, O Diallo, TM Pierson, H Ishiura, S Tsuji, N Hein, JK Fink, M Stoll, G Nicholson, MA Gonzalez, F Speziani, A Dürr, G Stevanin, LG Biesecker, J Accardi, DM Landis, WA Gahl, BJ Traynor, W Marques, S Züchner, C Blackstone, KH Fischbeck, BG Burnett. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.. Hum Mutat. 2013;34:1357-60",
"E Langwinska-Wosko, M Skowronska, T Kmiec, A Czlonkowska. Retinal and optic nerve abnormalities in neurodegeneration associated with mutations in C19orf12 (MPAN).. J Neurol Sci. 2016;370:237-240",
"U Löbel, F Schweser, M Nickel, A Deistung, R Grosse, C Hagel. Brain iron quantification by MRI in mitochondrial membrane protein-associated neurodegeneration under iron-chelating therapy.. Ann Clin Transl Neurol. 2014;1:1041-6",
"S Olgiati, O Doğu, Z Tufekcioglu, Y Diler, E Saka, M Gultekin, H Kaleagasi, D Kuipers, J Graafland, GJ Breedveld, M Quadri, R Sürmeli, G Sünter, T Doğan, AD Yalçın, B Bilgiç, B Elibol, M Emre, HA Hanagasi, V Bonifati. The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN.. Parkinsonism Relat Disord. 2017;39:64-70",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. uycdxTiming, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"G Schottmann, W Stenzel, S Lützkendorf, M Schuelke, E Knierim. A novel frameshift mutation of C19ORF12 causes NBIA4 with cerebellar atrophy and manifests with severe peripheral motor axonal neuropathy.. Clin Genet. 2014;85:290-2",
"EC Schulte, MC Claussen, A Jochim, T Haack, M Hartig, M Hempel, H Prokisch, U Haun-Jünger, J Winkelmann, B Hemmer, A Förschler, R Ilg. Mitochondrial membrane protein associated neurodegeneration: a novel variant of neurodegeneration with brain iron accumulation.. Mov Disord. 2013;28:224-7",
"M Selikhova, E Fedotova, S Wiethoff, LV Schottlaender, S Klyushnikov, SN Illarioshkin, H Houlden. A 30-year history of MPAN case from Russia.. Clin Neurol Neurosurg. 2017;159:111-3",
"M Skowronska, T Kmiec, E Jurkiewicz, K Malczyk, I Kurkowska-Jastrzebska, A Czlonkowska. Evolution and novel radiological changes of neurodegeneration associated with mutations in C19orf12.. Parkinsonism Relat Disord. 2017;39:71-76",
"PD Stenson, M Mort, EV Ball, K Evans, M Hayden, S Heywood, M Hussain, AD Phillips, DN Cooper. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.. Hum Genet. 2017;136:665-77"
] |
27/2/2014
|
4/3/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mt-overview
|
mt-overview
|
[
"Mitochondrial Disorders",
"Chorea and Dementia",
"Diabetes and Hearing Loss",
"Infantile Myopathy and Lactic Acidosis (Fatal and Non-Fatal Forms)",
"Leber Hereditary Optic Neuropathy",
"MELAS",
"MERRF",
"Single Large-Scale Mitochondrial DNA Deletion Syndromes",
"Mitochondrial DNA-Associated Leigh Syndrome Spectrum",
"Mitochondrial Myopathy with Diabetes",
"Nonsyndromic Hearing Loss and Deafness, Mitochondrial",
"MERRF/MELAS Overlap Syndrome",
"ATP synthase F(0) complex subunit a",
"NADH-ubiquinone oxidoreductase chain 1",
"NADH-ubiquinone oxidoreductase chain 4",
"NADH-ubiquinone oxidoreductase chain 5",
"NADH-ubiquinone oxidoreductase chain 6",
"Not applicable",
"MT-ATP6",
"MT-ND1",
"MT-ND4",
"MT-ND5",
"MT-ND6",
"MT-TA",
"MT-TC",
"MT-TD",
"MT-TF",
"MT-TH",
"MT-TK",
"MT-TL1",
"MT-TL2",
"MT-TM",
"MT-TQ",
"MT-TR",
"MT-TS1",
"MT-TS2",
"MT-TT",
"MT-TV",
"MT-TW",
"MT-TY",
"Primary Mitochondrial Disorders",
"Overview"
] |
Primary Mitochondrial Disorders Overview
|
Patrick F Chinnery
|
Summary The purpose of this overview is to: Describe the Provide Identify Inform
|
## Clinical Characteristics of Mitochondrial Disorders
Primary mitochondrial disorders are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. The mitochondrial respiratory chain is the essential final common pathway for aerobic metabolism; tissues and organs that are highly dependent on aerobic metabolism are preferentially involved in mitochondrial disorders [
More than 70 different polypeptides interact on the inner mitochondrial membrane to form the respiratory chain. Thirteen essential subunits are encoded by mitochondrial DNA (mtDNA) located within mitochondria, along with the ribosomal and transfer RNAs required for intra-mitochondrial protein synthesis. The remaining respiratory chain polypeptides, and proteins essential for the assembly of the respiratory chain, mitochondrial structure, and the maintenance and expression of mtDNA are encoded by the nuclear genome (nDNA).
The 1.1-kb D-loop (noncoding region) is involved in the regulation of transcription and replication of the molecule, and is the only region not directly involved in the synthesis of respiratory chain polypeptides.
The protein-encoding regions:
ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
CO I to CO III encode for three of respiratory chain complex IV (cytochrome
ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
Two ribosomal RNA genes (encoding 12S and 16S rRNA) and 22 transfer RNA genes are interspaced between the protein-encoding genes. These provide the necessary RNA components for intra-mitochondrial protein synthesis.
O
Each human cell contains thousands of copies of mtDNA. At birth these are usually all identical (homoplasmy). By contrast, individuals with mitochondrial disorders resulting from mtDNA pathogenic variants may harbor a mixture of mutated and wild type mtDNA within each cell (heteroplasmy) [
Single-cell studies have shown that the proportion of mtDNA pathogenic variants must exceed a critical threshold level before a cell expresses a biochemical abnormality of the mitochondrial respiratory chain (the threshold effect) [
The percentage level of mtDNA pathogenic variants may vary among individuals within the same family, and also among organs and tissues within an individual [
Important mitochondrial mechanisms controlled by nuclear genes include the following:
Mitochondrial protein synthesis
Respiratory chain complexes
Respiratory chain assembly factors
Mitochondrial structure
Some mitochondrial disorders affect a single organ (e.g., the eye in
Mitochondrial disorders may present at any age [
Common clinical features of mitochondrial disorders include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Diabetes mellitus and deafness is also a well-recognized clinical phenotype.
The central nervous system findings are often fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. Chorea and dementia may also be prominent features.
A high incidence of mid- and late-pregnancy loss is also a common feature.
Many individuals with a mtDNA disorder display a cluster of clinical features that fall into a discrete clinical syndrome (
Clinical Syndromes of mtDNA Disorders
External ophthalmoplegia
Bilateral ptosis
Mild proximal myopathy
PEO onset age <20 yrs
Pigmentary retinopathy
One of the following: CSF protein >1 g/L, cerebellar ataxia, heart block
Bilateral deafness
Myopathy
Dysphagia
Diabetes mellitus
Hypoparathyroidism
Dementia
Sideroblastic anemia of childhood
Pancytopenia
Exocrine pancreatic failure
Renal tubular defects
Subacute relapsing encephalopathy
Cerebellar & brain stem signs
Infantile onset
Basal ganglia lucencies
Maternal history of neurologic disease or Leigh syndrome
Late-childhood or adult-onset peripheral neuropathy
Ataxia
Pigmentary retinopathy
Basal ganglia lucencies
Abnormal electroretinogram
Sensorimotor neuropathy
Stroke-like episodes at age <40 yrs
Seizures &/or dementia
Ragged-red fibers &/or lactic acidosis
Diabetes mellitus
Cardiomyopathy (initially hypertrophic; later dilated)
Bilateral deafness
Pigmentary retinopathy
Cerebellar ataxia
Myoclonus
Seizures
Cerebellar ataxia
Myopathy
Dementia
Optic atrophy
Bilateral deafness
Peripheral neuropathy
Spasticity
Multiple lipomata
Subacute painless bilateral visual failure
Males:females ~4:1
Median age of onset 24 yrs
Dystonia
Cardiac pre-excitation syndromes
CPEO = chronic progressive external ophthalmoplegia; KSS = Kearns-Sayre syndrome; LHON = Leber hereditary optic neuropathy; MELAS = mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MERRF = myoclonic epilepsy with ragged-red fibers; NARP = neurogenic weakness with ataxia and retinitis pigmentosa
Nuclear DNA (nDNA) mitochondrial disorders often display considerable clinical variability and many affected individuals do not fit neatly into one particular category. For example, mutation of
Nuclear DNA mitochondrial disorders can be classified by disease mechanism (see
Classification of Representative nDNA Mitochondrial Disorders
Leukodystrophy w/complex II deficiency
Cardiomyopathy & encephalopathy (complex I deficiency)
Optic atrophy & ataxia (complex II deficiency)
Hypokalemia & lactic acidosis (complex III deficiency)
Hepatopathy & ketoacidosis
Cardiomyopathy & encephalopathy
Leukodystrophy & renal tubulopathy
Hypertrophic cardiomyopathy
Encephalopathy, liver failure, renal tubulopathy (w/complex III deficiency)
Encephalopathy (w/complex V deficiency)
Lactic acidosis, developmental failure, & dysmorphism
Myopathy & sideroblastic anemia
Leukodystrophy & polymicrogyria
Autosomal progressive external ophthalmoplegia
Alpers-Huttenlocher syndrome
Ataxia neuropathy syndromes
Mitochondrial encephalomyopathy w/combined RC deficiency
Reversible hepatopathy
Myopathy w/cataract & combined RC deficiency
Cardiomyopathy & lactic acidosis (mitochondrial phosphate carrier deficiency)
mt = mitochondrial; RC = respiratory chain
See
Includes MEMSA (myoclonic epilepsy myopathy sensory ataxia), MIRAS (mitochondrial recessive ataxia syndrome), SANDO (sensory ataxia neuropathy, dysarthria, ophthalmoplegia), and SCAE (spinocerebellar ataxia with epilepsy)
• The 1.1-kb D-loop (noncoding region) is involved in the regulation of transcription and replication of the molecule, and is the only region not directly involved in the synthesis of respiratory chain polypeptides.
• The protein-encoding regions:
• ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
• CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
• CO I to CO III encode for three of respiratory chain complex IV (cytochrome
• ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
• ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
• CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
• CO I to CO III encode for three of respiratory chain complex IV (cytochrome
• ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
• Two ribosomal RNA genes (encoding 12S and 16S rRNA) and 22 transfer RNA genes are interspaced between the protein-encoding genes. These provide the necessary RNA components for intra-mitochondrial protein synthesis.
• O
• ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
• CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
• CO I to CO III encode for three of respiratory chain complex IV (cytochrome
• ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
• Mitochondrial protein synthesis
•
• Respiratory chain complexes
• Respiratory chain assembly factors
• Mitochondrial structure
• External ophthalmoplegia
• Bilateral ptosis
• Mild proximal myopathy
• PEO onset age <20 yrs
• Pigmentary retinopathy
• One of the following: CSF protein >1 g/L, cerebellar ataxia, heart block
• Bilateral deafness
• Myopathy
• Dysphagia
• Diabetes mellitus
• Hypoparathyroidism
• Dementia
• Sideroblastic anemia of childhood
• Pancytopenia
• Exocrine pancreatic failure
• Renal tubular defects
• Subacute relapsing encephalopathy
• Cerebellar & brain stem signs
• Infantile onset
• Basal ganglia lucencies
• Maternal history of neurologic disease or Leigh syndrome
• Late-childhood or adult-onset peripheral neuropathy
• Ataxia
• Pigmentary retinopathy
• Basal ganglia lucencies
• Abnormal electroretinogram
• Sensorimotor neuropathy
• Stroke-like episodes at age <40 yrs
• Seizures &/or dementia
• Ragged-red fibers &/or lactic acidosis
• Diabetes mellitus
• Cardiomyopathy (initially hypertrophic; later dilated)
• Bilateral deafness
• Pigmentary retinopathy
• Cerebellar ataxia
• Myoclonus
• Seizures
• Cerebellar ataxia
• Myopathy
• Dementia
• Optic atrophy
• Bilateral deafness
• Peripheral neuropathy
• Spasticity
• Multiple lipomata
• Subacute painless bilateral visual failure
• Males:females ~4:1
• Median age of onset 24 yrs
• Dystonia
• Cardiac pre-excitation syndromes
• Leukodystrophy w/complex II deficiency
• Cardiomyopathy & encephalopathy (complex I deficiency)
• Optic atrophy & ataxia (complex II deficiency)
• Hypokalemia & lactic acidosis (complex III deficiency)
• Hepatopathy & ketoacidosis
• Cardiomyopathy & encephalopathy
• Leukodystrophy & renal tubulopathy
• Hypertrophic cardiomyopathy
• Encephalopathy, liver failure, renal tubulopathy (w/complex III deficiency)
• Encephalopathy (w/complex V deficiency)
• Lactic acidosis, developmental failure, & dysmorphism
• Myopathy & sideroblastic anemia
• Leukodystrophy & polymicrogyria
• Autosomal progressive external ophthalmoplegia
• Alpers-Huttenlocher syndrome
• Ataxia neuropathy syndromes
• Mitochondrial encephalomyopathy w/combined RC deficiency
• Reversible hepatopathy
• Myopathy w/cataract & combined RC deficiency
• Cardiomyopathy & lactic acidosis (mitochondrial phosphate carrier deficiency)
## Introduction
Primary mitochondrial disorders are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. The mitochondrial respiratory chain is the essential final common pathway for aerobic metabolism; tissues and organs that are highly dependent on aerobic metabolism are preferentially involved in mitochondrial disorders [
More than 70 different polypeptides interact on the inner mitochondrial membrane to form the respiratory chain. Thirteen essential subunits are encoded by mitochondrial DNA (mtDNA) located within mitochondria, along with the ribosomal and transfer RNAs required for intra-mitochondrial protein synthesis. The remaining respiratory chain polypeptides, and proteins essential for the assembly of the respiratory chain, mitochondrial structure, and the maintenance and expression of mtDNA are encoded by the nuclear genome (nDNA).
The 1.1-kb D-loop (noncoding region) is involved in the regulation of transcription and replication of the molecule, and is the only region not directly involved in the synthesis of respiratory chain polypeptides.
The protein-encoding regions:
ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
CO I to CO III encode for three of respiratory chain complex IV (cytochrome
ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
Two ribosomal RNA genes (encoding 12S and 16S rRNA) and 22 transfer RNA genes are interspaced between the protein-encoding genes. These provide the necessary RNA components for intra-mitochondrial protein synthesis.
O
Each human cell contains thousands of copies of mtDNA. At birth these are usually all identical (homoplasmy). By contrast, individuals with mitochondrial disorders resulting from mtDNA pathogenic variants may harbor a mixture of mutated and wild type mtDNA within each cell (heteroplasmy) [
Single-cell studies have shown that the proportion of mtDNA pathogenic variants must exceed a critical threshold level before a cell expresses a biochemical abnormality of the mitochondrial respiratory chain (the threshold effect) [
The percentage level of mtDNA pathogenic variants may vary among individuals within the same family, and also among organs and tissues within an individual [
Important mitochondrial mechanisms controlled by nuclear genes include the following:
Mitochondrial protein synthesis
Respiratory chain complexes
Respiratory chain assembly factors
Mitochondrial structure
• The 1.1-kb D-loop (noncoding region) is involved in the regulation of transcription and replication of the molecule, and is the only region not directly involved in the synthesis of respiratory chain polypeptides.
• The protein-encoding regions:
• ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
• CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
• CO I to CO III encode for three of respiratory chain complex IV (cytochrome
• ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
• ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
• CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
• CO I to CO III encode for three of respiratory chain complex IV (cytochrome
• ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
• Two ribosomal RNA genes (encoding 12S and 16S rRNA) and 22 transfer RNA genes are interspaced between the protein-encoding genes. These provide the necessary RNA components for intra-mitochondrial protein synthesis.
• O
• ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
• CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
• CO I to CO III encode for three of respiratory chain complex IV (cytochrome
• ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
• Mitochondrial protein synthesis
•
• Respiratory chain complexes
• Respiratory chain assembly factors
• Mitochondrial structure
## Mitochondrial DNA (mtDNA)
The 1.1-kb D-loop (noncoding region) is involved in the regulation of transcription and replication of the molecule, and is the only region not directly involved in the synthesis of respiratory chain polypeptides.
The protein-encoding regions:
ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
CO I to CO III encode for three of respiratory chain complex IV (cytochrome
ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
Two ribosomal RNA genes (encoding 12S and 16S rRNA) and 22 transfer RNA genes are interspaced between the protein-encoding genes. These provide the necessary RNA components for intra-mitochondrial protein synthesis.
O
Each human cell contains thousands of copies of mtDNA. At birth these are usually all identical (homoplasmy). By contrast, individuals with mitochondrial disorders resulting from mtDNA pathogenic variants may harbor a mixture of mutated and wild type mtDNA within each cell (heteroplasmy) [
Single-cell studies have shown that the proportion of mtDNA pathogenic variants must exceed a critical threshold level before a cell expresses a biochemical abnormality of the mitochondrial respiratory chain (the threshold effect) [
The percentage level of mtDNA pathogenic variants may vary among individuals within the same family, and also among organs and tissues within an individual [
• The 1.1-kb D-loop (noncoding region) is involved in the regulation of transcription and replication of the molecule, and is the only region not directly involved in the synthesis of respiratory chain polypeptides.
• The protein-encoding regions:
• ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
• CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
• CO I to CO III encode for three of respiratory chain complex IV (cytochrome
• ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
• ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
• CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
• CO I to CO III encode for three of respiratory chain complex IV (cytochrome
• ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
• Two ribosomal RNA genes (encoding 12S and 16S rRNA) and 22 transfer RNA genes are interspaced between the protein-encoding genes. These provide the necessary RNA components for intra-mitochondrial protein synthesis.
• O
• ND1 through ND6 and ND4L encode seven subunits of respiratory chain complex I.
• CYT b encodes the only mtDNA-encoded respiratory chain complex III subunit.
• CO I to CO III encode for three of respiratory chain complex IV (cytochrome
• ATPase6 and ATPase8 encode for two subunits of respiratory chain complex V: ATPase6 and ATPase8, respectively.
## Nuclear DNA (nDNA)
Important mitochondrial mechanisms controlled by nuclear genes include the following:
Mitochondrial protein synthesis
Respiratory chain complexes
Respiratory chain assembly factors
Mitochondrial structure
• Mitochondrial protein synthesis
•
• Respiratory chain complexes
• Respiratory chain assembly factors
• Mitochondrial structure
## Clinical Manifestations of Mitochondrial Disorders
Some mitochondrial disorders affect a single organ (e.g., the eye in
Mitochondrial disorders may present at any age [
Common clinical features of mitochondrial disorders include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Diabetes mellitus and deafness is also a well-recognized clinical phenotype.
The central nervous system findings are often fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. Chorea and dementia may also be prominent features.
A high incidence of mid- and late-pregnancy loss is also a common feature.
Many individuals with a mtDNA disorder display a cluster of clinical features that fall into a discrete clinical syndrome (
Clinical Syndromes of mtDNA Disorders
External ophthalmoplegia
Bilateral ptosis
Mild proximal myopathy
PEO onset age <20 yrs
Pigmentary retinopathy
One of the following: CSF protein >1 g/L, cerebellar ataxia, heart block
Bilateral deafness
Myopathy
Dysphagia
Diabetes mellitus
Hypoparathyroidism
Dementia
Sideroblastic anemia of childhood
Pancytopenia
Exocrine pancreatic failure
Renal tubular defects
Subacute relapsing encephalopathy
Cerebellar & brain stem signs
Infantile onset
Basal ganglia lucencies
Maternal history of neurologic disease or Leigh syndrome
Late-childhood or adult-onset peripheral neuropathy
Ataxia
Pigmentary retinopathy
Basal ganglia lucencies
Abnormal electroretinogram
Sensorimotor neuropathy
Stroke-like episodes at age <40 yrs
Seizures &/or dementia
Ragged-red fibers &/or lactic acidosis
Diabetes mellitus
Cardiomyopathy (initially hypertrophic; later dilated)
Bilateral deafness
Pigmentary retinopathy
Cerebellar ataxia
Myoclonus
Seizures
Cerebellar ataxia
Myopathy
Dementia
Optic atrophy
Bilateral deafness
Peripheral neuropathy
Spasticity
Multiple lipomata
Subacute painless bilateral visual failure
Males:females ~4:1
Median age of onset 24 yrs
Dystonia
Cardiac pre-excitation syndromes
CPEO = chronic progressive external ophthalmoplegia; KSS = Kearns-Sayre syndrome; LHON = Leber hereditary optic neuropathy; MELAS = mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MERRF = myoclonic epilepsy with ragged-red fibers; NARP = neurogenic weakness with ataxia and retinitis pigmentosa
Nuclear DNA (nDNA) mitochondrial disorders often display considerable clinical variability and many affected individuals do not fit neatly into one particular category. For example, mutation of
Nuclear DNA mitochondrial disorders can be classified by disease mechanism (see
Classification of Representative nDNA Mitochondrial Disorders
Leukodystrophy w/complex II deficiency
Cardiomyopathy & encephalopathy (complex I deficiency)
Optic atrophy & ataxia (complex II deficiency)
Hypokalemia & lactic acidosis (complex III deficiency)
Hepatopathy & ketoacidosis
Cardiomyopathy & encephalopathy
Leukodystrophy & renal tubulopathy
Hypertrophic cardiomyopathy
Encephalopathy, liver failure, renal tubulopathy (w/complex III deficiency)
Encephalopathy (w/complex V deficiency)
Lactic acidosis, developmental failure, & dysmorphism
Myopathy & sideroblastic anemia
Leukodystrophy & polymicrogyria
Autosomal progressive external ophthalmoplegia
Alpers-Huttenlocher syndrome
Ataxia neuropathy syndromes
Mitochondrial encephalomyopathy w/combined RC deficiency
Reversible hepatopathy
Myopathy w/cataract & combined RC deficiency
Cardiomyopathy & lactic acidosis (mitochondrial phosphate carrier deficiency)
mt = mitochondrial; RC = respiratory chain
See
Includes MEMSA (myoclonic epilepsy myopathy sensory ataxia), MIRAS (mitochondrial recessive ataxia syndrome), SANDO (sensory ataxia neuropathy, dysarthria, ophthalmoplegia), and SCAE (spinocerebellar ataxia with epilepsy)
• External ophthalmoplegia
• Bilateral ptosis
• Mild proximal myopathy
• PEO onset age <20 yrs
• Pigmentary retinopathy
• One of the following: CSF protein >1 g/L, cerebellar ataxia, heart block
• Bilateral deafness
• Myopathy
• Dysphagia
• Diabetes mellitus
• Hypoparathyroidism
• Dementia
• Sideroblastic anemia of childhood
• Pancytopenia
• Exocrine pancreatic failure
• Renal tubular defects
• Subacute relapsing encephalopathy
• Cerebellar & brain stem signs
• Infantile onset
• Basal ganglia lucencies
• Maternal history of neurologic disease or Leigh syndrome
• Late-childhood or adult-onset peripheral neuropathy
• Ataxia
• Pigmentary retinopathy
• Basal ganglia lucencies
• Abnormal electroretinogram
• Sensorimotor neuropathy
• Stroke-like episodes at age <40 yrs
• Seizures &/or dementia
• Ragged-red fibers &/or lactic acidosis
• Diabetes mellitus
• Cardiomyopathy (initially hypertrophic; later dilated)
• Bilateral deafness
• Pigmentary retinopathy
• Cerebellar ataxia
• Myoclonus
• Seizures
• Cerebellar ataxia
• Myopathy
• Dementia
• Optic atrophy
• Bilateral deafness
• Peripheral neuropathy
• Spasticity
• Multiple lipomata
• Subacute painless bilateral visual failure
• Males:females ~4:1
• Median age of onset 24 yrs
• Dystonia
• Cardiac pre-excitation syndromes
• Leukodystrophy w/complex II deficiency
• Cardiomyopathy & encephalopathy (complex I deficiency)
• Optic atrophy & ataxia (complex II deficiency)
• Hypokalemia & lactic acidosis (complex III deficiency)
• Hepatopathy & ketoacidosis
• Cardiomyopathy & encephalopathy
• Leukodystrophy & renal tubulopathy
• Hypertrophic cardiomyopathy
• Encephalopathy, liver failure, renal tubulopathy (w/complex III deficiency)
• Encephalopathy (w/complex V deficiency)
• Lactic acidosis, developmental failure, & dysmorphism
• Myopathy & sideroblastic anemia
• Leukodystrophy & polymicrogyria
• Autosomal progressive external ophthalmoplegia
• Alpers-Huttenlocher syndrome
• Ataxia neuropathy syndromes
• Mitochondrial encephalomyopathy w/combined RC deficiency
• Reversible hepatopathy
• Myopathy w/cataract & combined RC deficiency
• Cardiomyopathy & lactic acidosis (mitochondrial phosphate carrier deficiency)
## Mitochondrial DNA Disorders
Many individuals with a mtDNA disorder display a cluster of clinical features that fall into a discrete clinical syndrome (
Clinical Syndromes of mtDNA Disorders
External ophthalmoplegia
Bilateral ptosis
Mild proximal myopathy
PEO onset age <20 yrs
Pigmentary retinopathy
One of the following: CSF protein >1 g/L, cerebellar ataxia, heart block
Bilateral deafness
Myopathy
Dysphagia
Diabetes mellitus
Hypoparathyroidism
Dementia
Sideroblastic anemia of childhood
Pancytopenia
Exocrine pancreatic failure
Renal tubular defects
Subacute relapsing encephalopathy
Cerebellar & brain stem signs
Infantile onset
Basal ganglia lucencies
Maternal history of neurologic disease or Leigh syndrome
Late-childhood or adult-onset peripheral neuropathy
Ataxia
Pigmentary retinopathy
Basal ganglia lucencies
Abnormal electroretinogram
Sensorimotor neuropathy
Stroke-like episodes at age <40 yrs
Seizures &/or dementia
Ragged-red fibers &/or lactic acidosis
Diabetes mellitus
Cardiomyopathy (initially hypertrophic; later dilated)
Bilateral deafness
Pigmentary retinopathy
Cerebellar ataxia
Myoclonus
Seizures
Cerebellar ataxia
Myopathy
Dementia
Optic atrophy
Bilateral deafness
Peripheral neuropathy
Spasticity
Multiple lipomata
Subacute painless bilateral visual failure
Males:females ~4:1
Median age of onset 24 yrs
Dystonia
Cardiac pre-excitation syndromes
CPEO = chronic progressive external ophthalmoplegia; KSS = Kearns-Sayre syndrome; LHON = Leber hereditary optic neuropathy; MELAS = mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MERRF = myoclonic epilepsy with ragged-red fibers; NARP = neurogenic weakness with ataxia and retinitis pigmentosa
• External ophthalmoplegia
• Bilateral ptosis
• Mild proximal myopathy
• PEO onset age <20 yrs
• Pigmentary retinopathy
• One of the following: CSF protein >1 g/L, cerebellar ataxia, heart block
• Bilateral deafness
• Myopathy
• Dysphagia
• Diabetes mellitus
• Hypoparathyroidism
• Dementia
• Sideroblastic anemia of childhood
• Pancytopenia
• Exocrine pancreatic failure
• Renal tubular defects
• Subacute relapsing encephalopathy
• Cerebellar & brain stem signs
• Infantile onset
• Basal ganglia lucencies
• Maternal history of neurologic disease or Leigh syndrome
• Late-childhood or adult-onset peripheral neuropathy
• Ataxia
• Pigmentary retinopathy
• Basal ganglia lucencies
• Abnormal electroretinogram
• Sensorimotor neuropathy
• Stroke-like episodes at age <40 yrs
• Seizures &/or dementia
• Ragged-red fibers &/or lactic acidosis
• Diabetes mellitus
• Cardiomyopathy (initially hypertrophic; later dilated)
• Bilateral deafness
• Pigmentary retinopathy
• Cerebellar ataxia
• Myoclonus
• Seizures
• Cerebellar ataxia
• Myopathy
• Dementia
• Optic atrophy
• Bilateral deafness
• Peripheral neuropathy
• Spasticity
• Multiple lipomata
• Subacute painless bilateral visual failure
• Males:females ~4:1
• Median age of onset 24 yrs
• Dystonia
• Cardiac pre-excitation syndromes
## Nuclear DNA Mitochondrial Disorders
Nuclear DNA (nDNA) mitochondrial disorders often display considerable clinical variability and many affected individuals do not fit neatly into one particular category. For example, mutation of
Nuclear DNA mitochondrial disorders can be classified by disease mechanism (see
Classification of Representative nDNA Mitochondrial Disorders
Leukodystrophy w/complex II deficiency
Cardiomyopathy & encephalopathy (complex I deficiency)
Optic atrophy & ataxia (complex II deficiency)
Hypokalemia & lactic acidosis (complex III deficiency)
Hepatopathy & ketoacidosis
Cardiomyopathy & encephalopathy
Leukodystrophy & renal tubulopathy
Hypertrophic cardiomyopathy
Encephalopathy, liver failure, renal tubulopathy (w/complex III deficiency)
Encephalopathy (w/complex V deficiency)
Lactic acidosis, developmental failure, & dysmorphism
Myopathy & sideroblastic anemia
Leukodystrophy & polymicrogyria
Autosomal progressive external ophthalmoplegia
Alpers-Huttenlocher syndrome
Ataxia neuropathy syndromes
Mitochondrial encephalomyopathy w/combined RC deficiency
Reversible hepatopathy
Myopathy w/cataract & combined RC deficiency
Cardiomyopathy & lactic acidosis (mitochondrial phosphate carrier deficiency)
mt = mitochondrial; RC = respiratory chain
See
Includes MEMSA (myoclonic epilepsy myopathy sensory ataxia), MIRAS (mitochondrial recessive ataxia syndrome), SANDO (sensory ataxia neuropathy, dysarthria, ophthalmoplegia), and SCAE (spinocerebellar ataxia with epilepsy)
• Leukodystrophy w/complex II deficiency
• Cardiomyopathy & encephalopathy (complex I deficiency)
• Optic atrophy & ataxia (complex II deficiency)
• Hypokalemia & lactic acidosis (complex III deficiency)
• Hepatopathy & ketoacidosis
• Cardiomyopathy & encephalopathy
• Leukodystrophy & renal tubulopathy
• Hypertrophic cardiomyopathy
• Encephalopathy, liver failure, renal tubulopathy (w/complex III deficiency)
• Encephalopathy (w/complex V deficiency)
• Lactic acidosis, developmental failure, & dysmorphism
• Myopathy & sideroblastic anemia
• Leukodystrophy & polymicrogyria
• Autosomal progressive external ophthalmoplegia
• Alpers-Huttenlocher syndrome
• Ataxia neuropathy syndromes
• Mitochondrial encephalomyopathy w/combined RC deficiency
• Reversible hepatopathy
• Myopathy w/cataract & combined RC deficiency
• Cardiomyopathy & lactic acidosis (mitochondrial phosphate carrier deficiency)
## Evaluation Strategies to Identify the Genetic Cause of a Mitochondrial Disorder in a Proband
With more than 1,000 nuclear genes encoding mitochondrial proteins, the molecular diagnosis of mitochondrial disorders can be challenging. Establishing a molecular genetic diagnosis has important implications for the recurrence risk counseling of individuals with mitochondrial disease [
Mitochondrial dysfunction should be considered in the differential diagnosis of any progressive multisystem disorder. A full evaluation for a mitochondrial disorder is often warranted in individuals with a complex neurologic picture or a single neurologic manifestation and other system involvement.
Findings that can suggest a mitochondrial disorder include clinical phenotype (physical examination including neurologic examination), mode of inheritance (family history), and extent of the phenotype (other investigations to establish the extent of the phenotype).
Molecular genetic testing is used to establish the diagnosis.
A comprehensive physical examination is essential to identify asymptomatic organ involvement that would allow a syndromic diagnosis, or to identify asymptomatic complications that require management. Mitochondrial disorders can affect most organ systems, but a particular emphasis on the neuromuscular system and cardiovascular system is important.
A three-generation family history should be taken, with attention to relatives with manifestations of mitochondrial disorders and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing.
Autosomal dominant inheritance associated with a
A single occurrence of an autosomal recessive, X-linked, or maternally inherited disorder
An acquired (non-genetic) cause
Many individuals with a childhood-onset encephalomyopathy and most adults with PEO or KSS represent simplex cases (
Clinical tests are used to support a diagnosis of mitochondrial disease [
When the clinical picture is nonspecific but highly suggestive of a mitochondrial disorder, the clinician should start with measurement of plasma or CSF lactic acid concentration, ketone bodies, plasma acylcarnitines, and urinary organic acids.
Measurement of plasma lactate concentration is indicated in individuals with features of a myopathy or CNS disease. Fasting blood lactate concentrations above 3 mm/L support a diagnosis of mitochondrial disease.
Measurement of CSF lactate concentration is indicated in individuals with suspected CNS disease. Fasting CSF lactate concentrations above 1.5 mm/L support a diagnosis of mitochondrial disease.
Note: Normal plasma or CSF lactic acid concentration does not exclude the presence of a mitochondrial disorder.
Electroencephalography (EEG) is indicated in individuals with suspected encephalopathy or seizures. Encephalopathy may be associated with generalized slow wave activity on EEG. Generalized or focal spike and wave discharges may be seen in individuals with seizures.
Peripheral neurophysiologic studies are indicated in individuals with limb weakness, sensory symptoms, or areflexia. Electromyography (EMG) is often normal but may show myopathic features. Nerve conduction velocity (NCV) may be normal or may show a predominantly axonal sensorimotor polyneuropathy.
Magnetic resonance spectroscopy (MRS) and exercise testing (with measurement of blood concentration of lactate) may be used to detect evidence of abnormal mitochondrial function noninvasively.
Traditionally, the diagnosis of mitochondrial disorders has been based on demonstrating mitochondrial dysfunction in a relevant tissue biopsy (e.g., a skeletal muscle or liver biopsy, or skin fibroblasts), with the particular pattern of biochemical abnormality being used to direct targeted molecular genetic testing of mtDNA, specific nuclear genes, or both.
However, the more widespread availability of molecular diagnostic techniques and the advent of exome and genome sequencing has changed the diagnostic approach.
One important caveat arises from the fact that many mtDNA pathogenic variants are heteroplasmic, and the proportion of mutated mtDNA in blood may be undetectable. This can be circumvented by analyzing mtDNA from another tissue – typically skeletal muscle or urinary epithelium – in which the level of heteroplasmy tends to be higher. Some common mtDNA pathogenic variants (e.g., large-scale deletions causing CPEO) may only be detected in skeletal muscle.
Approaches to molecular genetic testing of a proband to consider are use of a multigene panel (
In contrast to genomic testing, multigene panel testing relies on the clinician developing a hypothesis about which specific gene or set of genes to test. Hypotheses may be based on (1) mode of inheritance, (2) distinguishing clinical features, and/or (3) other discriminating features.
In individuals with a specific clinical phenotype (e.g., MELAS, LHON,
For an introduction to multigene panels click
Note: (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single-gene testing or multigene molecular genetic testing panels. (2) Most laboratories confirm positive results using a second, well-established method. (3) Certain DNA variants – such as large deletions or duplications (>8-10 bp in length), triplet repeat expansions, and epigenetic alterations – may not be detectable through genomic testing [
In many individuals in whom molecular genetic testing does not yield or confirm a diagnosis, further investigation of suspected mitochondrial disease can involve a range of different clinical tests, including muscle biopsy for respiratory chain function.
• Autosomal dominant inheritance associated with a
• A single occurrence of an autosomal recessive, X-linked, or maternally inherited disorder
• An acquired (non-genetic) cause
• Measurement of plasma lactate concentration is indicated in individuals with features of a myopathy or CNS disease. Fasting blood lactate concentrations above 3 mm/L support a diagnosis of mitochondrial disease.
• Measurement of CSF lactate concentration is indicated in individuals with suspected CNS disease. Fasting CSF lactate concentrations above 1.5 mm/L support a diagnosis of mitochondrial disease.
• Electroencephalography (EEG) is indicated in individuals with suspected encephalopathy or seizures. Encephalopathy may be associated with generalized slow wave activity on EEG. Generalized or focal spike and wave discharges may be seen in individuals with seizures.
• Peripheral neurophysiologic studies are indicated in individuals with limb weakness, sensory symptoms, or areflexia. Electromyography (EMG) is often normal but may show myopathic features. Nerve conduction velocity (NCV) may be normal or may show a predominantly axonal sensorimotor polyneuropathy.
• Magnetic resonance spectroscopy (MRS) and exercise testing (with measurement of blood concentration of lactate) may be used to detect evidence of abnormal mitochondrial function noninvasively.
## Physical Examination and Neurologic Evaluation
A comprehensive physical examination is essential to identify asymptomatic organ involvement that would allow a syndromic diagnosis, or to identify asymptomatic complications that require management. Mitochondrial disorders can affect most organ systems, but a particular emphasis on the neuromuscular system and cardiovascular system is important.
## Family History
A three-generation family history should be taken, with attention to relatives with manifestations of mitochondrial disorders and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing.
Autosomal dominant inheritance associated with a
A single occurrence of an autosomal recessive, X-linked, or maternally inherited disorder
An acquired (non-genetic) cause
Many individuals with a childhood-onset encephalomyopathy and most adults with PEO or KSS represent simplex cases (
• Autosomal dominant inheritance associated with a
• A single occurrence of an autosomal recessive, X-linked, or maternally inherited disorder
• An acquired (non-genetic) cause
## Other Investigations to Establish the Extent of the Phenotype
Clinical tests are used to support a diagnosis of mitochondrial disease [
When the clinical picture is nonspecific but highly suggestive of a mitochondrial disorder, the clinician should start with measurement of plasma or CSF lactic acid concentration, ketone bodies, plasma acylcarnitines, and urinary organic acids.
Measurement of plasma lactate concentration is indicated in individuals with features of a myopathy or CNS disease. Fasting blood lactate concentrations above 3 mm/L support a diagnosis of mitochondrial disease.
Measurement of CSF lactate concentration is indicated in individuals with suspected CNS disease. Fasting CSF lactate concentrations above 1.5 mm/L support a diagnosis of mitochondrial disease.
Note: Normal plasma or CSF lactic acid concentration does not exclude the presence of a mitochondrial disorder.
Electroencephalography (EEG) is indicated in individuals with suspected encephalopathy or seizures. Encephalopathy may be associated with generalized slow wave activity on EEG. Generalized or focal spike and wave discharges may be seen in individuals with seizures.
Peripheral neurophysiologic studies are indicated in individuals with limb weakness, sensory symptoms, or areflexia. Electromyography (EMG) is often normal but may show myopathic features. Nerve conduction velocity (NCV) may be normal or may show a predominantly axonal sensorimotor polyneuropathy.
Magnetic resonance spectroscopy (MRS) and exercise testing (with measurement of blood concentration of lactate) may be used to detect evidence of abnormal mitochondrial function noninvasively.
• Measurement of plasma lactate concentration is indicated in individuals with features of a myopathy or CNS disease. Fasting blood lactate concentrations above 3 mm/L support a diagnosis of mitochondrial disease.
• Measurement of CSF lactate concentration is indicated in individuals with suspected CNS disease. Fasting CSF lactate concentrations above 1.5 mm/L support a diagnosis of mitochondrial disease.
• Electroencephalography (EEG) is indicated in individuals with suspected encephalopathy or seizures. Encephalopathy may be associated with generalized slow wave activity on EEG. Generalized or focal spike and wave discharges may be seen in individuals with seizures.
• Peripheral neurophysiologic studies are indicated in individuals with limb weakness, sensory symptoms, or areflexia. Electromyography (EMG) is often normal but may show myopathic features. Nerve conduction velocity (NCV) may be normal or may show a predominantly axonal sensorimotor polyneuropathy.
• Magnetic resonance spectroscopy (MRS) and exercise testing (with measurement of blood concentration of lactate) may be used to detect evidence of abnormal mitochondrial function noninvasively.
## Molecular Genetic Testing
Traditionally, the diagnosis of mitochondrial disorders has been based on demonstrating mitochondrial dysfunction in a relevant tissue biopsy (e.g., a skeletal muscle or liver biopsy, or skin fibroblasts), with the particular pattern of biochemical abnormality being used to direct targeted molecular genetic testing of mtDNA, specific nuclear genes, or both.
However, the more widespread availability of molecular diagnostic techniques and the advent of exome and genome sequencing has changed the diagnostic approach.
One important caveat arises from the fact that many mtDNA pathogenic variants are heteroplasmic, and the proportion of mutated mtDNA in blood may be undetectable. This can be circumvented by analyzing mtDNA from another tissue – typically skeletal muscle or urinary epithelium – in which the level of heteroplasmy tends to be higher. Some common mtDNA pathogenic variants (e.g., large-scale deletions causing CPEO) may only be detected in skeletal muscle.
Approaches to molecular genetic testing of a proband to consider are use of a multigene panel (
In contrast to genomic testing, multigene panel testing relies on the clinician developing a hypothesis about which specific gene or set of genes to test. Hypotheses may be based on (1) mode of inheritance, (2) distinguishing clinical features, and/or (3) other discriminating features.
In individuals with a specific clinical phenotype (e.g., MELAS, LHON,
For an introduction to multigene panels click
Note: (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single-gene testing or multigene molecular genetic testing panels. (2) Most laboratories confirm positive results using a second, well-established method. (3) Certain DNA variants – such as large deletions or duplications (>8-10 bp in length), triplet repeat expansions, and epigenetic alterations – may not be detectable through genomic testing [
## Option 1
In contrast to genomic testing, multigene panel testing relies on the clinician developing a hypothesis about which specific gene or set of genes to test. Hypotheses may be based on (1) mode of inheritance, (2) distinguishing clinical features, and/or (3) other discriminating features.
In individuals with a specific clinical phenotype (e.g., MELAS, LHON,
For an introduction to multigene panels click
## Option 2
Note: (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single-gene testing or multigene molecular genetic testing panels. (2) Most laboratories confirm positive results using a second, well-established method. (3) Certain DNA variants – such as large deletions or duplications (>8-10 bp in length), triplet repeat expansions, and epigenetic alterations – may not be detectable through genomic testing [
## Other (Non-Molecular Genetic) Testing
In many individuals in whom molecular genetic testing does not yield or confirm a diagnosis, further investigation of suspected mitochondrial disease can involve a range of different clinical tests, including muscle biopsy for respiratory chain function.
## Patient Care Guidelines
Several centers worldwide have produced guidelines on the clinical management of mitochondrial disease, including the international Mitochondrial Medicine Society [
There are currently no treatments known to influence the disease course in mitochondrial disease. Idebenone has been licensed as a treatment for
## Genetic Counseling
Mitochondrial disorders may be caused by mutation of a mitochondrial DNA (mtDNA) gene or mutation of a nuclear gene (nDNA).
mtDNA pathogenic variants are transmitted by maternal inheritance (mitochondrial inheritance).
nDNA pathogenic variants may be inherited in an autosomal recessive, autosomal dominant, or X-linked manner.
Note: The predisposition to form multiple mtDNA deletions can be inherited in an autosomal dominant or an autosomal recessive manner.
Single mtDNA deletions
mtDNA deletions generally occur
When single mtDNA deletions are transmitted, inheritance is from the mother.
mtDNA single-nucleotide variants and duplications
mtDNA single-nucleotide variants and duplications may be transmitted (through the maternal line only).
The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms.
The father of a proband is not at risk of having the mtDNA pathogenic variant.
The risk to the sibs depends on the genetic status of the mother: if the mother has the mtDNA pathogenic variant, all sibs will inherit it. If the mother of the proband is heteroplasmic for the mtDNA pathogenic variant, the proportion of mutated mtDNA she transmits to offspring varies.
Clinical expression in sibs depends on the proportion of mutated mtDNA (mutational load), and the organs and tissues in which they are found (tissue distribution and threshold effect). Sibs often inherit different proportions of mutated mtDNA, and thus can have a wide range of clinical manifestations.
When a proband has a single mtDNA deletion, the current best estimate of the recurrence risk to sibs is 1/24 [
Offspring of males with a mtDNA pathogenic variant will not inherit the variant.
All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. If the female proband is heteroplasmic for the mtDNA pathogenic variant, the proportion of mutated mtDNA she transmits to offspring varies.
Clinical expression in offspring depends on the proportion of mutated mtDNA (mutational load), and the organs and tissues in which they are found (tissue distribution and threshold effect). Offspring often inherit different proportions of mutated mtDNA and therefore can have a wide range of clinical manifestations.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
Molecular genetic testing for the pathogenic variants identified in the proband is recommended for the parents of the proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a causative pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Some individuals diagnosed with an autosomal dominant mitochondrial disorder inherited a pathogenic variant from a heterozygous parent who may or may not have symptoms.
Alternatively, a proband may have the disorder as the result of a
Molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of an individual diagnosed with an autosomal dominant mitochondrial disorder may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the causative pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous may or may not be affected.
If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.
The interpretation of a CVS result is difficult for most heteroplasmic mtDNA pathogenic variants. However, the variants m.8993T>G and m.8993T>C show a more even tissue distribution, and the percentage level of these two variants does not appear to change significantly over time. Successful prenatal molecular diagnosis has been carried out for pathogenic variants using DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or CVS (usually performed at ~10-12 weeks' gestation) [
• mtDNA pathogenic variants are transmitted by maternal inheritance (mitochondrial inheritance).
• nDNA pathogenic variants may be inherited in an autosomal recessive, autosomal dominant, or X-linked manner.
• Single mtDNA deletions
• mtDNA deletions generally occur
• When single mtDNA deletions are transmitted, inheritance is from the mother.
• mtDNA deletions generally occur
• When single mtDNA deletions are transmitted, inheritance is from the mother.
• mtDNA single-nucleotide variants and duplications
• mtDNA single-nucleotide variants and duplications may be transmitted (through the maternal line only).
• The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms.
• The father of a proband is not at risk of having the mtDNA pathogenic variant.
• mtDNA single-nucleotide variants and duplications may be transmitted (through the maternal line only).
• The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms.
• The father of a proband is not at risk of having the mtDNA pathogenic variant.
• mtDNA deletions generally occur
• When single mtDNA deletions are transmitted, inheritance is from the mother.
• mtDNA single-nucleotide variants and duplications may be transmitted (through the maternal line only).
• The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms.
• The father of a proband is not at risk of having the mtDNA pathogenic variant.
• The risk to the sibs depends on the genetic status of the mother: if the mother has the mtDNA pathogenic variant, all sibs will inherit it. If the mother of the proband is heteroplasmic for the mtDNA pathogenic variant, the proportion of mutated mtDNA she transmits to offspring varies.
• Clinical expression in sibs depends on the proportion of mutated mtDNA (mutational load), and the organs and tissues in which they are found (tissue distribution and threshold effect). Sibs often inherit different proportions of mutated mtDNA, and thus can have a wide range of clinical manifestations.
• When a proband has a single mtDNA deletion, the current best estimate of the recurrence risk to sibs is 1/24 [
• Offspring of males with a mtDNA pathogenic variant will not inherit the variant.
• All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. If the female proband is heteroplasmic for the mtDNA pathogenic variant, the proportion of mutated mtDNA she transmits to offspring varies.
• Clinical expression in offspring depends on the proportion of mutated mtDNA (mutational load), and the organs and tissues in which they are found (tissue distribution and threshold effect). Offspring often inherit different proportions of mutated mtDNA and therefore can have a wide range of clinical manifestations.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
• Molecular genetic testing for the pathogenic variants identified in the proband is recommended for the parents of the proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a causative pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Some individuals diagnosed with an autosomal dominant mitochondrial disorder inherited a pathogenic variant from a heterozygous parent who may or may not have symptoms.
• Alternatively, a proband may have the disorder as the result of a
• Molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of an individual diagnosed with an autosomal dominant mitochondrial disorder may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
• The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the causative pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous may or may not be affected.
• If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.
## Mode of Inheritance
Mitochondrial disorders may be caused by mutation of a mitochondrial DNA (mtDNA) gene or mutation of a nuclear gene (nDNA).
mtDNA pathogenic variants are transmitted by maternal inheritance (mitochondrial inheritance).
nDNA pathogenic variants may be inherited in an autosomal recessive, autosomal dominant, or X-linked manner.
Note: The predisposition to form multiple mtDNA deletions can be inherited in an autosomal dominant or an autosomal recessive manner.
• mtDNA pathogenic variants are transmitted by maternal inheritance (mitochondrial inheritance).
• nDNA pathogenic variants may be inherited in an autosomal recessive, autosomal dominant, or X-linked manner.
## Mitochondrial Inheritance – Risk to Family Members
Single mtDNA deletions
mtDNA deletions generally occur
When single mtDNA deletions are transmitted, inheritance is from the mother.
mtDNA single-nucleotide variants and duplications
mtDNA single-nucleotide variants and duplications may be transmitted (through the maternal line only).
The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms.
The father of a proband is not at risk of having the mtDNA pathogenic variant.
The risk to the sibs depends on the genetic status of the mother: if the mother has the mtDNA pathogenic variant, all sibs will inherit it. If the mother of the proband is heteroplasmic for the mtDNA pathogenic variant, the proportion of mutated mtDNA she transmits to offspring varies.
Clinical expression in sibs depends on the proportion of mutated mtDNA (mutational load), and the organs and tissues in which they are found (tissue distribution and threshold effect). Sibs often inherit different proportions of mutated mtDNA, and thus can have a wide range of clinical manifestations.
When a proband has a single mtDNA deletion, the current best estimate of the recurrence risk to sibs is 1/24 [
Offspring of males with a mtDNA pathogenic variant will not inherit the variant.
All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. If the female proband is heteroplasmic for the mtDNA pathogenic variant, the proportion of mutated mtDNA she transmits to offspring varies.
Clinical expression in offspring depends on the proportion of mutated mtDNA (mutational load), and the organs and tissues in which they are found (tissue distribution and threshold effect). Offspring often inherit different proportions of mutated mtDNA and therefore can have a wide range of clinical manifestations.
• Single mtDNA deletions
• mtDNA deletions generally occur
• When single mtDNA deletions are transmitted, inheritance is from the mother.
• mtDNA deletions generally occur
• When single mtDNA deletions are transmitted, inheritance is from the mother.
• mtDNA single-nucleotide variants and duplications
• mtDNA single-nucleotide variants and duplications may be transmitted (through the maternal line only).
• The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms.
• The father of a proband is not at risk of having the mtDNA pathogenic variant.
• mtDNA single-nucleotide variants and duplications may be transmitted (through the maternal line only).
• The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms.
• The father of a proband is not at risk of having the mtDNA pathogenic variant.
• mtDNA deletions generally occur
• When single mtDNA deletions are transmitted, inheritance is from the mother.
• mtDNA single-nucleotide variants and duplications may be transmitted (through the maternal line only).
• The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms.
• The father of a proband is not at risk of having the mtDNA pathogenic variant.
• The risk to the sibs depends on the genetic status of the mother: if the mother has the mtDNA pathogenic variant, all sibs will inherit it. If the mother of the proband is heteroplasmic for the mtDNA pathogenic variant, the proportion of mutated mtDNA she transmits to offspring varies.
• Clinical expression in sibs depends on the proportion of mutated mtDNA (mutational load), and the organs and tissues in which they are found (tissue distribution and threshold effect). Sibs often inherit different proportions of mutated mtDNA, and thus can have a wide range of clinical manifestations.
• When a proband has a single mtDNA deletion, the current best estimate of the recurrence risk to sibs is 1/24 [
• Offspring of males with a mtDNA pathogenic variant will not inherit the variant.
• All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. If the female proband is heteroplasmic for the mtDNA pathogenic variant, the proportion of mutated mtDNA she transmits to offspring varies.
• Clinical expression in offspring depends on the proportion of mutated mtDNA (mutational load), and the organs and tissues in which they are found (tissue distribution and threshold effect). Offspring often inherit different proportions of mutated mtDNA and therefore can have a wide range of clinical manifestations.
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
Molecular genetic testing for the pathogenic variants identified in the proband is recommended for the parents of the proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a causative pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
• Molecular genetic testing for the pathogenic variants identified in the proband is recommended for the parents of the proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a causative pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Autosomal Dominant Inheritance – Risk to Family Members
Some individuals diagnosed with an autosomal dominant mitochondrial disorder inherited a pathogenic variant from a heterozygous parent who may or may not have symptoms.
Alternatively, a proband may have the disorder as the result of a
Molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of an individual diagnosed with an autosomal dominant mitochondrial disorder may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
• Some individuals diagnosed with an autosomal dominant mitochondrial disorder inherited a pathogenic variant from a heterozygous parent who may or may not have symptoms.
• Alternatively, a proband may have the disorder as the result of a
• Molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of an individual diagnosed with an autosomal dominant mitochondrial disorder may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
## X-Linked Inheritance – Risk to Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the causative pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous may or may not be affected.
If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.
• The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the causative pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous may or may not be affected.
• If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.
## Prenatal Testing
The interpretation of a CVS result is difficult for most heteroplasmic mtDNA pathogenic variants. However, the variants m.8993T>G and m.8993T>C show a more even tissue distribution, and the percentage level of these two variants does not appear to change significantly over time. Successful prenatal molecular diagnosis has been carried out for pathogenic variants using DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or CVS (usually performed at ~10-12 weeks' gestation) [
## Resources
NY
Italy
United Kingdom
United Kingdom
•
•
•
•
•
•
• NY
•
•
•
•
•
•
•
• Italy
•
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
## Chapter Notes
29 July 2021 (bp) Comprehensive update posted live
14 August 2014 (me) Comprehensive update posted live
16 September 2010 (me) Comprehensive update posted live
18 December 2003 (me) Comprehensive update posted live
8 June 2000 (tk, pb) Overview posted live
20 April 2000 (pfc) Original submission
• 29 July 2021 (bp) Comprehensive update posted live
• 14 August 2014 (me) Comprehensive update posted live
• 16 September 2010 (me) Comprehensive update posted live
• 18 December 2003 (me) Comprehensive update posted live
• 8 June 2000 (tk, pb) Overview posted live
• 20 April 2000 (pfc) Original submission
## Revision History
29 July 2021 (bp) Comprehensive update posted live
14 August 2014 (me) Comprehensive update posted live
16 September 2010 (me) Comprehensive update posted live
18 December 2003 (me) Comprehensive update posted live
8 June 2000 (tk, pb) Overview posted live
20 April 2000 (pfc) Original submission
• 29 July 2021 (bp) Comprehensive update posted live
• 14 August 2014 (me) Comprehensive update posted live
• 16 September 2010 (me) Comprehensive update posted live
• 18 December 2003 (me) Comprehensive update posted live
• 8 June 2000 (tk, pb) Overview posted live
• 20 April 2000 (pfc) Original submission
## References
## Literature Cited
The human mitochondrial genome
|
[] |
8/6/2000
|
29/7/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mtdna-md-ov
|
mtdna-md-ov
|
[
"Mitochondrial DNA Maintenance Defects",
"Overview"
] |
Mitochondrial DNA Maintenance Defects Overview
|
Ayman W El-Hattab, William J Craigen, Lee-Jun C Wong, Fernando Scaglia
|
Summary This purpose of this overview is to: Describe the Review the genetic Describe the Provide clinical and laboratory Summarize current Inform
|
## Mitochondrial DNA Maintenance Defects
The maintenance of mtDNA is essential to the functioning of the mitochondria and, thus, to meeting the energy needs of all cells. The maintenance of mtDNA requires proteins essential for mtDNA synthesis, for maintenance of the mitochondrial nucleotide pool, and for mediating mitochondrial fusion [
Mitochondrial DNA is synthesized continuously and is not regulated by the cell cycle. The enzymes that synthesize mtDNA require a balanced supply of intramitochondrial nucleotides. These are supplied through mitochondrial nucleotide salvage pathways and the import of nucleotides from the cytosol via specific transporters. To function properly in mtDNA synthesis the quantities of these enzymes need to be perfectly balanced, a phenomenon achieved – in part – by the exchange of content between mitochondria through the process of mitochondrial fission and fusion.
The proteins known to be required for mtDNA synthesis are encoded by nuclear genes (i.e., genes found in the nucleus of cells). When pathogenic variants disrupt the function of any one of the proteins encoded by these genes, mtDNA synthesis is impaired, resulting in either quantitative defects in mtDNA (mtDNA depletion) or qualitative defects in mtDNA (multiple mtDNA deletions). These defects in mtDNA maintenance result in energy deficiency within cells. Cellular energy production insufficient to meet the needs of a given organ results in organ dysfunction (see
When first identified, defects in mtDNA maintenance were viewed as two clinically distinct groups of disorders:
Mitochondrial DNA depletion syndromes that typically present during infancy and are characterized by severe disease manifestations and shortened life expectancy; and
Multiple mtDNA deletion syndromes that typically present in adulthood and are characterized by milder disease manifestations including progressive external ophthalmoplegia (CPEO) and myopathy.
However, with the current understanding that both mtDNA depletion and multiple mtDNA deletions result from failure of proper mtDNA maintenance, it has become evident that these two groups of disorders represent the ends of a phenotypic continuum. The term "mtDNA maintenance defects" is used to represent the broad disease spectrum that encompasses both presentations as well as those that are intermediate.
• Mitochondrial DNA depletion syndromes that typically present during infancy and are characterized by severe disease manifestations and shortened life expectancy; and
• Multiple mtDNA deletion syndromes that typically present in adulthood and are characterized by milder disease manifestations including progressive external ophthalmoplegia (CPEO) and myopathy.
## Causes of mtDNA Maintenance Defects
To date, pathogenic variants in 20 nuclear genes are known to be associated with mtDNA maintenance defects. These genes and their primary presenting features are organized in
Note: Disorders of mtDNA are not the subject of this overview (see
Categories of mtDNA Maintenance Defects: Genes and Primary Presenting Features
## Clinical Characteristics of mtDNA Maintenance Defects
Mitochondrial DNA maintenance defects are characterized by mtDNA depletion and/or multiple mtDNA deletions in mitochondria of cells of affected organs. The organs/tissues affected most often are the brain, liver, skeletal muscle, peripheral nerves, and gastrointestinal tract. Depending on the organ(s) predominantly affected, these disorders can be classified into groups associated mainly with
Mitochondrial DNA maintenance defects manifesting as encephalohepatopathy (hepatocerebral) are typically associated with mtDNA depletion and generally present in neonates or infants with neurologic manifestations (including developmental delay and epilepsy), and with liver dysfunction and failure. Other common manifestations include growth failure, lactic acidosis, and hypoglycemia.
Mitochondrial DNA Maintenance Defects Presenting with Encephalohepatopathy
DD
Hypotonia
Nystagmus
Lactic acidosis
DD
Hypotonia
Failure to thrive
Hearing impairment
Lactic acidosis
DD
Psychomotor regression
Epilepsy
Hearing impairment
IUGR
Hypoglycemia
DD
Hypotonia
Lactic acidosis
AR = autosomal recessive; DD = developmental delay; IUGR = intrauterine growth restriction; MOI = mode of inheritance; mtDNA = mitochondrial DNA
The majority of encephalomyopathic mtDNA maintenance defects are associated with mtDNA depletion and are early-onset diseases with an infantile presentation. The two disorders, however, that are usually associated with multiple mtDNA deletions rather than depletion are adult-onset diseases:
Mitochondrial DNA Maintenance Defects Presenting with Encephalomyopathy
DD
Hypotonia
Epilepsy
↑ GABA in plasma, urine, & CSF
DD
Hypotonia
Epilepsy
Hearing impairment
Lactic acidosis
DD
HCM
Optic atrophy
Epilepsy
Ataxia
Ophthalmoplegia
Ptosis
Ataxia
DD
Hypotonia
GI dysmotility
Renal tubulopathy
DD
Hypotonia
Dystonia
Hearing impairment
↑ methylmalonic acid
DD
Hypotonia
Hearing impairment
↑ methylmalonic acid
AR = autosomal recessive; CSF = cerebrospinal fluid; DD = developmental delay; GI = gastrointestinal; MOI = mode of inheritance; mtDNA = mitochondrial DNA
Mitochondrial DNA maintenance defects exhibiting encephaloneuropathy can be associated with mtDNA depletion or multiple mtDNA deletions, and are characterized by manifestations related to the central and peripheral nervous systems.
Mitochondrial DNA Maintenance Defects Presenting with Encephaloneuropathy
Vision impairment
Optic nerve pallor
Hypotonia
Hearing impairment
AR = autosomal recessive; MOI = mode of inheritance; mtDNA = mitochondrial DNA
Mitochondrial DNA Maintenance Defects Presenting with Neurogastrointestinal Encephalopathy
GI dysmotility
Cachexia
Peripheral neuropathy
Ophthalmoplegia
Muscle weakness
Leukoencephalopathy
AR = autosomal recessive ; GI = gastrointestinal; MOI = mode of inheritance; mtDNA = mitochondrial DNA
Note: Leukoencephalopathy is not present in
Myopathic mtDNA maintenance defects include a group of diseases that vary in their age of onset. Skeletal muscles are the main system involved in all of them. Cardiomyopathy can occur in some of these disorders.
Mitochondrial DNA Maintenance Defects Presenting with Myopathy
Hypotonia
Hypertrophic cardiomyopathy
Cataracts
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Exercise intolerance / easy fatigability
Hypertrophic cardiomyopathy
Hypotonia
Hypertrophic cardiomyopathy
Hypotonia
Loss of acquired motor skills
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mtDNA = mitochondrial DNA
Mitochondrial DNA maintenance defects that cause ophthalmoplegia are associated with multiple DNA deletions and are characterized by progressive weakness of the extraocular eye muscles resulting in ptosis (drooping of the eyelids) and ophthalmoplegia (paralysis of the extraocular muscles causing limitation in horizontal and vertical eye movements).
Although these are typically diseases of adulthood, earlier onset can be seen in the recessively inherited diseases. Although ophthalmoplegia and ptosis are consistent, and are the main manifestations in these diseases, a more generalized myopathy (sometimes mild) can be observed in some affected individuals.
Mitochondrial DNA Maintenance Defects Presenting with Ophthalmoplegia
Muscle weakness
Bulbar dysfunction
Ataxia
Muscle weakness
Bulbar dysfunction
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mtDNA = mitochondrial DNA
Mitochondrial DNA Maintenance Defects Presenting with Optic Atrophy
Vision impairment
Optic nerve pallor
Peripheral neuropathy
Muscle weakness
AD = autosomal dominant; MOI = mode of inheritance
Mitochondrial DNA Maintenance Defects Presenting with Neuropathy
AD = autosomal dominant; MOI = mode of inheritance; mtDNA = mitochondrial DNA; NA= not available
• DD
• Hypotonia
• Nystagmus
• Lactic acidosis
• DD
• Hypotonia
• Failure to thrive
• Hearing impairment
• Lactic acidosis
• DD
• Psychomotor regression
• Epilepsy
• Hearing impairment
• IUGR
• Hypoglycemia
• DD
• Hypotonia
• Lactic acidosis
• DD
• Hypotonia
• Epilepsy
• ↑ GABA in plasma, urine, & CSF
• DD
• Hypotonia
• Epilepsy
• Hearing impairment
• Lactic acidosis
• DD
• HCM
• Optic atrophy
• Epilepsy
• Ataxia
• Ophthalmoplegia
• Ptosis
• Ataxia
• DD
• Hypotonia
• GI dysmotility
• Renal tubulopathy
• DD
• Hypotonia
• Dystonia
• Hearing impairment
• ↑ methylmalonic acid
• DD
• Hypotonia
• Hearing impairment
• ↑ methylmalonic acid
• Vision impairment
• Optic nerve pallor
• Hypotonia
• Hearing impairment
• GI dysmotility
• Cachexia
• Peripheral neuropathy
• Ophthalmoplegia
• Muscle weakness
• Leukoencephalopathy
• Hypotonia
• Hypertrophic cardiomyopathy
• Cataracts
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Exercise intolerance / easy fatigability
• Hypertrophic cardiomyopathy
• Hypotonia
• Hypertrophic cardiomyopathy
• Hypotonia
• Loss of acquired motor skills
• Muscle weakness
• Bulbar dysfunction
• Ataxia
• Muscle weakness
• Bulbar dysfunction
• Vision impairment
• Optic nerve pallor
• Peripheral neuropathy
• Muscle weakness
## Mitochondrial DNA Maintenance Defects Presenting with Encephalohepatopathy
Mitochondrial DNA maintenance defects manifesting as encephalohepatopathy (hepatocerebral) are typically associated with mtDNA depletion and generally present in neonates or infants with neurologic manifestations (including developmental delay and epilepsy), and with liver dysfunction and failure. Other common manifestations include growth failure, lactic acidosis, and hypoglycemia.
Mitochondrial DNA Maintenance Defects Presenting with Encephalohepatopathy
DD
Hypotonia
Nystagmus
Lactic acidosis
DD
Hypotonia
Failure to thrive
Hearing impairment
Lactic acidosis
DD
Psychomotor regression
Epilepsy
Hearing impairment
IUGR
Hypoglycemia
DD
Hypotonia
Lactic acidosis
AR = autosomal recessive; DD = developmental delay; IUGR = intrauterine growth restriction; MOI = mode of inheritance; mtDNA = mitochondrial DNA
• DD
• Hypotonia
• Nystagmus
• Lactic acidosis
• DD
• Hypotonia
• Failure to thrive
• Hearing impairment
• Lactic acidosis
• DD
• Psychomotor regression
• Epilepsy
• Hearing impairment
• IUGR
• Hypoglycemia
• DD
• Hypotonia
• Lactic acidosis
## Mitochondrial DNA Maintenance Defects Presenting with Encephalomyopathy
The majority of encephalomyopathic mtDNA maintenance defects are associated with mtDNA depletion and are early-onset diseases with an infantile presentation. The two disorders, however, that are usually associated with multiple mtDNA deletions rather than depletion are adult-onset diseases:
Mitochondrial DNA Maintenance Defects Presenting with Encephalomyopathy
DD
Hypotonia
Epilepsy
↑ GABA in plasma, urine, & CSF
DD
Hypotonia
Epilepsy
Hearing impairment
Lactic acidosis
DD
HCM
Optic atrophy
Epilepsy
Ataxia
Ophthalmoplegia
Ptosis
Ataxia
DD
Hypotonia
GI dysmotility
Renal tubulopathy
DD
Hypotonia
Dystonia
Hearing impairment
↑ methylmalonic acid
DD
Hypotonia
Hearing impairment
↑ methylmalonic acid
AR = autosomal recessive; CSF = cerebrospinal fluid; DD = developmental delay; GI = gastrointestinal; MOI = mode of inheritance; mtDNA = mitochondrial DNA
• DD
• Hypotonia
• Epilepsy
• ↑ GABA in plasma, urine, & CSF
• DD
• Hypotonia
• Epilepsy
• Hearing impairment
• Lactic acidosis
• DD
• HCM
• Optic atrophy
• Epilepsy
• Ataxia
• Ophthalmoplegia
• Ptosis
• Ataxia
• DD
• Hypotonia
• GI dysmotility
• Renal tubulopathy
• DD
• Hypotonia
• Dystonia
• Hearing impairment
• ↑ methylmalonic acid
• DD
• Hypotonia
• Hearing impairment
• ↑ methylmalonic acid
## Mitochondrial DNA Maintenance Defects Presenting with Encephaloneuropathy
Mitochondrial DNA maintenance defects exhibiting encephaloneuropathy can be associated with mtDNA depletion or multiple mtDNA deletions, and are characterized by manifestations related to the central and peripheral nervous systems.
Mitochondrial DNA Maintenance Defects Presenting with Encephaloneuropathy
Vision impairment
Optic nerve pallor
Hypotonia
Hearing impairment
AR = autosomal recessive; MOI = mode of inheritance; mtDNA = mitochondrial DNA
• Vision impairment
• Optic nerve pallor
• Hypotonia
• Hearing impairment
## Mitochondrial DNA Maintenance Defects Presenting with Neurogastrointestinal Encephalopathy
Mitochondrial DNA Maintenance Defects Presenting with Neurogastrointestinal Encephalopathy
GI dysmotility
Cachexia
Peripheral neuropathy
Ophthalmoplegia
Muscle weakness
Leukoencephalopathy
AR = autosomal recessive ; GI = gastrointestinal; MOI = mode of inheritance; mtDNA = mitochondrial DNA
Note: Leukoencephalopathy is not present in
• GI dysmotility
• Cachexia
• Peripheral neuropathy
• Ophthalmoplegia
• Muscle weakness
• Leukoencephalopathy
## Mitochondrial DNA Maintenance Defects Presenting with Myopathy
Myopathic mtDNA maintenance defects include a group of diseases that vary in their age of onset. Skeletal muscles are the main system involved in all of them. Cardiomyopathy can occur in some of these disorders.
Mitochondrial DNA Maintenance Defects Presenting with Myopathy
Hypotonia
Hypertrophic cardiomyopathy
Cataracts
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Exercise intolerance / easy fatigability
Hypertrophic cardiomyopathy
Hypotonia
Hypertrophic cardiomyopathy
Hypotonia
Loss of acquired motor skills
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mtDNA = mitochondrial DNA
• Hypotonia
• Hypertrophic cardiomyopathy
• Cataracts
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Exercise intolerance / easy fatigability
• Hypertrophic cardiomyopathy
• Hypotonia
• Hypertrophic cardiomyopathy
• Hypotonia
• Loss of acquired motor skills
## Mitochondrial DNA Maintenance Defects Presenting with Ophthalmoplegia
Mitochondrial DNA maintenance defects that cause ophthalmoplegia are associated with multiple DNA deletions and are characterized by progressive weakness of the extraocular eye muscles resulting in ptosis (drooping of the eyelids) and ophthalmoplegia (paralysis of the extraocular muscles causing limitation in horizontal and vertical eye movements).
Although these are typically diseases of adulthood, earlier onset can be seen in the recessively inherited diseases. Although ophthalmoplegia and ptosis are consistent, and are the main manifestations in these diseases, a more generalized myopathy (sometimes mild) can be observed in some affected individuals.
Mitochondrial DNA Maintenance Defects Presenting with Ophthalmoplegia
Muscle weakness
Bulbar dysfunction
Ataxia
Muscle weakness
Bulbar dysfunction
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mtDNA = mitochondrial DNA
• Muscle weakness
• Bulbar dysfunction
• Ataxia
• Muscle weakness
• Bulbar dysfunction
## Mitochondrial DNA Maintenance Defects Presenting with Optic Atrophy
Mitochondrial DNA Maintenance Defects Presenting with Optic Atrophy
Vision impairment
Optic nerve pallor
Peripheral neuropathy
Muscle weakness
AD = autosomal dominant; MOI = mode of inheritance
• Vision impairment
• Optic nerve pallor
• Peripheral neuropathy
• Muscle weakness
## Mitochondrial DNA Maintenance Defects Presenting with Neuropathy
Mitochondrial DNA Maintenance Defects Presenting with Neuropathy
AD = autosomal dominant; MOI = mode of inheritance; mtDNA = mitochondrial DNA; NA= not available
## Evaluation Strategies to Diagnose mtDNA Maintenance Defects and to Establish a Genetic Cause in a Proband
Establishing a specific genetic cause of a mtDNA maintenance defect can aid in discussion of prognosis (which is beyond the scope of this
Establishing the specific genetic cause of a mtDNA maintenance defect usually requires a medical history, physical and neurologic examination, laboratory testing including routine studies and specialized biochemical genetic studies, imaging studies such as brain MRI, echocardiogram, abdominal ultrasound examination, family history, and genomic/genetic testing.
The diagnosis of a mtDNA maintenance defect is suspected based on the involved organs, age of onset, and results of commonly available laboratory tests (e.g., presence of lactic acidemia or methylmalonic aciduria).
Biopsies of affected tissues typically show mtDNA depletion and/or multiple mtDNA deletions as well as decreased activity of multiple electron transport complexes (ETC). However, because tissue biopsies are often invasive procedures, molecular genetic testing of leukocyte DNA is typically performed first to determine if the diagnosis of a mtDNA maintenance defect can be established. When molecular genetic test results are equivocal or fail to confirm the diagnosis of a mtDNA maintenance defect, tissue samples can be obtained to assay for mtDNA depletion and/or multiple mtDNA deletions and to assess ETC activity.
A three-generation family history should be obtained, with attention to relatives with signs and symptoms that could be related to a mtDNA maintenance defect and documentation of relevant findings through direct physical examination, or review of medical records, including results of molecular genetic testing.
Approaches include gene-targeted testing (multigene panel, single-gene testing) or comprehensive genomic testing (exome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing may not. Options for testing include the following:
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical and Laboratory Findings
The diagnosis of a mtDNA maintenance defect is suspected based on the involved organs, age of onset, and results of commonly available laboratory tests (e.g., presence of lactic acidemia or methylmalonic aciduria).
Biopsies of affected tissues typically show mtDNA depletion and/or multiple mtDNA deletions as well as decreased activity of multiple electron transport complexes (ETC). However, because tissue biopsies are often invasive procedures, molecular genetic testing of leukocyte DNA is typically performed first to determine if the diagnosis of a mtDNA maintenance defect can be established. When molecular genetic test results are equivocal or fail to confirm the diagnosis of a mtDNA maintenance defect, tissue samples can be obtained to assay for mtDNA depletion and/or multiple mtDNA deletions and to assess ETC activity.
## Family History
A three-generation family history should be obtained, with attention to relatives with signs and symptoms that could be related to a mtDNA maintenance defect and documentation of relevant findings through direct physical examination, or review of medical records, including results of molecular genetic testing.
## Molecular Genetic Testing
Approaches include gene-targeted testing (multigene panel, single-gene testing) or comprehensive genomic testing (exome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing may not. Options for testing include the following:
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Management of Individuals with mtDNA Maintenance Defects
Most mtDNA maintenance defects affect multiple organs; therefore, affected individuals need comprehensive evaluations to assess the degree of involvement of different organs. Management should also involve a multidisciplinary team to provide clinical care for these multiorgan diseases.
For individuals with chronic disease,
Recommended Evaluations Following Initial Diagnosis in a Proband with a mtDNA Maintenance Defect Resulting in Chronic Disease
Echocardiogram
Electrocardiogram
Venous blood gases
Pulse oximetry & pulmonary function tests
Polysomnography
Liver function test (transaminases, albumin, coagulation profile)
Liver ultrasound
Consultation w/gastroenterologist
Depending on manifestations: abdominal films, abdominal CT, upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, antroduodenal manometry
Swallowing assessment
Nutritional eval
Urinalysis
Urine amino acids, calcium, phosphate, & protein
Comprehensive neurologic exam
Brain MRI & MRS
Nerve conduction studies & electromyography (if neuropathy is suspected)
Electroencephalography (if seizures are suspected)
Consultation w/clinical geneticist &/or genetic counselor
Lactate level to evaluate for lactic acidosis
Glucose level to evaluate for hypoglycemia
Currently there is no clinical therapy to treat the primary defect in affected individuals. Management, which is primarily supportive, is outlined in
As exogenous thymidine phosphorylase can improve outcome in MNGIE resulting from thymidine phosphorylase deficiency, experimental therapy for MNGIE includes both bone marrow and liver transplantation.
Nucleoside therapy has been considered in TK2 deficiency.
Affected individuals may be at increased risk for acidosis and hypoglycemia during illness and surgery and protocols to prevent prolonged fasting should be provided.
Certain medications and anesthetic agents should be avoided; see
Treatment of Manifestations in a Proband with a mtDNA Maintenance Defect Resulting in Chronic Disease
Referral to cardiologist
Standard treatment
Referral to pulmonologist &/or sleep medicine physician
Aggressive antibiotic treatment of chest infections
Chest physiotherapy
Artificial ventilation including assisted nasal ventilation (CPAP or BiPAP) or intubation w/use of tracheostomy & ventilator (See
Referral to hepatologist
Reduction in dietary protein
Correction of coagulopathy
Frequent or continuous feeding to prevent hypoglycemia
Consideration of liver transplant
Referral to gastroenterologist
Nutritional support
Total parenteral nutrition
Domperidone
Antibiotic therapy for intestinal bacterial overgrowth
Celiac plexus & splanchnic nerve block (See
Nutritional support
Gastrostomy tube placement
Referral to nephrologist
Correction of acidosis & other metabolic derangements
Referral to neurologist
Amitriptyline, nortriptyline, & gabapentin
Referral to neurologist
Standard ASM (Refractory epilepsy may require high doses &/or use of multiple ASMs.)
Frequent feeding & avoidance of fasting
Uncooked cornstarch
ASM = anti-seizure medication
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, guardianship, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Echocardiogram
• Electrocardiogram
• Venous blood gases
• Pulse oximetry & pulmonary function tests
• Polysomnography
• Liver function test (transaminases, albumin, coagulation profile)
• Liver ultrasound
• Consultation w/gastroenterologist
• Depending on manifestations: abdominal films, abdominal CT, upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, antroduodenal manometry
• Swallowing assessment
• Nutritional eval
• Urinalysis
• Urine amino acids, calcium, phosphate, & protein
• Comprehensive neurologic exam
• Brain MRI & MRS
• Nerve conduction studies & electromyography (if neuropathy is suspected)
• Electroencephalography (if seizures are suspected)
• Consultation w/clinical geneticist &/or genetic counselor
• Lactate level to evaluate for lactic acidosis
• Glucose level to evaluate for hypoglycemia
• As exogenous thymidine phosphorylase can improve outcome in MNGIE resulting from thymidine phosphorylase deficiency, experimental therapy for MNGIE includes both bone marrow and liver transplantation.
• Nucleoside therapy has been considered in TK2 deficiency.
• Affected individuals may be at increased risk for acidosis and hypoglycemia during illness and surgery and protocols to prevent prolonged fasting should be provided.
• Certain medications and anesthetic agents should be avoided; see
• Referral to cardiologist
• Standard treatment
• Referral to pulmonologist &/or sleep medicine physician
• Aggressive antibiotic treatment of chest infections
• Chest physiotherapy
• Artificial ventilation including assisted nasal ventilation (CPAP or BiPAP) or intubation w/use of tracheostomy & ventilator (See
• Referral to hepatologist
• Reduction in dietary protein
• Correction of coagulopathy
• Frequent or continuous feeding to prevent hypoglycemia
• Consideration of liver transplant
• Referral to gastroenterologist
• Nutritional support
• Total parenteral nutrition
• Domperidone
• Antibiotic therapy for intestinal bacterial overgrowth
• Celiac plexus & splanchnic nerve block (See
• Nutritional support
• Gastrostomy tube placement
• Referral to nephrologist
• Correction of acidosis & other metabolic derangements
• Referral to neurologist
• Amitriptyline, nortriptyline, & gabapentin
• Referral to neurologist
• Standard ASM (Refractory epilepsy may require high doses &/or use of multiple ASMs.)
• Frequent feeding & avoidance of fasting
• Uncooked cornstarch
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, guardianship, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Assessment of Disease Extent
For individuals with chronic disease,
Recommended Evaluations Following Initial Diagnosis in a Proband with a mtDNA Maintenance Defect Resulting in Chronic Disease
Echocardiogram
Electrocardiogram
Venous blood gases
Pulse oximetry & pulmonary function tests
Polysomnography
Liver function test (transaminases, albumin, coagulation profile)
Liver ultrasound
Consultation w/gastroenterologist
Depending on manifestations: abdominal films, abdominal CT, upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, antroduodenal manometry
Swallowing assessment
Nutritional eval
Urinalysis
Urine amino acids, calcium, phosphate, & protein
Comprehensive neurologic exam
Brain MRI & MRS
Nerve conduction studies & electromyography (if neuropathy is suspected)
Electroencephalography (if seizures are suspected)
Consultation w/clinical geneticist &/or genetic counselor
Lactate level to evaluate for lactic acidosis
Glucose level to evaluate for hypoglycemia
• Echocardiogram
• Electrocardiogram
• Venous blood gases
• Pulse oximetry & pulmonary function tests
• Polysomnography
• Liver function test (transaminases, albumin, coagulation profile)
• Liver ultrasound
• Consultation w/gastroenterologist
• Depending on manifestations: abdominal films, abdominal CT, upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, antroduodenal manometry
• Swallowing assessment
• Nutritional eval
• Urinalysis
• Urine amino acids, calcium, phosphate, & protein
• Comprehensive neurologic exam
• Brain MRI & MRS
• Nerve conduction studies & electromyography (if neuropathy is suspected)
• Electroencephalography (if seizures are suspected)
• Consultation w/clinical geneticist &/or genetic counselor
• Lactate level to evaluate for lactic acidosis
• Glucose level to evaluate for hypoglycemia
## Treatment of Manifestations
Currently there is no clinical therapy to treat the primary defect in affected individuals. Management, which is primarily supportive, is outlined in
As exogenous thymidine phosphorylase can improve outcome in MNGIE resulting from thymidine phosphorylase deficiency, experimental therapy for MNGIE includes both bone marrow and liver transplantation.
Nucleoside therapy has been considered in TK2 deficiency.
Affected individuals may be at increased risk for acidosis and hypoglycemia during illness and surgery and protocols to prevent prolonged fasting should be provided.
Certain medications and anesthetic agents should be avoided; see
Treatment of Manifestations in a Proband with a mtDNA Maintenance Defect Resulting in Chronic Disease
Referral to cardiologist
Standard treatment
Referral to pulmonologist &/or sleep medicine physician
Aggressive antibiotic treatment of chest infections
Chest physiotherapy
Artificial ventilation including assisted nasal ventilation (CPAP or BiPAP) or intubation w/use of tracheostomy & ventilator (See
Referral to hepatologist
Reduction in dietary protein
Correction of coagulopathy
Frequent or continuous feeding to prevent hypoglycemia
Consideration of liver transplant
Referral to gastroenterologist
Nutritional support
Total parenteral nutrition
Domperidone
Antibiotic therapy for intestinal bacterial overgrowth
Celiac plexus & splanchnic nerve block (See
Nutritional support
Gastrostomy tube placement
Referral to nephrologist
Correction of acidosis & other metabolic derangements
Referral to neurologist
Amitriptyline, nortriptyline, & gabapentin
Referral to neurologist
Standard ASM (Refractory epilepsy may require high doses &/or use of multiple ASMs.)
Frequent feeding & avoidance of fasting
Uncooked cornstarch
ASM = anti-seizure medication
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, guardianship, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• As exogenous thymidine phosphorylase can improve outcome in MNGIE resulting from thymidine phosphorylase deficiency, experimental therapy for MNGIE includes both bone marrow and liver transplantation.
• Nucleoside therapy has been considered in TK2 deficiency.
• Affected individuals may be at increased risk for acidosis and hypoglycemia during illness and surgery and protocols to prevent prolonged fasting should be provided.
• Certain medications and anesthetic agents should be avoided; see
• Referral to cardiologist
• Standard treatment
• Referral to pulmonologist &/or sleep medicine physician
• Aggressive antibiotic treatment of chest infections
• Chest physiotherapy
• Artificial ventilation including assisted nasal ventilation (CPAP or BiPAP) or intubation w/use of tracheostomy & ventilator (See
• Referral to hepatologist
• Reduction in dietary protein
• Correction of coagulopathy
• Frequent or continuous feeding to prevent hypoglycemia
• Consideration of liver transplant
• Referral to gastroenterologist
• Nutritional support
• Total parenteral nutrition
• Domperidone
• Antibiotic therapy for intestinal bacterial overgrowth
• Celiac plexus & splanchnic nerve block (See
• Nutritional support
• Gastrostomy tube placement
• Referral to nephrologist
• Correction of acidosis & other metabolic derangements
• Referral to neurologist
• Amitriptyline, nortriptyline, & gabapentin
• Referral to neurologist
• Standard ASM (Refractory epilepsy may require high doses &/or use of multiple ASMs.)
• Frequent feeding & avoidance of fasting
• Uncooked cornstarch
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, guardianship, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, guardianship, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, guardianship, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Genetic Counseling
Mitochondrial DNA maintenance defects can be inherited in an autosomal recessive or autosomal dominant manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one mtDNA maintenance defect-related pathogenic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Most individuals diagnosed with a mtDNA maintenance defect have an affected parent.
Some individuals diagnosed with a mtDNA maintenance defect have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with a mtDNA maintenance defect may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history is not definitive unless appropriate clinical evaluation and/or molecular genetic testing has been performed for the parents of the proband.
The risk to sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected and/or is heterozygous for the pathogenic variant identified in the proband, the risk to sibs is 50%.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents have not been tested for the mtDNA maintenance defect-related pathogenic variant but are clinically unaffected, the risk to sibs of a proband appears to be low.
Once the mtDNA maintenance defect-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mtDNA maintenance defect-related pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Most individuals diagnosed with a mtDNA maintenance defect have an affected parent.
• Some individuals diagnosed with a mtDNA maintenance defect have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with a mtDNA maintenance defect may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history is not definitive unless appropriate clinical evaluation and/or molecular genetic testing has been performed for the parents of the proband.
• The risk to sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or is heterozygous for the pathogenic variant identified in the proband, the risk to sibs is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents have not been tested for the mtDNA maintenance defect-related pathogenic variant but are clinically unaffected, the risk to sibs of a proband appears to be low.
## Mode of Inheritance
Mitochondrial DNA maintenance defects can be inherited in an autosomal recessive or autosomal dominant manner.
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one mtDNA maintenance defect-related pathogenic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mtDNA maintenance defect-related pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with a mtDNA maintenance defect have an affected parent.
Some individuals diagnosed with a mtDNA maintenance defect have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with a mtDNA maintenance defect may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history is not definitive unless appropriate clinical evaluation and/or molecular genetic testing has been performed for the parents of the proband.
The risk to sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected and/or is heterozygous for the pathogenic variant identified in the proband, the risk to sibs is 50%.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents have not been tested for the mtDNA maintenance defect-related pathogenic variant but are clinically unaffected, the risk to sibs of a proband appears to be low.
• Most individuals diagnosed with a mtDNA maintenance defect have an affected parent.
• Some individuals diagnosed with a mtDNA maintenance defect have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with a mtDNA maintenance defect may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history is not definitive unless appropriate clinical evaluation and/or molecular genetic testing has been performed for the parents of the proband.
• The risk to sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or is heterozygous for the pathogenic variant identified in the proband, the risk to sibs is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents have not been tested for the mtDNA maintenance defect-related pathogenic variant but are clinically unaffected, the risk to sibs of a proband appears to be low.
## Prenatal Testing and Preimplantation Genetic Testing
Once the mtDNA maintenance defect-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Chapter Notes
8 March 2018 (bp) Review posted live
13 October 2017 (aeh) Original submission
• 8 March 2018 (bp) Review posted live
• 13 October 2017 (aeh) Original submission
## Revision History
8 March 2018 (bp) Review posted live
13 October 2017 (aeh) Original submission
• 8 March 2018 (bp) Review posted live
• 13 October 2017 (aeh) Original submission
## References
## Literature Cited
A diagram showing the proteins that are involved in mtDNA maintenance and known to be associated with mtDNA maintenance defects
|
[] |
8/3/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
mthfr-homocystinuria
|
mthfr-homocystinuria
|
[
"Homocystinuria due to MTHFR Deficiency",
"Homocystinuria due to MTHFR Deficiency",
"Methylenetetrahydrofolate reductase (NADPH)",
"MTHFR",
"Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity"
] |
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity
|
Muhammad Umair, Majid Alfadhel
|
Summary Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase (MTHFR) activity can present in the neonatal period, adolescence, or adulthood. Neonatal onset is typically characterized by postnatal microcephaly, developmental delays, feeding difficulties, growth deficiency, seizures, intellectual disability, neonatal apneas, motor and gait abnormalities, psychiatric manifestations, a history of stroke, and progressive neurologic deterioration. Individuals with adolescent or adult onset may present with milder clinical manifestations, which may include thromboembolic events, lens dislocation, and less commonly cognitive decline, psychiatric manifestations, seizures, and/or motor and gait abnormalities. The diagnosis of homocystinuria due to deficiency of N(5,10)-MTHFR activity is established in a proband with characteristic clinical and laboratory findings (low plasma methionine, increased plasma and urine homocysteine, low plasma and CSF 5-methyltetrahydrofolate [MTHF]) and biallelic pathogenic variants in Homocystinuria due to deficiency of N(5,10)-MTHFR activity is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
No consensus clinical diagnostic criteria for homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase (MTHFR) activity have been published.
A diagnosis of homocystinuria due to deficiency of N(5,10)-MTHFR activity may be suspected due to an abnormal newborn screening (NBS) result prior to onset of suggestive findings (see
NBS for homocystinuria due to deficiency of N(5,10)-MTHFR activity is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify methionine and homocysteine concentrations by tandem mass spectrometry (MS/MS). For information on NBS by state in the US, see
Immediately on receipt of out-of-range NBS results (i.e., low methionine and elevated homocysteine), further evaluation to confirm a diagnosis is required and presumptive management should be considered.
See
For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
If a metabolic specialist is not available, consider initiating targeted therapy and supportive treatment (see
A symptomatic individual can have either (1) typical findings associated with later-diagnosed homocystinuria due to deficiency of N(5,10)-MTHFR activity or (2) untreated infantile-onset homocystinuria due to deficiency of N(5,10)-MTHFR activity resulting from any of the following: NBS not performed, false negative NBS result, clinical findings prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. Homocystinuria due to deficiency of N(5,10)-MTHFR activity
Microcephaly (typically develops postnatally)
Developmental delay (mild to profound)
Feeding problems and growth deficiency
Seizures (multifocal, generalized tonic-clonic, and/or febrile)
Intellectual disability (mild to profound)
Neonatal apneas
Motor & gait abnormalities (poor motor coordination, gait instability, and muscle weakness)
Psychiatric manifestations
History of stroke
History of thromboembolic events (e.g., stroke)
Lens dislocation
Neurologic deterioration (cognitive decline, psychiatric manifestations)
Seizures (multifocal, generalized tonic clonic, and/or febrile)
Motor and gait abnormalities (ataxia, unsteady gait, and difficulty with coordination)
Low plasma methionine concentration
Increased plasma and urine homocysteine concentration
Low 5-methyltetrahydrofolate (5-MTHF) in both plasma and cerebrospinal fluid
Low N(5,10)-MTHFR enzyme activity in lymphocytes and fibroblasts
Communicating hydrocephalus
Cerebral and cerebellar atrophy
Microgyria
Cerebral white matter lesions
Corpus callosum thinning
The diagnosis of homocystinuria due to deficiency of N(5,10)-MTHFR activity
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: Targeted analysis for known
For an introduction to multigene panels click
When the diagnosis of homocystinuria due to deficiency of N(5,10)-MTHFR activity has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
To date, two large intragenic deletions/duplications have been reported in individuals with homocystinuria due to deficiency of N(5,10)-MTHFR activity [
• See
• For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
• If a metabolic specialist is not available, consider initiating targeted therapy and supportive treatment (see
• Microcephaly (typically develops postnatally)
• Developmental delay (mild to profound)
• Feeding problems and growth deficiency
• Seizures (multifocal, generalized tonic-clonic, and/or febrile)
• Intellectual disability (mild to profound)
• Neonatal apneas
• Motor & gait abnormalities (poor motor coordination, gait instability, and muscle weakness)
• Psychiatric manifestations
• History of stroke
• History of thromboembolic events (e.g., stroke)
• Lens dislocation
• Neurologic deterioration (cognitive decline, psychiatric manifestations)
• Seizures (multifocal, generalized tonic clonic, and/or febrile)
• Motor and gait abnormalities (ataxia, unsteady gait, and difficulty with coordination)
• Low plasma methionine concentration
• Increased plasma and urine homocysteine concentration
• Low 5-methyltetrahydrofolate (5-MTHF) in both plasma and cerebrospinal fluid
• Low N(5,10)-MTHFR enzyme activity in lymphocytes and fibroblasts
• Communicating hydrocephalus
• Cerebral and cerebellar atrophy
• Microgyria
• Cerebral white matter lesions
• Corpus callosum thinning
## Suggestive Findings
A diagnosis of homocystinuria due to deficiency of N(5,10)-MTHFR activity may be suspected due to an abnormal newborn screening (NBS) result prior to onset of suggestive findings (see
NBS for homocystinuria due to deficiency of N(5,10)-MTHFR activity is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify methionine and homocysteine concentrations by tandem mass spectrometry (MS/MS). For information on NBS by state in the US, see
Immediately on receipt of out-of-range NBS results (i.e., low methionine and elevated homocysteine), further evaluation to confirm a diagnosis is required and presumptive management should be considered.
See
For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
If a metabolic specialist is not available, consider initiating targeted therapy and supportive treatment (see
A symptomatic individual can have either (1) typical findings associated with later-diagnosed homocystinuria due to deficiency of N(5,10)-MTHFR activity or (2) untreated infantile-onset homocystinuria due to deficiency of N(5,10)-MTHFR activity resulting from any of the following: NBS not performed, false negative NBS result, clinical findings prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. Homocystinuria due to deficiency of N(5,10)-MTHFR activity
Microcephaly (typically develops postnatally)
Developmental delay (mild to profound)
Feeding problems and growth deficiency
Seizures (multifocal, generalized tonic-clonic, and/or febrile)
Intellectual disability (mild to profound)
Neonatal apneas
Motor & gait abnormalities (poor motor coordination, gait instability, and muscle weakness)
Psychiatric manifestations
History of stroke
History of thromboembolic events (e.g., stroke)
Lens dislocation
Neurologic deterioration (cognitive decline, psychiatric manifestations)
Seizures (multifocal, generalized tonic clonic, and/or febrile)
Motor and gait abnormalities (ataxia, unsteady gait, and difficulty with coordination)
Low plasma methionine concentration
Increased plasma and urine homocysteine concentration
Low 5-methyltetrahydrofolate (5-MTHF) in both plasma and cerebrospinal fluid
Low N(5,10)-MTHFR enzyme activity in lymphocytes and fibroblasts
Communicating hydrocephalus
Cerebral and cerebellar atrophy
Microgyria
Cerebral white matter lesions
Corpus callosum thinning
• See
• For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
• If a metabolic specialist is not available, consider initiating targeted therapy and supportive treatment (see
• Microcephaly (typically develops postnatally)
• Developmental delay (mild to profound)
• Feeding problems and growth deficiency
• Seizures (multifocal, generalized tonic-clonic, and/or febrile)
• Intellectual disability (mild to profound)
• Neonatal apneas
• Motor & gait abnormalities (poor motor coordination, gait instability, and muscle weakness)
• Psychiatric manifestations
• History of stroke
• History of thromboembolic events (e.g., stroke)
• Lens dislocation
• Neurologic deterioration (cognitive decline, psychiatric manifestations)
• Seizures (multifocal, generalized tonic clonic, and/or febrile)
• Motor and gait abnormalities (ataxia, unsteady gait, and difficulty with coordination)
• Low plasma methionine concentration
• Increased plasma and urine homocysteine concentration
• Low 5-methyltetrahydrofolate (5-MTHF) in both plasma and cerebrospinal fluid
• Low N(5,10)-MTHFR enzyme activity in lymphocytes and fibroblasts
• Communicating hydrocephalus
• Cerebral and cerebellar atrophy
• Microgyria
• Cerebral white matter lesions
• Corpus callosum thinning
## Scenario 1: Abnormal NBS Result
NBS for homocystinuria due to deficiency of N(5,10)-MTHFR activity is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify methionine and homocysteine concentrations by tandem mass spectrometry (MS/MS). For information on NBS by state in the US, see
Immediately on receipt of out-of-range NBS results (i.e., low methionine and elevated homocysteine), further evaluation to confirm a diagnosis is required and presumptive management should be considered.
See
For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
If a metabolic specialist is not available, consider initiating targeted therapy and supportive treatment (see
• See
• For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
• If a metabolic specialist is not available, consider initiating targeted therapy and supportive treatment (see
## Scenario 2: Symptomatic Individual
A symptomatic individual can have either (1) typical findings associated with later-diagnosed homocystinuria due to deficiency of N(5,10)-MTHFR activity or (2) untreated infantile-onset homocystinuria due to deficiency of N(5,10)-MTHFR activity resulting from any of the following: NBS not performed, false negative NBS result, clinical findings prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. Homocystinuria due to deficiency of N(5,10)-MTHFR activity
Microcephaly (typically develops postnatally)
Developmental delay (mild to profound)
Feeding problems and growth deficiency
Seizures (multifocal, generalized tonic-clonic, and/or febrile)
Intellectual disability (mild to profound)
Neonatal apneas
Motor & gait abnormalities (poor motor coordination, gait instability, and muscle weakness)
Psychiatric manifestations
History of stroke
History of thromboembolic events (e.g., stroke)
Lens dislocation
Neurologic deterioration (cognitive decline, psychiatric manifestations)
Seizures (multifocal, generalized tonic clonic, and/or febrile)
Motor and gait abnormalities (ataxia, unsteady gait, and difficulty with coordination)
Low plasma methionine concentration
Increased plasma and urine homocysteine concentration
Low 5-methyltetrahydrofolate (5-MTHF) in both plasma and cerebrospinal fluid
Low N(5,10)-MTHFR enzyme activity in lymphocytes and fibroblasts
Communicating hydrocephalus
Cerebral and cerebellar atrophy
Microgyria
Cerebral white matter lesions
Corpus callosum thinning
• Microcephaly (typically develops postnatally)
• Developmental delay (mild to profound)
• Feeding problems and growth deficiency
• Seizures (multifocal, generalized tonic-clonic, and/or febrile)
• Intellectual disability (mild to profound)
• Neonatal apneas
• Motor & gait abnormalities (poor motor coordination, gait instability, and muscle weakness)
• Psychiatric manifestations
• History of stroke
• History of thromboembolic events (e.g., stroke)
• Lens dislocation
• Neurologic deterioration (cognitive decline, psychiatric manifestations)
• Seizures (multifocal, generalized tonic clonic, and/or febrile)
• Motor and gait abnormalities (ataxia, unsteady gait, and difficulty with coordination)
• Low plasma methionine concentration
• Increased plasma and urine homocysteine concentration
• Low 5-methyltetrahydrofolate (5-MTHF) in both plasma and cerebrospinal fluid
• Low N(5,10)-MTHFR enzyme activity in lymphocytes and fibroblasts
• Communicating hydrocephalus
• Cerebral and cerebellar atrophy
• Microgyria
• Cerebral white matter lesions
• Corpus callosum thinning
## Establishing the Diagnosis
The diagnosis of homocystinuria due to deficiency of N(5,10)-MTHFR activity
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: Targeted analysis for known
For an introduction to multigene panels click
When the diagnosis of homocystinuria due to deficiency of N(5,10)-MTHFR activity has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
To date, two large intragenic deletions/duplications have been reported in individuals with homocystinuria due to deficiency of N(5,10)-MTHFR activity [
## Option 1
Note: Targeted analysis for known
For an introduction to multigene panels click
## Option 2
When the diagnosis of homocystinuria due to deficiency of N(5,10)-MTHFR activity has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
To date, two large intragenic deletions/duplications have been reported in individuals with homocystinuria due to deficiency of N(5,10)-MTHFR activity [
## Clinical Characteristics
The clinical manifestations of homocystinuria due to deficiency in N(5,10)-methylenetetrahydrofolate reductase (MTHFR) activity can present at different stages of life, either in the neonatal period or during adolescence and adulthood. Neonatal onset is typically characterized by neonatal apnea, feeding difficulties, seizures, microcephaly, developmental delays, intellectual disability, motor and gait abnormalities, psychiatric manifestations, a history of stroke, and progressive neurologic deterioration. Individuals with adolescent or adult onset may present with milder clinical manifestations, which may include thromboembolic events, lens dislocation, and less commonly cognitive decline, psychiatric manifestations, seizures, and/or motor and gait abnormalities. To date, 150 individuals have been identified with biallelic pathogenic variants in
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Frequency of Select Features in Those with Neonatal Onset
Based on
The prognosis is highly variable. Deficiency of N(5,10)-MTHFR activity can cause neurologic degeneration, especially if the condition is not well managed or if serious complications occur. Neurologic symptoms such as developmental delay, intellectual disability, and motor abnormalities may progress if not treated adequately. Complications such as stroke can be a significant cause of mortality. With early initiation of betaine, methionine, vitamin B
Genotype-phenotype correlations have not been identified in homocystinuria due to deficiency in N(5,10)-MTHFR activity because of the high number of private pathogenic variants. Given that higher residual MTHFR activity is associated with later onset of the disease, it is likely that residual MTHFR activity plays a major influence in the severity of this disorder [
Individuals homozygous for
The term "MTHFR deficiency" is often used in the medical literature to refer to homocystinuria due to deficiency of N(5,10)-MTHFR activity. Because individuals with mildly or moderately reduced N(5,10)-MTHFR activity typically do not have homocystinuria, the more specific designation "homocystinuria due to deficiency of N(5,10)-MTHFR activity" is preferred in this
The estimated prevalence of homocystinuria due to deficiency of N(5,10)-MTHFR activity is approximately one in 10,000-50,000 individuals globally, although this varies by population. This condition is notably more prevalent in certain populations, including Bukharan Jewish and Amish communities, in which founder
## Clinical Description
The clinical manifestations of homocystinuria due to deficiency in N(5,10)-methylenetetrahydrofolate reductase (MTHFR) activity can present at different stages of life, either in the neonatal period or during adolescence and adulthood. Neonatal onset is typically characterized by neonatal apnea, feeding difficulties, seizures, microcephaly, developmental delays, intellectual disability, motor and gait abnormalities, psychiatric manifestations, a history of stroke, and progressive neurologic deterioration. Individuals with adolescent or adult onset may present with milder clinical manifestations, which may include thromboembolic events, lens dislocation, and less commonly cognitive decline, psychiatric manifestations, seizures, and/or motor and gait abnormalities. To date, 150 individuals have been identified with biallelic pathogenic variants in
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Frequency of Select Features in Those with Neonatal Onset
Based on
The prognosis is highly variable. Deficiency of N(5,10)-MTHFR activity can cause neurologic degeneration, especially if the condition is not well managed or if serious complications occur. Neurologic symptoms such as developmental delay, intellectual disability, and motor abnormalities may progress if not treated adequately. Complications such as stroke can be a significant cause of mortality. With early initiation of betaine, methionine, vitamin B
## Neonatal Onset
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Frequency of Select Features in Those with Neonatal Onset
Based on
## Adolescent and Adult Onset
## Prognosis
The prognosis is highly variable. Deficiency of N(5,10)-MTHFR activity can cause neurologic degeneration, especially if the condition is not well managed or if serious complications occur. Neurologic symptoms such as developmental delay, intellectual disability, and motor abnormalities may progress if not treated adequately. Complications such as stroke can be a significant cause of mortality. With early initiation of betaine, methionine, vitamin B
## Genotype-Phenotype Correlations
Genotype-phenotype correlations have not been identified in homocystinuria due to deficiency in N(5,10)-MTHFR activity because of the high number of private pathogenic variants. Given that higher residual MTHFR activity is associated with later onset of the disease, it is likely that residual MTHFR activity plays a major influence in the severity of this disorder [
Individuals homozygous for
## Nomenclature
The term "MTHFR deficiency" is often used in the medical literature to refer to homocystinuria due to deficiency of N(5,10)-MTHFR activity. Because individuals with mildly or moderately reduced N(5,10)-MTHFR activity typically do not have homocystinuria, the more specific designation "homocystinuria due to deficiency of N(5,10)-MTHFR activity" is preferred in this
## Prevalence
The estimated prevalence of homocystinuria due to deficiency of N(5,10)-MTHFR activity is approximately one in 10,000-50,000 individuals globally, although this varies by population. This condition is notably more prevalent in certain populations, including Bukharan Jewish and Amish communities, in which founder
## Genetically Related (Allelic) Disorders
No disorders other than those discussed in this
## Differential Diagnosis
Genetic Disorders Associated with Elevated Homocysteine in the Differential Diagnosis of Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity
Combined methylmalonic acidemia & homocystinuria (in cblC, cblD-combined, cblF, & cblJ)
Homocystinuria (in cblD-homocystinuria, cblE, cblG)
Low/normal methionine
Variable phenotype & age of onset
In cblC – assoc w/
Methylmalonic acidemia & homocystinuria
Vitamin B
Neurocognitive involvement
Macrocytic anemia ± proteinuria
Ectopia lentis &/or severe myopia
Skeletal system involvement (excessive height, long limbs, scoliosis, & pectus excavatum)
Vascular system involvement (thromboembolism)
DD/ID
Megaloblastic anemia
Hemolytic uremic syndrome
Microangiopathy w/retinopathy
SCID-like syndrome
Methylmalonic acidemia & homocystinuria
↓ unsaturated vitamin B
Infantile onset of megaloblastic anemia
Poor growth
Neurologic involvement
Immunologic disease
AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
The majority of disorders of intracellular cobalamin metabolism are inherited in an autosomal recessive manner. The disorder of intracellular cobalamin metabolism caused by pathogenic variants in
Individuals with
• Combined methylmalonic acidemia & homocystinuria (in cblC, cblD-combined, cblF, & cblJ)
• Homocystinuria (in cblD-homocystinuria, cblE, cblG)
• Low/normal methionine
• Variable phenotype & age of onset
• In cblC – assoc w/
• Methylmalonic acidemia & homocystinuria
• Vitamin B
• Neurocognitive involvement
• Macrocytic anemia ± proteinuria
• Ectopia lentis &/or severe myopia
• Skeletal system involvement (excessive height, long limbs, scoliosis, & pectus excavatum)
• Vascular system involvement (thromboembolism)
• DD/ID
• Megaloblastic anemia
• Hemolytic uremic syndrome
• Microangiopathy w/retinopathy
• SCID-like syndrome
• Methylmalonic acidemia & homocystinuria
• ↓ unsaturated vitamin B
• Infantile onset of megaloblastic anemia
• Poor growth
• Neurologic involvement
• Immunologic disease
• Individuals with
•
## Management
No clinical practice guidelines for homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase (MTHFR) activity have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
To establish the extent of disease and needs in an individual diagnosed with homocystinuria due to deficiency of N(5,10)-MTHFR activity, the evaluations summarized in
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Recommended Evaluations Following Initial Diagnosis
Measure plasma homocysteine concentration & plasma amino acids to assess methionine concentration.
Measure CSF 5-MTHF & CSF methionine concentration.
Assessment for respiratory compromise
Apnea monitoring
Sleep study
Regular eval is important to identify any breathing difficulties that may arise due to the disorder.
Apnea monitoring is essential for newborns or infants, as homocystinuria can be assoc w/apnea & other respiratory issues.
Assessment of growth & caloric intake
Feeding team eval as needed
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To incl brain MRI
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CSF = cerebrospinal fluid; MOI = mode of inheritance; MRA = MR angiography; MRV = MR venography; MTHF = methyltetrahydrofolate; MTHFR = methylenetetrahydrofolate reductase; OT = occupational therapy/therapist; PT = physical therapy/therapist
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for homocystinuria due to deficiency of N(5,10)-MTHFR activity. The treatment is mainly supportive and requires a multidisciplinary team approach.
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Targeted Therapies
100-150 mg/kg
↑ dose as needed depending on homocysteine level
Max dose 9 g/day
Adult dose: 3 g 2x/daily & up to 20 g/day
Effective in ↓ homocysteine concentration
Regular monitoring of plasma homocysteine & kidney function is recommended.
Adjust dose to maintain upper normal range of plasma & CSF methionine.
Use cautiously due to potential to ↑ homocysteine concentration.
Individualized dosing based on response & tolerance
Can ↓ homocysteine concentration & improve clinical manifestations, particularly in those w/vitamin B
Regular monitoring of vitamin B
CSF = cerebrospinal fluid; MTHF = methyltetrahydrofolate; MTHFR = methylenetetrahydrofolate reductase
Although there is a clear biochemical rationale for using 5-methyltetrahydrofolate (L-5-MTHF or CH
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Recommended Surveillance
Assessment for respiratory compromise & apnea
Sleep study if indicated
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CSF = cerebrospinal fluid; MTHF = methyltetrahydrofolate; OT = occupational therapy; PT = physical therapy
See
In pregnant woman with homocystinuria due to deficiency of N(5,10)-MTHFR activity, management focuses on maintaining metabolic stability to prevent complications. This includes close monitoring of homocysteine and methionine levels throughout pregnancy, as elevated homocysteine can increase the risk of complications such as preeclampsia, placental abruption, and thromboembolic events. Treatment typically involves the use of betaine, folic acid, and vitamin B
Regular follow up with a metabolic specialist and high-risk obstetric care is recommended to ensure both maternal and fetal well-being.
To date, no clinical trials specifically for homocystinuria due to deficiency of N(5,10)-MTHFR activity have been identified.
Search
• Measure plasma homocysteine concentration & plasma amino acids to assess methionine concentration.
• Measure CSF 5-MTHF & CSF methionine concentration.
• Assessment for respiratory compromise
• Apnea monitoring
• Sleep study
• Regular eval is important to identify any breathing difficulties that may arise due to the disorder.
• Apnea monitoring is essential for newborns or infants, as homocystinuria can be assoc w/apnea & other respiratory issues.
• Assessment of growth & caloric intake
• Feeding team eval as needed
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support
• Home nursing referral
• 100-150 mg/kg
• ↑ dose as needed depending on homocysteine level
• Max dose 9 g/day
• Adult dose: 3 g 2x/daily & up to 20 g/day
• Effective in ↓ homocysteine concentration
• Regular monitoring of plasma homocysteine & kidney function is recommended.
• Adjust dose to maintain upper normal range of plasma & CSF methionine.
• Use cautiously due to potential to ↑ homocysteine concentration.
• Individualized dosing based on response & tolerance
• Can ↓ homocysteine concentration & improve clinical manifestations, particularly in those w/vitamin B
• Regular monitoring of vitamin B
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Assessment for respiratory compromise & apnea
• Sleep study if indicated
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with homocystinuria due to deficiency of N(5,10)-MTHFR activity, the evaluations summarized in
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Recommended Evaluations Following Initial Diagnosis
Measure plasma homocysteine concentration & plasma amino acids to assess methionine concentration.
Measure CSF 5-MTHF & CSF methionine concentration.
Assessment for respiratory compromise
Apnea monitoring
Sleep study
Regular eval is important to identify any breathing difficulties that may arise due to the disorder.
Apnea monitoring is essential for newborns or infants, as homocystinuria can be assoc w/apnea & other respiratory issues.
Assessment of growth & caloric intake
Feeding team eval as needed
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To incl brain MRI
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CSF = cerebrospinal fluid; MOI = mode of inheritance; MRA = MR angiography; MRV = MR venography; MTHF = methyltetrahydrofolate; MTHFR = methylenetetrahydrofolate reductase; OT = occupational therapy/therapist; PT = physical therapy/therapist
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Measure plasma homocysteine concentration & plasma amino acids to assess methionine concentration.
• Measure CSF 5-MTHF & CSF methionine concentration.
• Assessment for respiratory compromise
• Apnea monitoring
• Sleep study
• Regular eval is important to identify any breathing difficulties that may arise due to the disorder.
• Apnea monitoring is essential for newborns or infants, as homocystinuria can be assoc w/apnea & other respiratory issues.
• Assessment of growth & caloric intake
• Feeding team eval as needed
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for homocystinuria due to deficiency of N(5,10)-MTHFR activity. The treatment is mainly supportive and requires a multidisciplinary team approach.
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Targeted Therapies
100-150 mg/kg
↑ dose as needed depending on homocysteine level
Max dose 9 g/day
Adult dose: 3 g 2x/daily & up to 20 g/day
Effective in ↓ homocysteine concentration
Regular monitoring of plasma homocysteine & kidney function is recommended.
Adjust dose to maintain upper normal range of plasma & CSF methionine.
Use cautiously due to potential to ↑ homocysteine concentration.
Individualized dosing based on response & tolerance
Can ↓ homocysteine concentration & improve clinical manifestations, particularly in those w/vitamin B
Regular monitoring of vitamin B
CSF = cerebrospinal fluid; MTHF = methyltetrahydrofolate; MTHFR = methylenetetrahydrofolate reductase
Although there is a clear biochemical rationale for using 5-methyltetrahydrofolate (L-5-MTHF or CH
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• 100-150 mg/kg
• ↑ dose as needed depending on homocysteine level
• Max dose 9 g/day
• Adult dose: 3 g 2x/daily & up to 20 g/day
• Effective in ↓ homocysteine concentration
• Regular monitoring of plasma homocysteine & kidney function is recommended.
• Adjust dose to maintain upper normal range of plasma & CSF methionine.
• Use cautiously due to potential to ↑ homocysteine concentration.
• Individualized dosing based on response & tolerance
• Can ↓ homocysteine concentration & improve clinical manifestations, particularly in those w/vitamin B
• Regular monitoring of vitamin B
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Targeted Therapies
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Targeted Therapies
100-150 mg/kg
↑ dose as needed depending on homocysteine level
Max dose 9 g/day
Adult dose: 3 g 2x/daily & up to 20 g/day
Effective in ↓ homocysteine concentration
Regular monitoring of plasma homocysteine & kidney function is recommended.
Adjust dose to maintain upper normal range of plasma & CSF methionine.
Use cautiously due to potential to ↑ homocysteine concentration.
Individualized dosing based on response & tolerance
Can ↓ homocysteine concentration & improve clinical manifestations, particularly in those w/vitamin B
Regular monitoring of vitamin B
CSF = cerebrospinal fluid; MTHF = methyltetrahydrofolate; MTHFR = methylenetetrahydrofolate reductase
Although there is a clear biochemical rationale for using 5-methyltetrahydrofolate (L-5-MTHF or CH
• 100-150 mg/kg
• ↑ dose as needed depending on homocysteine level
• Max dose 9 g/day
• Adult dose: 3 g 2x/daily & up to 20 g/day
• Effective in ↓ homocysteine concentration
• Regular monitoring of plasma homocysteine & kidney function is recommended.
• Adjust dose to maintain upper normal range of plasma & CSF methionine.
• Use cautiously due to potential to ↑ homocysteine concentration.
• Individualized dosing based on response & tolerance
• Can ↓ homocysteine concentration & improve clinical manifestations, particularly in those w/vitamin B
• Regular monitoring of vitamin B
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
##
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
##
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
##
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Recommended Surveillance
Assessment for respiratory compromise & apnea
Sleep study if indicated
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CSF = cerebrospinal fluid; MTHF = methyltetrahydrofolate; OT = occupational therapy; PT = physical therapy
• Assessment for respiratory compromise & apnea
• Sleep study if indicated
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
See
## Pregnancy Management
In pregnant woman with homocystinuria due to deficiency of N(5,10)-MTHFR activity, management focuses on maintaining metabolic stability to prevent complications. This includes close monitoring of homocysteine and methionine levels throughout pregnancy, as elevated homocysteine can increase the risk of complications such as preeclampsia, placental abruption, and thromboembolic events. Treatment typically involves the use of betaine, folic acid, and vitamin B
Regular follow up with a metabolic specialist and high-risk obstetric care is recommended to ensure both maternal and fetal well-being.
## Therapies Under Investigation
To date, no clinical trials specifically for homocystinuria due to deficiency of N(5,10)-MTHFR activity have been identified.
Search
## Genetic Counseling
Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase (MTHFR) activity is inherited in an autosomal recessive manner.
The parents of an affected individual are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals known to be carriers of an
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to be carriers of an
## Mode of Inheritance
Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase (MTHFR) activity is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals known to be carriers of an
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to be carriers of an
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity (
Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase (MTHFR) is caused by disease-causing variants in
Genetic alterations in
Note: A common
Variants listed in the table have been provided by the authors.
This substitution affects the nucleotide two base pairs upstream of the donor splice site of intron 3 and is known to cause abnormal splicing.
## Molecular Pathogenesis
Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase (MTHFR) is caused by disease-causing variants in
Genetic alterations in
Note: A common
Variants listed in the table have been provided by the authors.
This substitution affects the nucleotide two base pairs upstream of the donor splice site of intron 3 and is known to cause abnormal splicing.
## Chapter Notes
Dr Muhammad Umair (
Dr Umair and Professor Alfadhel are also interested in hearing from clinicians treating families affected by metabolic and neurodevelopmental disorders in whom no causative variant has been identified through molecular genetic testing.
Contact Dr Umair and Professor Alfadhel to inquire about review of
We would like to thank the patients, families, and clinicians who have participated in our previous publications delineating this condition.
We are grateful to the King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard-Health Affairs (MNGHA), Kingdom of Saudi Arabia (KSA).
10 July 2025 (sw) Revision: edits to
29 May 2025 (sw) Review posted live
4 November 2024 (mu) Original submission
• 10 July 2025 (sw) Revision: edits to
• 29 May 2025 (sw) Review posted live
• 4 November 2024 (mu) Original submission
## Author Notes
Dr Muhammad Umair (
Dr Umair and Professor Alfadhel are also interested in hearing from clinicians treating families affected by metabolic and neurodevelopmental disorders in whom no causative variant has been identified through molecular genetic testing.
Contact Dr Umair and Professor Alfadhel to inquire about review of
## Acknowledgments
We would like to thank the patients, families, and clinicians who have participated in our previous publications delineating this condition.
We are grateful to the King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard-Health Affairs (MNGHA), Kingdom of Saudi Arabia (KSA).
## Revision History
10 July 2025 (sw) Revision: edits to
29 May 2025 (sw) Review posted live
4 November 2024 (mu) Original submission
• 10 July 2025 (sw) Revision: edits to
• 29 May 2025 (sw) Review posted live
• 4 November 2024 (mu) Original submission
## Key Sections in This
## References
## Literature Cited
|
[] |
29/5/2025
|
10/7/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mtm
|
mtm
|
[
"Myotubular Myopathy (MTM)",
"XLCNM",
"X-Linked Centronuclear Myopathy",
"XLMTM",
"Myotubular Myopathy (MTM)",
"XLCNM",
"X-Linked Centronuclear Myopathy",
"XLMTM",
"Myotubularin",
"MTM1",
"X-Linked Myotubular Myopathy"
] |
X-Linked Myotubular Myopathy
|
James J Dowling, Michael W Lawlor, Soma Das
|
Summary X-linked myotubular myopathy (X-MTM), also known as myotubular myopathy (MTM), is characterized by muscle weakness that ranges from severe to mild. Approximately 80% of affected males present with severe (classic) X-MTM characterized by polyhydramnios, decreased fetal movement, and neonatal weakness, hypotonia, and respiratory failure. Motor milestones are significantly delayed and most individuals fail to achieve independent ambulation. Weakness is profound and often involves facial and extraocular muscles. Respiratory failure is nearly uniform, with most individuals requiring 24-hour ventilatory assistance. It is estimated that at least 25% of boys with severe X-MTM die in the first year of life, and those who survive rarely live into adulthood. Males with mild or moderate X-MTM (~20%) achieve motor milestones more quickly than males with the severe form; many ambulate independently, and may live into adulthood. Most require gastrostomy tubes and/or ventilator support. In all subtypes of X-MTM, the muscle disease is not obviously progressive. Female carriers of X-MTM are generally asymptomatic, although manifesting heterozygotes are increasingly being identified. In affected females, symptoms range from severe, generalized weakness presenting in childhood, with infantile onset similar to affected male patients, to mild (often asymmetric) weakness manifesting in adulthood. Affected adult females may experience progressive respiratory decline and ultimately require ventilatory support. The diagnosis of X-MTM is established in a proband with suggestive clinical findings and identification of a hemizygous pathogenic variant in X-MTM is inherited in an X-linked manner. The risk to sibs of a male proband depends on the carrier status of the mother. If the mother is a carrier, each sib has a 50% chance of inheriting the
|
## Diagnosis
The diagnosis of X-linked myotubular myopathy (X-MTM), also known as myotubular myopathy (MTM),
Neonatal hypotonia
Neonatal respiratory failure
Significant and diffuse muscle weakness
Diminished muscle bulk
A family history suggestive of X-linked inheritance
Length and head circumference >90th centile
Cryptorchidism
Long fingers and toes
Involvement of the extraocular muscles (i.e., ophthalmoparesis)
Numerous small, rounded myofibers with internally located nuclei that are present at (or very near) the center of a myofiber. The nucleus often appears very large in comparison to the small fiber size.
Aberrant accumulation of centrally located staining with oxidative stains (SDH and NADH) and glycogen stains (PAS), often in conjunction with a halo-like area of subsarcolemmal clearing on these stains
Small, predominant type I fibers
Necklace fibers on hematoxylin-eosin stained sections and with succinate dehydrogenase staining; present in some individuals with sporadic late-onset X-MTM as a basophilic ring-like deposit that follows the contour of the myofiber and aligns with internal myonuclei
The diagnosis of X-MTM
Mild to moderate extremity weakness in a limb girdle pattern, often with prominent asymmetry
Asymmetric muscle growth
Facial weakness, ptosis, and ophthalmoparesis
A family history suggestive of X-linked inheritance (affected females may not have a family history of X-MTM)
Necklace fibers on muscle biopsy, or features of typical centronuclear myopathy
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of X-MTM is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of X-MTM, molecular genetic testing approaches can include a
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by myopathy,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Myotubular Myopathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The occurrence of deep intronic pathogenic variants has been described [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Neonatal hypotonia
• Neonatal respiratory failure
• Significant and diffuse muscle weakness
• Diminished muscle bulk
• A family history suggestive of X-linked inheritance
• Length and head circumference >90th centile
• Cryptorchidism
• Long fingers and toes
• Involvement of the extraocular muscles (i.e., ophthalmoparesis)
• Numerous small, rounded myofibers with internally located nuclei that are present at (or very near) the center of a myofiber. The nucleus often appears very large in comparison to the small fiber size.
• Aberrant accumulation of centrally located staining with oxidative stains (SDH and NADH) and glycogen stains (PAS), often in conjunction with a halo-like area of subsarcolemmal clearing on these stains
• Small, predominant type I fibers
• Necklace fibers on hematoxylin-eosin stained sections and with succinate dehydrogenase staining; present in some individuals with sporadic late-onset X-MTM as a basophilic ring-like deposit that follows the contour of the myofiber and aligns with internal myonuclei
• Mild to moderate extremity weakness in a limb girdle pattern, often with prominent asymmetry
• Asymmetric muscle growth
• Facial weakness, ptosis, and ophthalmoparesis
• A family history suggestive of X-linked inheritance (affected females may not have a family history of X-MTM)
• Necklace fibers on muscle biopsy, or features of typical centronuclear myopathy
• For an introduction to multigene panels click
## Suggestive Findings
The diagnosis of X-linked myotubular myopathy (X-MTM), also known as myotubular myopathy (MTM),
Neonatal hypotonia
Neonatal respiratory failure
Significant and diffuse muscle weakness
Diminished muscle bulk
A family history suggestive of X-linked inheritance
Length and head circumference >90th centile
Cryptorchidism
Long fingers and toes
Involvement of the extraocular muscles (i.e., ophthalmoparesis)
Numerous small, rounded myofibers with internally located nuclei that are present at (or very near) the center of a myofiber. The nucleus often appears very large in comparison to the small fiber size.
Aberrant accumulation of centrally located staining with oxidative stains (SDH and NADH) and glycogen stains (PAS), often in conjunction with a halo-like area of subsarcolemmal clearing on these stains
Small, predominant type I fibers
Necklace fibers on hematoxylin-eosin stained sections and with succinate dehydrogenase staining; present in some individuals with sporadic late-onset X-MTM as a basophilic ring-like deposit that follows the contour of the myofiber and aligns with internal myonuclei
The diagnosis of X-MTM
Mild to moderate extremity weakness in a limb girdle pattern, often with prominent asymmetry
Asymmetric muscle growth
Facial weakness, ptosis, and ophthalmoparesis
A family history suggestive of X-linked inheritance (affected females may not have a family history of X-MTM)
Necklace fibers on muscle biopsy, or features of typical centronuclear myopathy
• Neonatal hypotonia
• Neonatal respiratory failure
• Significant and diffuse muscle weakness
• Diminished muscle bulk
• A family history suggestive of X-linked inheritance
• Length and head circumference >90th centile
• Cryptorchidism
• Long fingers and toes
• Involvement of the extraocular muscles (i.e., ophthalmoparesis)
• Numerous small, rounded myofibers with internally located nuclei that are present at (or very near) the center of a myofiber. The nucleus often appears very large in comparison to the small fiber size.
• Aberrant accumulation of centrally located staining with oxidative stains (SDH and NADH) and glycogen stains (PAS), often in conjunction with a halo-like area of subsarcolemmal clearing on these stains
• Small, predominant type I fibers
• Necklace fibers on hematoxylin-eosin stained sections and with succinate dehydrogenase staining; present in some individuals with sporadic late-onset X-MTM as a basophilic ring-like deposit that follows the contour of the myofiber and aligns with internal myonuclei
• Mild to moderate extremity weakness in a limb girdle pattern, often with prominent asymmetry
• Asymmetric muscle growth
• Facial weakness, ptosis, and ophthalmoparesis
• A family history suggestive of X-linked inheritance (affected females may not have a family history of X-MTM)
• Necklace fibers on muscle biopsy, or features of typical centronuclear myopathy
## Establishing the Diagnosis
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of X-MTM is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of X-MTM, molecular genetic testing approaches can include a
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by myopathy,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Myotubular Myopathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The occurrence of deep intronic pathogenic variants has been described [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of X-MTM, molecular genetic testing approaches can include a
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by myopathy,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Myotubular Myopathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The occurrence of deep intronic pathogenic variants has been described [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
The clinical characteristics and disease course of X-linked myotubular myopathy (X-MTM) have been described in two retrospective natural history studies including nearly 200 genetically confirmed probands [
Following isolation of
Since publication of the phenotypic classification by
In males with the severe/classic phenotype, polyhydramnios and decreased fetal movement are frequently reported. Premature delivery is described in approximately one third of males [
Affected infants often have typical myopathic facies with dolichocephaly, high forehead, long face with midface retrusion, prominent eyes, narrow high-arched palate, and severe malocclusion. Ophthalmoparesis is also frequently observed. Additional features include length greater than the 90th centile with a proportionately lower weight (60% of infants), long fingers and/toes (43%), cryptorchidism and/or undescended testicle (>50%), contractures including clubfeet (30%), and areflexia (60%).
Most infants require lengthy NICU hospitalizations, with approximately 30%-50% of the first year spent in the hospital. Many infants with severe/classic X-MTM succumb to complications of the disorder. The percentage of infants that do not survive the first year of life has been difficult to determine. The reported causes of death are multifactorial, and include removal of ventilatory support. Approximately 25% of male infants die in the first year of life.
Most surviving males are discharged home on 24-hour ventilatory support via tracheostomy and gastrostomy tube feedings. In one study including all forms of X-MTM, 85% of individuals required ventilatory and G-tube support, and nearly all needed wheelchair support for ambulation [
The muscle disease may not be progressive. A prospective study of the ventilatory support requirements of 33 individuals over one year showed little change. Prospective analysis of muscle function in a small pilot group also detected no large changes over a one-year period [
Interestingly, and despite the severe disability and technology dependence of the disease, the annual rate of nonelective hospitalization after the first year of life is not as high as would be expected. In a prospective study of 33 individuals, the rate was 1.1 emergency room visits per year [
Additional features of the underlying myopathy are ophthalmoplegia, ptosis, and severe myopia. Dental malocclusion (requiring orthodontic care) may occur. Constipation is common. Scoliosis often develops in later childhood (75% of individuals in one study) and may require surgical intervention, though scoliosis surgery is documented in only a minority of individuals (≤10%). Scoliosis can exacerbate respiratory insufficiency, in some cases causing ventilator-independent males to become ventilator dependent again as it progresses. Additional orthopedic manifestations include hip dysplasia and long bone fractures [
At least three reports of multigenerational families with
Males with moderate or even mild disease are at increased risk for respiratory decompensation with intercurrent illness and may require transient or increased ventilatory support. They are also at risk for some of the same medical complications (including peliosis hepatis) as those with severe X-MTM [
There are several case reports describing adult males with mild disease and pathogenic variants in
The characteristic muscle biopsy demonstrates numerous small, rounded myofibers with varying percentages of centrally located nuclei. The myofiber size may be uniform throughout the tissue, which may lead to underestimation of the decreased myofiber size (as there may be no appropriately sized fibers for comparison). No diagnostic threshold of central nuclei has been established, as the percentage may increase over time. In rare instances, centrally located nuclei may be absent [
Periodic acid-Schiff (PAS) and nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase histochemical staining often demonstrate an accumulation of staining product in the center of the small myofibers, reflecting (respectively) maldistribution of glycogen and mitochondria/sarcotubular organelles [
ATPase histochemical staining may show type 1 myofiber predominance or small type 1 and type 2A fibers alongside relatively larger type 2B fibers [
The histopathologic findings listed are not specific to X-MTM and may be encountered in congenital myotonic dystrophy type 1 (see
Note: (1) The clinical and histopathologic features of
T-tubule disorganization visualized through immunohistochemistry has been described in X-MTM [
X-MTM is most frequently caused by nonsense, frameshift, and splice site variants that predict loss of function. Pathogenic variants are found throughout the gene with no concentration in any specific domain.
Nonsense and frameshift variants nearly always result in the severe/classic X-MTM phenotype.
Splice site and intronic variants may cause the severe presentation or can be associated with the milder phenotype.
Missense variants can be associated with both severe and mild/moderate phenotypes.
Variants associated with the phosphatase domain and the SET-interacting domain nearly always cause a severe phenotype. Pathogenic variants outside of these two domains are more likely to be associated with milder phenotypes [
A large number of pathogenic variants occur in hypermutable CpG dinucleotides; the most common is variant
Penetrance is thought to be 100% in males with a pathogenic variant in
Carrier females are generally asymptomatic, though an increasing number of manifesting heterozygotes are being identified [
X-MTM (or myotubular myopathy or X-linked centronuclear myopathy [X-CNM]) is considered a subtype of centronuclear myopathy based on the centrally located nuclei of muscle fibers on histologic examination, and based on shared pathogenic mechanisms. Autosomal dominant and autosomal recessive centronuclear myopathy should not be referred to as myotubular myopathy.
Males with X-MTM with identifiable pathogenic variants in
It has been estimated that X-MTM affects approximately one in 50,000 newborn males [
• The characteristic muscle biopsy demonstrates numerous small, rounded myofibers with varying percentages of centrally located nuclei. The myofiber size may be uniform throughout the tissue, which may lead to underestimation of the decreased myofiber size (as there may be no appropriately sized fibers for comparison). No diagnostic threshold of central nuclei has been established, as the percentage may increase over time. In rare instances, centrally located nuclei may be absent [
• Periodic acid-Schiff (PAS) and nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase histochemical staining often demonstrate an accumulation of staining product in the center of the small myofibers, reflecting (respectively) maldistribution of glycogen and mitochondria/sarcotubular organelles [
• ATPase histochemical staining may show type 1 myofiber predominance or small type 1 and type 2A fibers alongside relatively larger type 2B fibers [
• The histopathologic findings listed are not specific to X-MTM and may be encountered in congenital myotonic dystrophy type 1 (see
• Nonsense and frameshift variants nearly always result in the severe/classic X-MTM phenotype.
• Splice site and intronic variants may cause the severe presentation or can be associated with the milder phenotype.
• Missense variants can be associated with both severe and mild/moderate phenotypes.
• Variants associated with the phosphatase domain and the SET-interacting domain nearly always cause a severe phenotype. Pathogenic variants outside of these two domains are more likely to be associated with milder phenotypes [
• A large number of pathogenic variants occur in hypermutable CpG dinucleotides; the most common is variant
## Clinical Description
The clinical characteristics and disease course of X-linked myotubular myopathy (X-MTM) have been described in two retrospective natural history studies including nearly 200 genetically confirmed probands [
Following isolation of
Since publication of the phenotypic classification by
In males with the severe/classic phenotype, polyhydramnios and decreased fetal movement are frequently reported. Premature delivery is described in approximately one third of males [
Affected infants often have typical myopathic facies with dolichocephaly, high forehead, long face with midface retrusion, prominent eyes, narrow high-arched palate, and severe malocclusion. Ophthalmoparesis is also frequently observed. Additional features include length greater than the 90th centile with a proportionately lower weight (60% of infants), long fingers and/toes (43%), cryptorchidism and/or undescended testicle (>50%), contractures including clubfeet (30%), and areflexia (60%).
Most infants require lengthy NICU hospitalizations, with approximately 30%-50% of the first year spent in the hospital. Many infants with severe/classic X-MTM succumb to complications of the disorder. The percentage of infants that do not survive the first year of life has been difficult to determine. The reported causes of death are multifactorial, and include removal of ventilatory support. Approximately 25% of male infants die in the first year of life.
Most surviving males are discharged home on 24-hour ventilatory support via tracheostomy and gastrostomy tube feedings. In one study including all forms of X-MTM, 85% of individuals required ventilatory and G-tube support, and nearly all needed wheelchair support for ambulation [
The muscle disease may not be progressive. A prospective study of the ventilatory support requirements of 33 individuals over one year showed little change. Prospective analysis of muscle function in a small pilot group also detected no large changes over a one-year period [
Interestingly, and despite the severe disability and technology dependence of the disease, the annual rate of nonelective hospitalization after the first year of life is not as high as would be expected. In a prospective study of 33 individuals, the rate was 1.1 emergency room visits per year [
Additional features of the underlying myopathy are ophthalmoplegia, ptosis, and severe myopia. Dental malocclusion (requiring orthodontic care) may occur. Constipation is common. Scoliosis often develops in later childhood (75% of individuals in one study) and may require surgical intervention, though scoliosis surgery is documented in only a minority of individuals (≤10%). Scoliosis can exacerbate respiratory insufficiency, in some cases causing ventilator-independent males to become ventilator dependent again as it progresses. Additional orthopedic manifestations include hip dysplasia and long bone fractures [
At least three reports of multigenerational families with
Males with moderate or even mild disease are at increased risk for respiratory decompensation with intercurrent illness and may require transient or increased ventilatory support. They are also at risk for some of the same medical complications (including peliosis hepatis) as those with severe X-MTM [
There are several case reports describing adult males with mild disease and pathogenic variants in
The characteristic muscle biopsy demonstrates numerous small, rounded myofibers with varying percentages of centrally located nuclei. The myofiber size may be uniform throughout the tissue, which may lead to underestimation of the decreased myofiber size (as there may be no appropriately sized fibers for comparison). No diagnostic threshold of central nuclei has been established, as the percentage may increase over time. In rare instances, centrally located nuclei may be absent [
Periodic acid-Schiff (PAS) and nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase histochemical staining often demonstrate an accumulation of staining product in the center of the small myofibers, reflecting (respectively) maldistribution of glycogen and mitochondria/sarcotubular organelles [
ATPase histochemical staining may show type 1 myofiber predominance or small type 1 and type 2A fibers alongside relatively larger type 2B fibers [
The histopathologic findings listed are not specific to X-MTM and may be encountered in congenital myotonic dystrophy type 1 (see
Note: (1) The clinical and histopathologic features of
T-tubule disorganization visualized through immunohistochemistry has been described in X-MTM [
• The characteristic muscle biopsy demonstrates numerous small, rounded myofibers with varying percentages of centrally located nuclei. The myofiber size may be uniform throughout the tissue, which may lead to underestimation of the decreased myofiber size (as there may be no appropriately sized fibers for comparison). No diagnostic threshold of central nuclei has been established, as the percentage may increase over time. In rare instances, centrally located nuclei may be absent [
• Periodic acid-Schiff (PAS) and nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase histochemical staining often demonstrate an accumulation of staining product in the center of the small myofibers, reflecting (respectively) maldistribution of glycogen and mitochondria/sarcotubular organelles [
• ATPase histochemical staining may show type 1 myofiber predominance or small type 1 and type 2A fibers alongside relatively larger type 2B fibers [
• The histopathologic findings listed are not specific to X-MTM and may be encountered in congenital myotonic dystrophy type 1 (see
## Severe/Classic X-MTM
In males with the severe/classic phenotype, polyhydramnios and decreased fetal movement are frequently reported. Premature delivery is described in approximately one third of males [
Affected infants often have typical myopathic facies with dolichocephaly, high forehead, long face with midface retrusion, prominent eyes, narrow high-arched palate, and severe malocclusion. Ophthalmoparesis is also frequently observed. Additional features include length greater than the 90th centile with a proportionately lower weight (60% of infants), long fingers and/toes (43%), cryptorchidism and/or undescended testicle (>50%), contractures including clubfeet (30%), and areflexia (60%).
Most infants require lengthy NICU hospitalizations, with approximately 30%-50% of the first year spent in the hospital. Many infants with severe/classic X-MTM succumb to complications of the disorder. The percentage of infants that do not survive the first year of life has been difficult to determine. The reported causes of death are multifactorial, and include removal of ventilatory support. Approximately 25% of male infants die in the first year of life.
Most surviving males are discharged home on 24-hour ventilatory support via tracheostomy and gastrostomy tube feedings. In one study including all forms of X-MTM, 85% of individuals required ventilatory and G-tube support, and nearly all needed wheelchair support for ambulation [
The muscle disease may not be progressive. A prospective study of the ventilatory support requirements of 33 individuals over one year showed little change. Prospective analysis of muscle function in a small pilot group also detected no large changes over a one-year period [
Interestingly, and despite the severe disability and technology dependence of the disease, the annual rate of nonelective hospitalization after the first year of life is not as high as would be expected. In a prospective study of 33 individuals, the rate was 1.1 emergency room visits per year [
Additional features of the underlying myopathy are ophthalmoplegia, ptosis, and severe myopia. Dental malocclusion (requiring orthodontic care) may occur. Constipation is common. Scoliosis often develops in later childhood (75% of individuals in one study) and may require surgical intervention, though scoliosis surgery is documented in only a minority of individuals (≤10%). Scoliosis can exacerbate respiratory insufficiency, in some cases causing ventilator-independent males to become ventilator dependent again as it progresses. Additional orthopedic manifestations include hip dysplasia and long bone fractures [
## Mild and Moderate X-MTM
At least three reports of multigenerational families with
Males with moderate or even mild disease are at increased risk for respiratory decompensation with intercurrent illness and may require transient or increased ventilatory support. They are also at risk for some of the same medical complications (including peliosis hepatis) as those with severe X-MTM [
There are several case reports describing adult males with mild disease and pathogenic variants in
The characteristic muscle biopsy demonstrates numerous small, rounded myofibers with varying percentages of centrally located nuclei. The myofiber size may be uniform throughout the tissue, which may lead to underestimation of the decreased myofiber size (as there may be no appropriately sized fibers for comparison). No diagnostic threshold of central nuclei has been established, as the percentage may increase over time. In rare instances, centrally located nuclei may be absent [
Periodic acid-Schiff (PAS) and nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase histochemical staining often demonstrate an accumulation of staining product in the center of the small myofibers, reflecting (respectively) maldistribution of glycogen and mitochondria/sarcotubular organelles [
ATPase histochemical staining may show type 1 myofiber predominance or small type 1 and type 2A fibers alongside relatively larger type 2B fibers [
The histopathologic findings listed are not specific to X-MTM and may be encountered in congenital myotonic dystrophy type 1 (see
Note: (1) The clinical and histopathologic features of
T-tubule disorganization visualized through immunohistochemistry has been described in X-MTM [
• The characteristic muscle biopsy demonstrates numerous small, rounded myofibers with varying percentages of centrally located nuclei. The myofiber size may be uniform throughout the tissue, which may lead to underestimation of the decreased myofiber size (as there may be no appropriately sized fibers for comparison). No diagnostic threshold of central nuclei has been established, as the percentage may increase over time. In rare instances, centrally located nuclei may be absent [
• Periodic acid-Schiff (PAS) and nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase histochemical staining often demonstrate an accumulation of staining product in the center of the small myofibers, reflecting (respectively) maldistribution of glycogen and mitochondria/sarcotubular organelles [
• ATPase histochemical staining may show type 1 myofiber predominance or small type 1 and type 2A fibers alongside relatively larger type 2B fibers [
• The histopathologic findings listed are not specific to X-MTM and may be encountered in congenital myotonic dystrophy type 1 (see
## Genotype-Phenotype Correlations
X-MTM is most frequently caused by nonsense, frameshift, and splice site variants that predict loss of function. Pathogenic variants are found throughout the gene with no concentration in any specific domain.
Nonsense and frameshift variants nearly always result in the severe/classic X-MTM phenotype.
Splice site and intronic variants may cause the severe presentation or can be associated with the milder phenotype.
Missense variants can be associated with both severe and mild/moderate phenotypes.
Variants associated with the phosphatase domain and the SET-interacting domain nearly always cause a severe phenotype. Pathogenic variants outside of these two domains are more likely to be associated with milder phenotypes [
A large number of pathogenic variants occur in hypermutable CpG dinucleotides; the most common is variant
• Nonsense and frameshift variants nearly always result in the severe/classic X-MTM phenotype.
• Splice site and intronic variants may cause the severe presentation or can be associated with the milder phenotype.
• Missense variants can be associated with both severe and mild/moderate phenotypes.
• Variants associated with the phosphatase domain and the SET-interacting domain nearly always cause a severe phenotype. Pathogenic variants outside of these two domains are more likely to be associated with milder phenotypes [
• A large number of pathogenic variants occur in hypermutable CpG dinucleotides; the most common is variant
## Penetrance
Penetrance is thought to be 100% in males with a pathogenic variant in
Carrier females are generally asymptomatic, though an increasing number of manifesting heterozygotes are being identified [
## Nomenclature
X-MTM (or myotubular myopathy or X-linked centronuclear myopathy [X-CNM]) is considered a subtype of centronuclear myopathy based on the centrally located nuclei of muscle fibers on histologic examination, and based on shared pathogenic mechanisms. Autosomal dominant and autosomal recessive centronuclear myopathy should not be referred to as myotubular myopathy.
Males with X-MTM with identifiable pathogenic variants in
## Prevalence
It has been estimated that X-MTM affects approximately one in 50,000 newborn males [
## Genetically Related (Allelic) Disorders
No other phenotype is known to be associated with pathogenic variants in
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of X-Linked Myotubular Myopathy
Polyhydramnios
↓ fetal movements
Hypotonia
Myopathic facies
Respiratory distress
ID
Muscle biopsy possibly indistinguishable
Absence of ophthalmoparesis
AD family history
Hypotonia
Diffuse muscle weakness
Ptosis
Ophthalmoparesis
Myopathic facies
Muscle biopsy w/central nuclei
Clinical features possibly less severe
Normal/reduced growth parameters
"Spoke on wheel" changes w/oxidative stains on muscle biopsy
Neonatal hypotonia
Weakness
Ophthalmoparesis
Ptosis
Myopathic facies
Severe respiratory compromise
Muscle biopsy w/central nuclei
Clinical features possibly less severe
Normal/reduced growth parameters
May have other non-MTM features on biopsy (cores, dystrophic changes)
Onset in infancy possible
Muscle biopsy w/central nuclei
Clinical features less severe
Normal growth parameters
Onset in infancy
Diffuse weakness
Respiratory failure
Ophthalmoparesis
Muscle biopsy w/central nuclei
Can have prominent cardiac involvement
Biopsies may lack central nuclei.
Can present w/diffuse weakness starting in infancy, often w/prominent facial weakness
Biopsies can feature myofiber hypotrophy & type I fiber predominance.
Ophthalmoparesis is rare (except in
Muscle biopsy showing nemaline rod aggregates (essentially never seen in X-MTM)
Central nuclei usually not ↑
May present w/diffuse weakness starting from birth
Ophthalmoparesis in a subset of persons
Weakness usually less than in X-MTM
Muscle biopsy showing characteristic disruptions of mitochondrial & sarcotubular organization on oxidative stains (i.e., cores)
Central nuclei usually not ↑
Can present w/similar symptoms in early childhood, w/facial & extremity weakness & involvement of extraocular muscles
Both conditions may respond to mestinon.
Electrodiagnostic features of CMS (abnormal repetitive stimulation & jitter on single-fiber EMG) may be seen in X-MTM.
Fluctuating weakness variably present in CMS (not typical of X-MTM)
Biopsies are either normal or show nonspecific changes; features of X-MTM are not seen on biopsy in CMS.
AD = autosomal dominant; AR = autosomal recessive; CNM = centronuclear myopathy; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; MTM = myotubular myopathy
The occurrence of minicore myopathy in two generations in a few families – suggestive of autosomal dominant inheritance – has been reported.
See
• Polyhydramnios
• ↓ fetal movements
• Hypotonia
• Myopathic facies
• Respiratory distress
• ID
• Muscle biopsy possibly indistinguishable
• Absence of ophthalmoparesis
• AD family history
• Hypotonia
• Diffuse muscle weakness
• Ptosis
• Ophthalmoparesis
• Myopathic facies
• Muscle biopsy w/central nuclei
• Clinical features possibly less severe
• Normal/reduced growth parameters
• "Spoke on wheel" changes w/oxidative stains on muscle biopsy
• Neonatal hypotonia
• Weakness
• Ophthalmoparesis
• Ptosis
• Myopathic facies
• Severe respiratory compromise
• Muscle biopsy w/central nuclei
• Clinical features possibly less severe
• Normal/reduced growth parameters
• May have other non-MTM features on biopsy (cores, dystrophic changes)
• Onset in infancy possible
• Muscle biopsy w/central nuclei
• Clinical features less severe
• Normal growth parameters
• Onset in infancy
• Diffuse weakness
• Respiratory failure
• Ophthalmoparesis
• Muscle biopsy w/central nuclei
• Can have prominent cardiac involvement
• Biopsies may lack central nuclei.
• Can present w/diffuse weakness starting in infancy, often w/prominent facial weakness
• Biopsies can feature myofiber hypotrophy & type I fiber predominance.
• Ophthalmoparesis is rare (except in
• Muscle biopsy showing nemaline rod aggregates (essentially never seen in X-MTM)
• Central nuclei usually not ↑
• May present w/diffuse weakness starting from birth
• Ophthalmoparesis in a subset of persons
• Weakness usually less than in X-MTM
• Muscle biopsy showing characteristic disruptions of mitochondrial & sarcotubular organization on oxidative stains (i.e., cores)
• Central nuclei usually not ↑
• Can present w/similar symptoms in early childhood, w/facial & extremity weakness & involvement of extraocular muscles
• Both conditions may respond to mestinon.
• Electrodiagnostic features of CMS (abnormal repetitive stimulation & jitter on single-fiber EMG) may be seen in X-MTM.
• Fluctuating weakness variably present in CMS (not typical of X-MTM)
• Biopsies are either normal or show nonspecific changes; features of X-MTM are not seen on biopsy in CMS.
## Management
To establish the extent of disease and needs in an individual diagnosed with X-linked myotubular myopathy (X-MTM), the following evaluations are recommended if they have not already been completed:
Assessment of pulmonary function for long-term ventilatory management, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established.
Feeding/swallowing assessment, as performed by a qualified occupational therapist or equivalent allied health professional
Ophthalmologic evaluation, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established
In individuals with hemolysis or unexplained anemia, osmotic fragility test to detect spherocytosis
In the presence of infantile vomiting, investigation for pyloric stenosis
Consultation with a clinical geneticist and/or genetic counselor
In older children, evaluation for orthopedic complications, including examination for scoliosis
Management of individuals with X-MTM is based on supportive care measures and in large part is similar to that for other congenital myopathies [
Once the specific diagnosis of X-MTM is confirmed, management may be guided by family decisions regarding continued ventilatory support for the affected family member. Families may benefit from the involvement of professionals familiar with the data concerning the overall prognosis for X-MTM. Talking with other families who have children with the disorder can be extremely helpful, as can discussion with members of an MTM family foundation (see
Given the risks for aspiration pneumonia and respiratory failure in infants with moderate or severe disease, tracheostomy and G-tube feeding should be seriously considered. Even individuals with mild disease are at risk for significant morbidity and mortality from intercurrent respiratory infection and hypoventilation.
For ventilator-dependent individuals, communication support incorporates speech with a capped tracheostomy or Passy-Muir valve, sign language, and/or communication devices such as writing boards.
Affected individuals older than age five years attend school, usually assisted by a dedicated nurse or aide, or have home-based teachers to limit exposure to infectious agents. Based on the emerging natural history study data, neuropsychologic evaluation may help identify learning difficulties and enable optimized educational planning.
Ophthalmologists, orthopedists specializing in scoliosis management, and orthodontists should address specific medical complications related to the underlying myopathy.
Children with X-MTM and an unexpected decline in motor skills should be evaluated for a potential abnormality in neuromuscular junction (NMJ) function.
In addition, and even without signs of unexplained decline, individuals with X-MTM may have underlying abnormalities in NMJ structure and function and thus may benefit from treatment targeted at improving NMJ signaling. A preclinical study in a mouse model of X-MTM identified structural abnormalities in the NMJ and demonstrated significant improvement in muscle fatigue with pyridostigmine treatment [
Appropriate surveillance includes the following:
Annual pulmonary assessment, including pulmonary function testing if able to be performed
Polysomnography every one to three years unless symptoms of sleep-disordered breathing are present on history
Spinal examination for signs of scoliosis, particularly in late childhood and adolescence
Annual ophthalmologic exams for ophthalmoplegia, ptosis, myopia, and for protective assessment of the effect of impaired eyelid closure
Assessment for dental malocclusion, with referral for orthodontia if indicated
Currently, the risk for non-neurologic events including bleeding diatheses and gastrointestinal complications is uncertain. Furthermore, the benefit of screening for such abnormalities has yet to be determined. Potential screening tests may include the following, though these studies have not been found to reliably identify actionable abnormalities:
Annual blood counts [
Annual liver function test and abdominal ultrasound to address the potential risk of peliosis hepatis
Note: No advanced screening has been found to be useful for detecting hepatic peliosis prior to the development of clinically significant hemorrhage.
It is generally agreed that neuromuscular paralytics such as succinylcholine should be avoided as part of anesthesia for patients with X-MTM. However, it is important to note that individuals with X-MTM are NOT susceptible to malignant hyperthermia [
See
Gene replacement therapy is a promising treatment strategy for X-MTM. AAV-mediated delivery of
Several other strategies have shown promise in preclinical models of X-MTM. Lowering of DNM2, a key disease modifier, using either genetic or antisense oligonucleotide-mediated gene knockdown, resulted in increased strength and prolonged survival in a murine model of X-MTM [
Search
• Assessment of pulmonary function for long-term ventilatory management, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established.
• Feeding/swallowing assessment, as performed by a qualified occupational therapist or equivalent allied health professional
• Ophthalmologic evaluation, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established
• In individuals with hemolysis or unexplained anemia, osmotic fragility test to detect spherocytosis
• In the presence of infantile vomiting, investigation for pyloric stenosis
• Consultation with a clinical geneticist and/or genetic counselor
• In older children, evaluation for orthopedic complications, including examination for scoliosis
• Given the risks for aspiration pneumonia and respiratory failure in infants with moderate or severe disease, tracheostomy and G-tube feeding should be seriously considered. Even individuals with mild disease are at risk for significant morbidity and mortality from intercurrent respiratory infection and hypoventilation.
• For ventilator-dependent individuals, communication support incorporates speech with a capped tracheostomy or Passy-Muir valve, sign language, and/or communication devices such as writing boards.
• Affected individuals older than age five years attend school, usually assisted by a dedicated nurse or aide, or have home-based teachers to limit exposure to infectious agents. Based on the emerging natural history study data, neuropsychologic evaluation may help identify learning difficulties and enable optimized educational planning.
• Ophthalmologists, orthopedists specializing in scoliosis management, and orthodontists should address specific medical complications related to the underlying myopathy.
• Children with X-MTM and an unexpected decline in motor skills should be evaluated for a potential abnormality in neuromuscular junction (NMJ) function.
• In addition, and even without signs of unexplained decline, individuals with X-MTM may have underlying abnormalities in NMJ structure and function and thus may benefit from treatment targeted at improving NMJ signaling. A preclinical study in a mouse model of X-MTM identified structural abnormalities in the NMJ and demonstrated significant improvement in muscle fatigue with pyridostigmine treatment [
• Annual pulmonary assessment, including pulmonary function testing if able to be performed
• Polysomnography every one to three years unless symptoms of sleep-disordered breathing are present on history
• Spinal examination for signs of scoliosis, particularly in late childhood and adolescence
• Annual ophthalmologic exams for ophthalmoplegia, ptosis, myopia, and for protective assessment of the effect of impaired eyelid closure
• Assessment for dental malocclusion, with referral for orthodontia if indicated
• Annual blood counts [
• Annual liver function test and abdominal ultrasound to address the potential risk of peliosis hepatis
• Note: No advanced screening has been found to be useful for detecting hepatic peliosis prior to the development of clinically significant hemorrhage.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with X-linked myotubular myopathy (X-MTM), the following evaluations are recommended if they have not already been completed:
Assessment of pulmonary function for long-term ventilatory management, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established.
Feeding/swallowing assessment, as performed by a qualified occupational therapist or equivalent allied health professional
Ophthalmologic evaluation, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established
In individuals with hemolysis or unexplained anemia, osmotic fragility test to detect spherocytosis
In the presence of infantile vomiting, investigation for pyloric stenosis
Consultation with a clinical geneticist and/or genetic counselor
In older children, evaluation for orthopedic complications, including examination for scoliosis
• Assessment of pulmonary function for long-term ventilatory management, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established.
• Feeding/swallowing assessment, as performed by a qualified occupational therapist or equivalent allied health professional
• Ophthalmologic evaluation, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established
• In individuals with hemolysis or unexplained anemia, osmotic fragility test to detect spherocytosis
• In the presence of infantile vomiting, investigation for pyloric stenosis
• Consultation with a clinical geneticist and/or genetic counselor
• In older children, evaluation for orthopedic complications, including examination for scoliosis
## Treatment of Manifestations
Management of individuals with X-MTM is based on supportive care measures and in large part is similar to that for other congenital myopathies [
Once the specific diagnosis of X-MTM is confirmed, management may be guided by family decisions regarding continued ventilatory support for the affected family member. Families may benefit from the involvement of professionals familiar with the data concerning the overall prognosis for X-MTM. Talking with other families who have children with the disorder can be extremely helpful, as can discussion with members of an MTM family foundation (see
Given the risks for aspiration pneumonia and respiratory failure in infants with moderate or severe disease, tracheostomy and G-tube feeding should be seriously considered. Even individuals with mild disease are at risk for significant morbidity and mortality from intercurrent respiratory infection and hypoventilation.
For ventilator-dependent individuals, communication support incorporates speech with a capped tracheostomy or Passy-Muir valve, sign language, and/or communication devices such as writing boards.
Affected individuals older than age five years attend school, usually assisted by a dedicated nurse or aide, or have home-based teachers to limit exposure to infectious agents. Based on the emerging natural history study data, neuropsychologic evaluation may help identify learning difficulties and enable optimized educational planning.
Ophthalmologists, orthopedists specializing in scoliosis management, and orthodontists should address specific medical complications related to the underlying myopathy.
Children with X-MTM and an unexpected decline in motor skills should be evaluated for a potential abnormality in neuromuscular junction (NMJ) function.
In addition, and even without signs of unexplained decline, individuals with X-MTM may have underlying abnormalities in NMJ structure and function and thus may benefit from treatment targeted at improving NMJ signaling. A preclinical study in a mouse model of X-MTM identified structural abnormalities in the NMJ and demonstrated significant improvement in muscle fatigue with pyridostigmine treatment [
• Given the risks for aspiration pneumonia and respiratory failure in infants with moderate or severe disease, tracheostomy and G-tube feeding should be seriously considered. Even individuals with mild disease are at risk for significant morbidity and mortality from intercurrent respiratory infection and hypoventilation.
• For ventilator-dependent individuals, communication support incorporates speech with a capped tracheostomy or Passy-Muir valve, sign language, and/or communication devices such as writing boards.
• Affected individuals older than age five years attend school, usually assisted by a dedicated nurse or aide, or have home-based teachers to limit exposure to infectious agents. Based on the emerging natural history study data, neuropsychologic evaluation may help identify learning difficulties and enable optimized educational planning.
• Ophthalmologists, orthopedists specializing in scoliosis management, and orthodontists should address specific medical complications related to the underlying myopathy.
• Children with X-MTM and an unexpected decline in motor skills should be evaluated for a potential abnormality in neuromuscular junction (NMJ) function.
• In addition, and even without signs of unexplained decline, individuals with X-MTM may have underlying abnormalities in NMJ structure and function and thus may benefit from treatment targeted at improving NMJ signaling. A preclinical study in a mouse model of X-MTM identified structural abnormalities in the NMJ and demonstrated significant improvement in muscle fatigue with pyridostigmine treatment [
## Surveillance
Appropriate surveillance includes the following:
Annual pulmonary assessment, including pulmonary function testing if able to be performed
Polysomnography every one to three years unless symptoms of sleep-disordered breathing are present on history
Spinal examination for signs of scoliosis, particularly in late childhood and adolescence
Annual ophthalmologic exams for ophthalmoplegia, ptosis, myopia, and for protective assessment of the effect of impaired eyelid closure
Assessment for dental malocclusion, with referral for orthodontia if indicated
Currently, the risk for non-neurologic events including bleeding diatheses and gastrointestinal complications is uncertain. Furthermore, the benefit of screening for such abnormalities has yet to be determined. Potential screening tests may include the following, though these studies have not been found to reliably identify actionable abnormalities:
Annual blood counts [
Annual liver function test and abdominal ultrasound to address the potential risk of peliosis hepatis
Note: No advanced screening has been found to be useful for detecting hepatic peliosis prior to the development of clinically significant hemorrhage.
• Annual pulmonary assessment, including pulmonary function testing if able to be performed
• Polysomnography every one to three years unless symptoms of sleep-disordered breathing are present on history
• Spinal examination for signs of scoliosis, particularly in late childhood and adolescence
• Annual ophthalmologic exams for ophthalmoplegia, ptosis, myopia, and for protective assessment of the effect of impaired eyelid closure
• Assessment for dental malocclusion, with referral for orthodontia if indicated
• Annual blood counts [
• Annual liver function test and abdominal ultrasound to address the potential risk of peliosis hepatis
• Note: No advanced screening has been found to be useful for detecting hepatic peliosis prior to the development of clinically significant hemorrhage.
## Agents/Circumstances to Avoid
It is generally agreed that neuromuscular paralytics such as succinylcholine should be avoided as part of anesthesia for patients with X-MTM. However, it is important to note that individuals with X-MTM are NOT susceptible to malignant hyperthermia [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Gene replacement therapy is a promising treatment strategy for X-MTM. AAV-mediated delivery of
Several other strategies have shown promise in preclinical models of X-MTM. Lowering of DNM2, a key disease modifier, using either genetic or antisense oligonucleotide-mediated gene knockdown, resulted in increased strength and prolonged survival in a murine model of X-MTM [
Search
## Genetic Counseling
X-linked myotubular myopathy (X-MTM) is inherited in an X-linked manner.
The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
The carrier risk for a woman whose son has a confirmed
If the mother of the proband has an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Note: Postzygotic and germline mosaicism has been reported in the maternal grandfather of a severely affected male proband [
Note: Molecular genetic testing may be able to identify the family member in whom a
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.
Note: (1) Females who are heterozygous (carriers) for this X-linked disorder are generally asymptomatic, although symptomatic heterozygote females have been described [
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at increased risk of being heterozygotes (carriers).
Once the
Several instances of germline mosaicism for
• The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
• The carrier risk for a woman whose son has a confirmed
• If the mother of the proband has an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Note: Postzygotic and germline mosaicism has been reported in the maternal grandfather of a severely affected male proband [
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at increased risk of being heterozygotes (carriers).
## Mode of Inheritance
X-linked myotubular myopathy (X-MTM) is inherited in an X-linked manner.
## Risk to Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
The carrier risk for a woman whose son has a confirmed
If the mother of the proband has an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Note: Postzygotic and germline mosaicism has been reported in the maternal grandfather of a severely affected male proband [
Note: Molecular genetic testing may be able to identify the family member in whom a
• The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
• The carrier risk for a woman whose son has a confirmed
• If the mother of the proband has an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Note: Postzygotic and germline mosaicism has been reported in the maternal grandfather of a severely affected male proband [
## Heterozygote (Carrier) Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.
Note: (1) Females who are heterozygous (carriers) for this X-linked disorder are generally asymptomatic, although symptomatic heterozygote females have been described [
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at increased risk of being heterozygotes (carriers).
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at increased risk of being heterozygotes (carriers).
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Several instances of germline mosaicism for
## Resources
PO Box 2041
Ponte Vedra Beach FL 32004
United Kingdom
Germany
CMDIR/Cure CMD
•
• PO Box 2041
• Ponte Vedra Beach FL 32004
•
•
•
•
•
•
•
•
• United Kingdom
•
•
• Germany
•
•
•
• CMDIR/Cure CMD
•
•
•
•
•
## Molecular Genetics
X-Linked Myotubular Myopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for X-Linked Myotubular Myopathy (
A large number of pathogenic variants occur in hypermutable CpG dinucleotides and this mechanism may explain the recurrence of some variants. Six recurrent variants account for about 24% of cases in the MTM1-LOVD database [
Variants listed in the table have been provided by the authors.
NA = not applicable
See
Myotubularin functions primarily as a lipid phosphatase [
Myotubularin's cellular function is inferred in part from the known roles of the phosphoinositides upon which it acts and from the fact that it localizes to endosomes [
Myotubularin likely has roles in other cellular processes as well. It has been shown to interact with the intermediate filament network and specifically with desmin [
Myotubularin was the first described member of a large group of homologous, evolutionarily conserved proteins [
The mechanism(s) whereby lack or dysfunction of myotubularin produces the disease phenotype seen in X-MTM have come into focus. Based on data from animal models, the weakness in myotubular myopathy is caused, at least in part, by defective excitation-contraction (E-C) coupling [
Loss of myotubularin likely affects other aspects of muscle function as well. In both zebrafish and murine models of X-MTM, disorganization of the NMJ has been reported [
## References
## Literature Cited
## Chapter Notes
Soma Das, PhD (2002-present)James J Dowling, MD, PhD (2011-present)Gail Ellen Herman, MD, PhD; Nationwide Children's Hospital, Columbus (2002-2011)Michael W Lawlor, MD, PhD (2018-present)Christopher R Pierson, MD, PhD; Nationwide Children's Hospital, Columbus (2011-2018)
23 August 2018 (sw) Comprehensive update posted live
6 October 2011 (me) Comprehensive update posted live
5 October 2006 (me) Comprehensive update posted live
3 May 2004 (me) Comprehensive update posted live
25 February 2002 (me) Review posted live
2 October 2001 (gh) Original submission
• 23 August 2018 (sw) Comprehensive update posted live
• 6 October 2011 (me) Comprehensive update posted live
• 5 October 2006 (me) Comprehensive update posted live
• 3 May 2004 (me) Comprehensive update posted live
• 25 February 2002 (me) Review posted live
• 2 October 2001 (gh) Original submission
## Revision History
23 August 2018 (sw) Comprehensive update posted live
6 October 2011 (me) Comprehensive update posted live
5 October 2006 (me) Comprehensive update posted live
3 May 2004 (me) Comprehensive update posted live
25 February 2002 (me) Review posted live
2 October 2001 (gh) Original submission
• 23 August 2018 (sw) Comprehensive update posted live
• 6 October 2011 (me) Comprehensive update posted live
• 5 October 2006 (me) Comprehensive update posted live
• 3 May 2004 (me) Comprehensive update posted live
• 25 February 2002 (me) Review posted live
• 2 October 2001 (gh) Original submission
|
[
"A Al-Hashim, HD Gonorazky, K Amburgey, S Das, JJ Dowling. A novel intronic mutation in MTM1 detected by RNA analysis in a case of X-linked myotubular myopathy.. Neurol Genet. 2017;3",
"L Al-Qusairi, N Weiss, A Toussaint, C Berby, N Messaddeq, C Kretz, D Sanoudou, AH Beggs, B Allard, J-L Mandel, V Jacquemond, A Buj-Bello. T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase.. Proc Natl Acad Sci (USA) 2009;106:18763-8",
"K Amburgey, A Bailey, JH Hwang, MA Tarnopolsky, CG Bonnemann, L Medne, KD Mathews, J Collins, JR Daube, GP Wellman, B Callaghan, NF Clarke, JJ Dowling. Genotype-phenotype correlations in recessive RYR1-related myopathies.. Orphanet J Rare Dis. 2013a;8:117",
"K Amburgey, MW Lawlor, D Del Gaudio, YW Cheng, C Fitzpatrick, A Minor, X Li, D Aughton, S Das, AH Beggs, JJ Dowling. Large duplication in MTM1 associated with myotubular myopathy.. Neuromuscul Disord. 2013b;23:214-8",
"K Amburgey, E Tsuchiya, S de Chastonay, M Glueck, R Alverez, CT Nguyen, A Rutkowski, J Hornyak, AH Beggs, JJ Dowling. A natural history study of X-linked myotubular myopathy.. Neurology. 2017;89:1355-64",
"L Amoasii, DL Bertazzi, H Tronchère, K Hnia, G Chicanne, B Rinaldi, BS Cowling, A Ferry, B Klaholz, B Payrastre, J Laporte, S Friant. Phosphatase-dead myotubularin ameliorates X-linked centronuclear myopathy phenotypes in mice.. PLoS Genet. 2012;8",
"C Bachmann, H Jungbluth, F Muntoni, AY Manzur, F Zorzato, S Treves. Cellular, biochemical and molecular changes in muscles from patients with X-linked myotubular myopathy due to MTM1 mutations.. Hum Mol Genet. 2017;26:320-32",
"PG Barth, V Dubowitz. X-linked myotubular myopathy--a long-term follow-up study.. Eur J Paediatr Neurol 1998;2:49-56",
"O Bartsch, W Kress, A Wagner, E Seemanova. The novel contiguous gene syndrome of myotubular myopathy (MTM1), male hypogenitalism and Step in Xq28:report of the first familial case.. Cytogenet Cell Genet 1999;85:310-4",
"AH Beggs, BJ Byrne, S De Chastonay, T Haselkorn, I Hughes, ES James, NL Kuntz, J Simon, LC Swanson, ML Yang, ZF Yu, SW Yum, S Prasad. A multicenter, retrospective medical record review of X-linked myotubular myopathy: the recensus study.. Muscle Nerve. 2018;57:550-60",
"E Bertini, V Biancalana, A Bolino, A Buj Bello, M Clague, P Guicheney, H Jungbluth, W Kress, A Musaro', H Nandurkar, L Pirola, N Romero, J Senderek, U Suter, C Sewry, H Tronchere, C Wallgren-Pettersson, MJ Wishart, J Laporte. 118th ENMC International Workshop on Advances in Myotubular Myopathy. 26-28 September 2003, Naarden, The Netherlands. (5th Workshop of the International Consortium on Myotubular Myopathy).. Neuromuscul Disord. 2004;14:387-96",
"JA Bevilacqua, M Bitoun, V Biancalana, A Oldfors, G Stoltenburg, KG Claeys, E Lacène, G Brochier, L Manéré, P Laforêt, B Eymard, P Guicheney, M Fardeau, NB Romero. \"Necklace\" fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy.. Acta Neuropathol. 2009;117:283-91",
"V Biancalana, O Caron, S Gallati, F Baas, W Kress, G Novelli, MR D'Apice, C Lagier-Tourenne, A Buj-Bello, NB Romero, JL Mandel. Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype.. Hum Genet. 2003;112:135-42",
"V Biancalana, S Scheidecker, M Miguet, A Laquerrière, NB Romero, T Stojkovic, O Abath Neto, S Mercier, N Voermans, L Tanner, C Rogers, E Ollagnon-Roman, H Roper, C Boutte, S Ben-Shachar, X Lornage, N Vasli, E Schaefer, P Laforet, J Pouget, A Moerman, L Pasquier, P Marcorelle, A Magot, B Küsters, N Streichenberger, C Tranchant, N Dondaine, R Schneider, C Gasnier, N Calmels, V Kremer, K Nguyen, J Perrier, EJ Kamsteeg, P Carlier, RY Carlier, J Thompson, A Boland, JF Deleuze, M Fardeau, E Zanoteli, B Eymard, J Laporte. Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues.. Acta Neuropathol. 2017;134:889-904",
"PJ Cahill, AS Rinella, RJ Bielski. Orthopaedic complications of myotubular myopathy.. J Pediatr Orthop. 2007;27:98-103",
"C Cao, J Laporte, JM Backer, A Wandinger-Ness, MP Stein. Myotubularin lipid phosphatase binds the hVPS15/hVPS34 lipid kinase complex on endosomes.. Traffic. 2007;8:1052-67",
"C Chaussade, L Pirola, S Bonnafous, F Blondeau, S Brenz-Verca, H Tronchère, F Portis, S Rusconi, B Payrastre, J Laporte, E Van Obberghen. Expression of myotubularin by an adenoviral vector demonstrates its function as a phosphatidylinositol 3-phosphate [PtdIns(3)P] phosphatase in muscle cell lines: involvement of PtdIns(3)P in insulin-stimulated glucose transport.. Mol Endocrinol. 2003;17:2448-60",
"MK Childers, R Joubert, K Poulard, C Moal, RW Grange, JA Doering, MW Lawlor, BE Rider, T Jamet, N Danièle, S Martin, C Rivière, T Soker, C Hammer, L Van Wittenberghe, M Lockard, X Guan, M Goddard, E Mitchell, J Barber, JK Williams, DL Mack, ME Furth, A Vignaud, C Masurier, F Mavilio, P Moullier, AH Beggs, A Buj-Bello. Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy.. Sci Transl Med. 2014;6",
"BS Cowling, T Chevremont, I Prokic, C Kretz, A Ferry, C Coirault, O Koutsopoulos, V Laugel, NB Romero, J Laporte. Reducing dynamin 2 expression rescues X-linked centronuclear myopathy.. J Clin Invest. 2014;124:1350-63",
"N Dahl, LJ Hu, M Chery, M Fardeau, S Gilgenkrantz, A Nivelon-Chevallier, I Sidaner-Noisette, F Mugneret, JB Gouyon, A Gal. Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region.. Am J Hum Genet 1995;56:1108-15",
"BM de Gouyon, W Zhao, J Laporte, JL Mandel, A Metzenberg, GE Herman. Characterization of mutations in the myotubularin gene in twenty six patients with X-linked myotubular myopathy.. Hum Mol Genet 1997;6:1499-504",
"JJ Dowling, EM Gibbs, EL Feldman. Membrane traffic and muscle: lessons from human disease.. Traffic. 2008;9:1035-43",
"JJ Dowling, R Joubert, SE Low, AN Durban, N Messaddeq, X Li, AN Dulin-Smith, AD Snyder, ML Marshall, JT Marshall, AH Beggs, A Buj-Bello, CR Pierson. Myotubular myopathy and the neuromuscular junction: a novel therapeutic approach from mouse models.. Dis Model Mech. 2012;5:852-9",
"JJ Dowling, AP Vreede, SE Low, EM Gibbs, JY Kuwada, CG Bonnemann, EL Feldman. Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy.. PLoS Genet. 2009;5",
"S Falcone, W Roman, K Hnia, V Gache, N Didier, J Lainé, F Auradé, I Marty, I Nishino, N Charlet-Berguerand, NB Romero, G Marazzi, D Sassoon, J Laporte, ER Gomes. N-WASP is required for Amphiphysin-2/BIN1-dependent nuclear positioning and triad organization in skeletal muscle and is involved in the pathophysiology of centronuclear myopathy.. EMBO Mol Med. 2014;6:1455-75",
"KJ Felice, CH Whitaker, Q Wu. Whole exome sequencing discloses a pathogenic MTM1 gene mutation and ends the diagnostic odyssey in an older woman with a progressive and seemingly sporadic myopathy: case report and literature review of MTM1 manifesting female carriers.. Neuromuscul Disord. 2018;28:339-45",
"C Gavriilidis, L Laredj, R Solinhac, N Messaddeq, J Viaud, J Laporte, I Sumara, K. Hnia. The MTM1-UBQLN2-HSP complex mediates degradation of misfolded intermediate filaments in skeletal muscle.. Nat Cell Biol. 2018;20:198-210",
"BG Häne, RC Rogers, CE Schwartz. Germline mosaicism in X-linked myotubular myopathy.. Clin Genet 1999;56:77-81",
"TR Helliwell, IH Ellis, RE Appleton. Myotubular myopathy: morphological, immunohistochemical and clinical variation.. Neuromuscul Disord 1998;8:152-61",
"C Hedberg-Oldfors, K Visuttijai, A Topa, M Tulinius, A Oldfors. Grand paternal inheritance of X-linked myotubular myopathy due to mosaicism, and identification of necklace fibers in an asymptomatic male.. Neuromuscul Disord. 2017;27:843-7",
"GE Herman, M Finegold, W Zhao, B de Gouyon, A Metzenberg. Medical complications in long-term survivors with X-linked myotubular myopathy.. J Pediatr 1999;134:206-14",
"GE Herman, K Kopacz, W Zhao, PL Mills, A Metzenberg, S Das. Characterization of mutations in fifty North American patients with X-linked myotubular myopathy.. Hum Mutat 2002;19:114-21",
"K Hnia, H Tronchère, KK Tomczak, L Amoasii, P Schultz, AH Beggs, B Payrastre, JL Mandel, J Laporte. Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle.. J Clin Invest. 2011;121:70-85",
"S Hoffjan, C Thiels, M Vorgerd, E Neuen-Jacob, JT Epplen, W Kress. Extreme phenotypic variability in a German family with X-linked myotubular myopathy associated with E404K mutation in MTM1.. Neuromuscul Disord 2006;16:749-53",
"LJ Hu, J Laporte, W Kress, P Kioschis, R Siebenhaar, A Poustka, M Fardeau, A Metzenberg, EA Janssen, N Thomas, JL Mandel, N Dahl. Deletions in Xq28 in two boys with myotubular myopathy and abnormal genital development define a new contiguous gene syndrome in a 430 kb region.. Hum Mol Genet 1996;5:139-43",
"H Jungbluth, S Treves, F Zorzato, A Sarkozy, J Ochala, C Sewry, R Phadke, M Gautel, F. Muntoni. Congenital myopathies: disorders of excitation-contraction coupling and muscle contraction.. Nat Rev Neurol. 2018;14:151-67",
"K Ketel, M Krauss, AS Nicot, D Puchkov, M Wieffer, R Müller, D Subramanian, C Schultz, J Laporte, V Haucke. A phosphoinositide conversion mechanism for exit from endosomes.. Nature. 2016;529:408-12",
"J Laporte, V Biancalana, SM Tanner, W Kress, V Schneider, C Wallgren-Pettersson, F Herger, A Buj-Bello, F Blondeau, S Liechti-Gallati, JL Mandel. MTM1 mutations in X-linked myotubular myopathy.. Hum Mutat 2000;15:393-409",
"J Laporte, F Blondeau, A Buj-Bello, JL Mandel. The myotubularin family: from genetic disease to phosphoinositide metabolism.. Trends Genet 2001a;17:221-8",
"J Laporte, F Blondeau, A Gansmuller, Y Lutz, JL Vonesch, JL Mandel. The PtdIns3P phosphatase myotubularin is a cytoplasmic protein that also localizes to Rac1-inducible plasma membrane ruffles.. J Cell Sci. 2002;115:3105-17",
"J Laporte, C Guiraud-Chaumeil, SM Tanner, F Blondeau, LJ Hu, S Vicaire, S Liechti-Gallati, JL Mandel. Genomic organization of the MTM1 gene implicated in X-linked myotubular myopathy.. Eur J Hum Genet 1998;6:325-30",
"J Laporte, C Guiraud-Chaumeil, MC Vincent, JL Mandel, SM Tanner, S Liechti-Gallati, C Wallgren-Pettersson, N Dahl, W Kress, PA Bolhuis, M Fardeau, F Samson, E Bertini. Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. ENMC International Consortium on Myotubular Myopathy. European Neuro-Muscular Center.. Hum Mol Genet 1997;6:1505-11",
"J Laporte, LJ Hu, C Kretz, JL Mandel, P Kioschis, JF Coy, SM Klauck, A Poustka, N Dahl. A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast.. Nat Genet 1996;13:175-82",
"J Laporte, W Kress, JL Mandel. Diagnosis of X-linked myotubular myopathy by detection of myotubularin.. Ann Neurol 2001b;50:42-6",
"MW Lawlor, D Armstrong, MG Viola, JJ Widrick, H Meng, RW Grange, MK Childers, CP Hsu, M O'Callaghan, CR Pierson, A Buj-Bello, AH Beggs. Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy.. Hum Mol Genet. 2013;22:1525-38",
"MW Lawlor, AH Beggs, A Buj-Bello, MK Childers, JJ Dowling, ES James, H Meng, SA Moore, S Prasad, B Schoser, CA Sewry. Skeletal Muscle Pathology in X-Linked Myotubular Myopathy: Review With Cross-Species Comparisons.. J Neuropathol Exp Neurol. 2016;75:102-10",
"M Lek, KJ Karczewski, EV Minikel, KE Samocha, E Banks, T Fennell, AH O'Donnell-Luria, JS Ware, AJ Hill, BB Cummings, T Tukiainen, DP Birnbaum, JA Kosmicki, LE Duncan, K Estrada, F Zhao, J Zou, E Pierce-Hoffman, J Berghout, DN Cooper, N Deflaux, M DePristo, R Do, J Flannick, M Fromer, L Gauthier, J Goldstein, N Gupta, D Howrigan, A Kiezun, MI Kurki, AL Moonshine, P Natarajan, L Orozco, GM Peloso, R Poplin, MA Rivas, V Ruano-Rubio, SA Rose, DM Ruderfer, K Shakir, PD Stenson, C Stevens, BP Thomas, G Tiao, MT Tusie-Luna, B Weisburd, HH Won, D Yu, DM Altshuler, D Ardissino, M Boehnke, J Danesh, S Donnelly, R Elosua, JC Florez, SB Gabriel, G Getz, SJ Glatt, CM Hultman, S Kathiresan, M Laakso, S McCarroll, MI McCarthy, D McGovern, R McPherson, BM Neale, A Palotie, SM Purcell, D Saleheen, JM Scharf, P Sklar, PF Sullivan, J Tuomilehto, MT Tsuang, HC Watkins, JG Wilson, MJ Daly, DG MacArthur. Analysis of protein-coding genetic variation in 60,706 humans.. Nature. 2016;536:285-91",
"RS Litman, SM Griggs, JJ Dowling, S Riazi. Malignant Hyperthermia Susceptibility and Related Diseases.. Anesthesiology. 2018;128:159-67",
"DL Mack, K Poulard, MA Goddard, V Latournerie, JM Snyder, RW Grange, MR Elverman, J Denard, P Veron, L Buscara, C Le Bec, JY Hogrel, AG Brezovec, H Meng, L Yang, F Liu, M O'Callaghan, N Gopal, VE Kelly, BK Smith, JL Strande, F Mavilio, AH Beggs, F Mingozzi, MW Lawlor, A Buj-Bello, MK Childers. Systemic AAV8-mediated gene therapy drives whole-body correction of myotubular myopathy in dogs.. Mol Ther. 2017;25:839-54",
"HJ McCrea, C Kretz, J Laporte, LR Ment. Dementia in a child with myotubular myopathy.. Pediatr Neurol 2009;40:483-5",
"T Motoki, M Fukuda, T Nakano, S Matsukage, A Fukui, S Akiyoshi, YK Hayashi, E Ishii, I Nishino. Fatal hepatic hemorrhage by peliosis hepatis in X-linked myotubular myopathy: a case report.. Neuromuscul Disord. 2013;23:917-21",
"J Oliveira, ME Oliveira, W Kress, R Taipa, MM Pires, P Hilbert, P Baxter, M Santos, H Buermans, JT den Dunnen, R Santos. Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database.. Eur J Hum Genet. 2013;21:540-9",
"CR Pierson, PB Agrawal, J Blasko, AH Beggs. Myofiber size correlates with MTM1 mutation type and outcome in X-linked myotubular myopathy.. Neuromuscul Disord. 2007;17:562-8",
"CR Pierson, K Tomczak, P Agrawal, B Moghadaszadeh, AH Beggs. X-linked myotubular and centronuclear myopathies.. J Neuropathol Exp Neurol. 2005;64:555-64",
"MA Raess, S Friant, BS Cowling, J Laporte. WANTED - Dead or alive: Myotubularins, a large disease-associated protein family.. Adv Biol Regul. 2017;63:49-58",
"SA Robb, CA Sewry, JJ Dowling, L Feng, T Cullup, S Lillis, S Abbs, MM Lees, J Laporte, AY Manzur, RK Knight, KR Mills, MG Pike, W Kress, D Beeson, H Jungbluth, MC Pitt, F Muntoni. Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies.. Neuromuscul Disord. 2011;21:379-86",
"FL Robinson, JE Dixon. Myotubularin phosphatases: policing 3-phosphoinositides.. Trends Cell Biol. 2006;16:403-12",
"W Roman, JP Martins, FA Carvalho, R Voituriez, JVG Abella, NC Santos, B Cadot, M Way, ER Gomes. Myofibril contraction and crosslinking drive nuclear movement to the periphery of skeletal muscle.. Nat Cell Biol. 2017;19:1189-201",
"NB Romero. Centronuclear myopathies: a widening concept.. Neuromuscul Disord. 2010;20:223-8",
"N Sabha, JR Volpatti, H Gonorazky, A Reifler, AE Davidson, X Li, NM Eltayeb, C Dall'Armi, G Di Paolo, SV Brooks, A Buj-Bello, EL Feldman, JJ Dowling. PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models.. J Clin Invest. 2016;126:3613-25",
"HB Sarnat. Myotubular myopathy: arrest of morphogenesis of myofibres associated with persistence of fetal vimentin and desmin. Four cases compared with fetal and neonatal muscle.. Can J Neurol Sci 1990;17:109-23",
"M Savarese, O Musumeci, T Giugliano, A Rubegni, C Fiorillo, F Fattori, A Torella, R Battini, C Rodolico, A Pugliese, G Piluso, L Maggi, A D'Amico, C Bruno, E Bertini, FM Santorelli, M Mora, A Toscano, C Minetti, V Nigro. Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers.. Neuromuscul Disord. 2016;26:292-9",
"CA Sewry. The role of immunocytochemistry in congenital myopathies.. Neuromuscul Disord 1998;8:394-400",
"H Tasfaout, S Buono, S Guo, C Kretz, N Messaddeq, S Booten, S Greenlee, BP Monia, BS Cowling, J Laporte. Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice.. Nat Commun. 2017;8:15661",
"GS Taylor, T Maehama, JE Dixon. Inaugural article: myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate.. Proc Natl Acad Sci U S A 2000;97:8910-5",
"V Tosch, N Vasli, C Kretz, AS Nicot, C Gasnier, N Dondaine, D Oriot, M Barth, H Puissant, NB Romero, CG Bonnemann, B Heller, G Duval, V Biancalana, J Laporte. Novel molecular diagnostic approaches for X-linked centronuclear (myotubular) myopathy reveal intronic mutations.. Neuromuscul Disord 2010;20:375-81",
"A Toussaint, BS Cowling, K Hnia, M Mohr, A Oldfors, Y Schwab, U Yis, T Maisonobe, T Stojkovic, C Wallgren-Pettersson, V Laugel, A Echaniz-Laguna, J-L Mandel, I Nishino, J Laporte. Defects in amphiphysin 2 (Bin1) and triads in several forms of centronuclear myopathies.. Acta Neuropathol 2011;121:253-66",
"TC Tsai, H Horinouchi, S Noguchi, N Minami, K Murayama, YK Hayashi, I Nonaka, I Nishino. Characterization of MTM1 mutations in 31 Japanese families with myotubular myopathy, including a patient carrying 240 kb deletion in Xq28 without male hypogenitalism.. Neuromuscul Disord 2005;15:245-52",
"K Tsujita, T Itoh, T Ijuin, A Yamamoto, A Shisheva, J Laporte, T Takenawa. Myotubularin regulates the function of the late endosome through the gram domain-phosphatidylinositol 3,5-bisphosphate interaction.. J Biol Chem 2004;279:13817-24",
"MC Vincent, C Guiraud-Chaumeil, J Laporte, S Manouvrier-Hanu, JL Mandel. Extensive germinal mosaicism in a family with X-linked myotubular myopathy simulates genetic heterogeneity.. J Med Genet 1998;35:241-3",
"CH Wang, JJ Dowling, K North, MK Schroth, T Sejersen, F Shapiro, J Bellini, H Weiss, M Guillet, K Amburgey, S Apkon, E Bertini, C Bonnemann, N Clarke, AM Connolly, B Estournet-Mathiaud, D Fitzgerald, JM Florence, R Gee, J Gurgel-Giannetti, AM Glanzman, B Hofmeister, H Jungbluth, AC Koumbourlis, NG Laing, M Main, LA Morrison, C Munns, K Rose, PM Schuler, C Sewry, K Storhaug, M Vainzof, N Yuan. Consensus statement on standard of care for congenital myopathies.. J Child Neurol. 2012;27:363-82",
"JM Wilmshurst, S Lillis, H Zhou, K Pillay, H Henderson, W Kress, CR Müller, A Ndondo, V Cloke, T Cullup, E Bertini, C Boennemann, V Straub, R Quinlivan, JJ Dowling, S Al-Sarraj, S Treves, S Abbs, AY Manzur, CA Sewry, F Muntoni, H Jungbluth. RYR1 mutations are a common cause of congenital myopathies with central nuclei.. Ann Neurol. 2010;68:717-26",
"S Yu, J Manson, S White, A Bourne, H Waddy, M Davis, E Haan. X-linked myotubular myopathy in a family with three adult survivors.. Clin Genet 2003;64:148-52"
] |
25/2/2002
|
23/8/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
muenke
|
muenke
|
[
"Fibroblast growth factor receptor 3",
"FGFR3",
"Muenke Syndrome"
] |
Muenke Syndrome
|
Paul Kruszka, Myron Rolle, Kristopher T Kahle, Maximilian Muenke
|
Summary Muenke syndrome is characterized by considerable phenotypic variability; features may include coronal synostosis (more often bilateral than unilateral); synostosis of other sutures, all sutures (pan synostosis), or no sutures; or macrocephaly. Bilateral coronal synostosis typically results in brachycephaly, although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly. Other craniofacial findings typically include temporal bossing, widely spaced eyes, ptosis or mild proptosis, mild midface retrusion, and highly arched palate or cleft lip and palate. Strabismus is common. Other findings can include hearing loss, developmental delay, intellectual disability, behavioral issues, intracranial anomalies, epilepsy, ocular anomalies, brachydactyly, carpal and/or tarsal bone fusions, broad thumbs and great toes, clinodactyly, and radiographic findings of short and broad middle phalanges and/or cone-shaped epiphyses. Of note, some individuals who have the p.Pro250Arg pathogenic variant may have no signs of Muenke syndrome on physical or radiographic examination. The diagnosis of Muenke syndrome is established by the identification of the Muenke syndrome is inherited in an autosomal dominant manner. Each child of an individual with Muenke syndrome has a 50% chance of inheriting the pathogenic variant. Because penetrance is reduced and the phenotype is variable within families, the manifestations in a child who inherits the pathogenic variant cannot be predicted based on the phenotypes of other heterozygous family members. Once the
|
## Diagnosis
Muenke syndrome
Facial asymmetry
Brachycephaly, turribrachycephaly (a "tower-shaped" skull), or cloverleaf skull
Sutural ridging over both (or less commonly one) of the coronal sutures accompanied by:
Ipsilaterally: flattening of the forehead, elevation of the superior orbital rim, elevation of the eyebrow, anterior placement of the ear, deviation of the nasal root
Contralaterally: frontal bossing of the forehead, depression of the eyebrow
Temporal bossing
Macrocephaly without craniosynostosis
Craniosynostosis with sensorineural hearing loss
Head CT with three-dimensional reconstruction demonstrating:
Unilateral coronal craniosynostosis
Bilateral coronal craniosynostosis
Synostosis of other sutures (lambdoid, metopic, sagittal, squamosal)
Extracranial radiographic features can include:
Fusion of the carpal bones (commonly the capitate and hamate or trapezoid and trapezium bones) [
Fusion of the tarsal bones (commonly the calcaneus and cuboid bones) [
Thimble-like (short and broad) middle phalanges of the hands and feet [
Epiphyseal coning [
The diagnosis of Muenke syndrome
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Muenke Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Muenke syndrome is defined by the specific pathogenic variant
• Facial asymmetry
• Brachycephaly, turribrachycephaly (a "tower-shaped" skull), or cloverleaf skull
• Sutural ridging over both (or less commonly one) of the coronal sutures accompanied by:
• Ipsilaterally: flattening of the forehead, elevation of the superior orbital rim, elevation of the eyebrow, anterior placement of the ear, deviation of the nasal root
• Contralaterally: frontal bossing of the forehead, depression of the eyebrow
• Ipsilaterally: flattening of the forehead, elevation of the superior orbital rim, elevation of the eyebrow, anterior placement of the ear, deviation of the nasal root
• Contralaterally: frontal bossing of the forehead, depression of the eyebrow
• Temporal bossing
• Macrocephaly without craniosynostosis
• Craniosynostosis with sensorineural hearing loss
• Ipsilaterally: flattening of the forehead, elevation of the superior orbital rim, elevation of the eyebrow, anterior placement of the ear, deviation of the nasal root
• Contralaterally: frontal bossing of the forehead, depression of the eyebrow
• Head CT with three-dimensional reconstruction demonstrating:
• Unilateral coronal craniosynostosis
• Bilateral coronal craniosynostosis
• Synostosis of other sutures (lambdoid, metopic, sagittal, squamosal)
• Unilateral coronal craniosynostosis
• Bilateral coronal craniosynostosis
• Synostosis of other sutures (lambdoid, metopic, sagittal, squamosal)
• Extracranial radiographic features can include:
• Fusion of the carpal bones (commonly the capitate and hamate or trapezoid and trapezium bones) [
• Fusion of the tarsal bones (commonly the calcaneus and cuboid bones) [
• Thimble-like (short and broad) middle phalanges of the hands and feet [
• Epiphyseal coning [
• Fusion of the carpal bones (commonly the capitate and hamate or trapezoid and trapezium bones) [
• Fusion of the tarsal bones (commonly the calcaneus and cuboid bones) [
• Thimble-like (short and broad) middle phalanges of the hands and feet [
• Epiphyseal coning [
• Unilateral coronal craniosynostosis
• Bilateral coronal craniosynostosis
• Synostosis of other sutures (lambdoid, metopic, sagittal, squamosal)
• Fusion of the carpal bones (commonly the capitate and hamate or trapezoid and trapezium bones) [
• Fusion of the tarsal bones (commonly the calcaneus and cuboid bones) [
• Thimble-like (short and broad) middle phalanges of the hands and feet [
• Epiphyseal coning [
• For an introduction to multigene panels click
## Suggestive Findings
Muenke syndrome
Facial asymmetry
Brachycephaly, turribrachycephaly (a "tower-shaped" skull), or cloverleaf skull
Sutural ridging over both (or less commonly one) of the coronal sutures accompanied by:
Ipsilaterally: flattening of the forehead, elevation of the superior orbital rim, elevation of the eyebrow, anterior placement of the ear, deviation of the nasal root
Contralaterally: frontal bossing of the forehead, depression of the eyebrow
Temporal bossing
Macrocephaly without craniosynostosis
Craniosynostosis with sensorineural hearing loss
Head CT with three-dimensional reconstruction demonstrating:
Unilateral coronal craniosynostosis
Bilateral coronal craniosynostosis
Synostosis of other sutures (lambdoid, metopic, sagittal, squamosal)
Extracranial radiographic features can include:
Fusion of the carpal bones (commonly the capitate and hamate or trapezoid and trapezium bones) [
Fusion of the tarsal bones (commonly the calcaneus and cuboid bones) [
Thimble-like (short and broad) middle phalanges of the hands and feet [
Epiphyseal coning [
• Facial asymmetry
• Brachycephaly, turribrachycephaly (a "tower-shaped" skull), or cloverleaf skull
• Sutural ridging over both (or less commonly one) of the coronal sutures accompanied by:
• Ipsilaterally: flattening of the forehead, elevation of the superior orbital rim, elevation of the eyebrow, anterior placement of the ear, deviation of the nasal root
• Contralaterally: frontal bossing of the forehead, depression of the eyebrow
• Ipsilaterally: flattening of the forehead, elevation of the superior orbital rim, elevation of the eyebrow, anterior placement of the ear, deviation of the nasal root
• Contralaterally: frontal bossing of the forehead, depression of the eyebrow
• Temporal bossing
• Macrocephaly without craniosynostosis
• Craniosynostosis with sensorineural hearing loss
• Ipsilaterally: flattening of the forehead, elevation of the superior orbital rim, elevation of the eyebrow, anterior placement of the ear, deviation of the nasal root
• Contralaterally: frontal bossing of the forehead, depression of the eyebrow
• Head CT with three-dimensional reconstruction demonstrating:
• Unilateral coronal craniosynostosis
• Bilateral coronal craniosynostosis
• Synostosis of other sutures (lambdoid, metopic, sagittal, squamosal)
• Unilateral coronal craniosynostosis
• Bilateral coronal craniosynostosis
• Synostosis of other sutures (lambdoid, metopic, sagittal, squamosal)
• Extracranial radiographic features can include:
• Fusion of the carpal bones (commonly the capitate and hamate or trapezoid and trapezium bones) [
• Fusion of the tarsal bones (commonly the calcaneus and cuboid bones) [
• Thimble-like (short and broad) middle phalanges of the hands and feet [
• Epiphyseal coning [
• Fusion of the carpal bones (commonly the capitate and hamate or trapezoid and trapezium bones) [
• Fusion of the tarsal bones (commonly the calcaneus and cuboid bones) [
• Thimble-like (short and broad) middle phalanges of the hands and feet [
• Epiphyseal coning [
• Unilateral coronal craniosynostosis
• Bilateral coronal craniosynostosis
• Synostosis of other sutures (lambdoid, metopic, sagittal, squamosal)
• Fusion of the carpal bones (commonly the capitate and hamate or trapezoid and trapezium bones) [
• Fusion of the tarsal bones (commonly the calcaneus and cuboid bones) [
• Thimble-like (short and broad) middle phalanges of the hands and feet [
• Epiphyseal coning [
## Establishing the Diagnosis
The diagnosis of Muenke syndrome
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Muenke Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Muenke syndrome is defined by the specific pathogenic variant
• For an introduction to multigene panels click
## Clinical Characteristics
Muenke syndrome is characterized by coronal synostosis, and occasionally synostosis of other sutures, abnormal skull shape in those with synostosis, characteristic facies, hearing loss, and strabismus. Additional features can include developmental delay, intellectual disability, epilepsy, intracranial anomalies, brachydactyly, broad thumbs and great toes, and/or clinodactyly. Penetrance is incomplete, and phenotypic variability is considerable even within the same family. Some individuals have minor clinical signs such as macrocephaly and subtle facial findings without craniosynostosis; some have only radiographic features [
Muenke Syndrome: Frequency of Select Features
Bilateral coronal synostosis typically results in brachycephaly, although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly (asymmetry of the skull and face).
Other craniofacial findings typically include temporal bossing, widely spaced eyes, ptosis or proptosis (usually mild), and midface retrusion (usually mild). Rarer craniofacial features include malar flattening, a short nose with anteverted nares and a depressed nasal bridge, deviation of the nasal septum, an overhanging nasal tip, high-arched palate, cleft lip and/or palate, dental malocclusion, mild retrognathia, hypoplastic auricles, and low-set ears.
Children with Muenke syndrome and craniosynostosis can develop hearing loss following a normal newborn hearing screen [E Doherty & M Muenke, personal observation]. Individuals may have recurrent episodes of otitis media treated with myringotomy tube placement [
Compared to normative populations, individuals with Muenke syndrome have also been reported to be at increased risk for developing some behavioral and emotional issues [
Individuals with Muenke syndrome were at increased risk for developing adaptive and executive functioning issues [
The following intracranial anomalies have been reported:
Hippocampus and bilateral medial temporal dysgenesis in one person [
Bilateral lateral ventricular dilatation and a small cerebellum in one person [
Porencephalic cyst of the occipital horn of left ventricle and absence of the corpus callosum in one person [
Epilepsy was reported in 13 individuals with Muenke syndrome by
One individual had a cranial nerve VI deficit leading to paralytic strabismus [
Strabismus is the most common ocular finding in Muenke syndrome. Children with Muenke syndrome also have a higher incidence of anisometropia, downward lateral canthal dystopia, and amblyopia [
Ptosis of the upper eyelids has been described in 13 affected individuals [
Nystagmus has been described in four affected individuals [
Penetrance is reduced. Some individuals heterozygous for the
The phrase "Muenke nonsyndromic coronal craniosynostosis" is occasionally used to mean Muenke syndrome. The authors discourage the use of this phrase because it inaccurately implies a "non-genetic" cause of Muenke syndrome.
The term "Adelaide-type craniosynostosis" is no longer used to describe Muenke syndrome.
The birth prevalence of Muenke syndrome is approximately one in 30,000.
In a prospective study of 214 individuals with craniosynostosis born between 1993 and 2005,
Muenke syndrome is estimated to account for 25%-30% of all genetic causes of craniosynostosis [
• The following intracranial anomalies have been reported:
• Hippocampus and bilateral medial temporal dysgenesis in one person [
• Bilateral lateral ventricular dilatation and a small cerebellum in one person [
• Porencephalic cyst of the occipital horn of left ventricle and absence of the corpus callosum in one person [
• Hippocampus and bilateral medial temporal dysgenesis in one person [
• Bilateral lateral ventricular dilatation and a small cerebellum in one person [
• Porencephalic cyst of the occipital horn of left ventricle and absence of the corpus callosum in one person [
• Epilepsy was reported in 13 individuals with Muenke syndrome by
• One individual had a cranial nerve VI deficit leading to paralytic strabismus [
• Hippocampus and bilateral medial temporal dysgenesis in one person [
• Bilateral lateral ventricular dilatation and a small cerebellum in one person [
• Porencephalic cyst of the occipital horn of left ventricle and absence of the corpus callosum in one person [
• Strabismus is the most common ocular finding in Muenke syndrome. Children with Muenke syndrome also have a higher incidence of anisometropia, downward lateral canthal dystopia, and amblyopia [
• Ptosis of the upper eyelids has been described in 13 affected individuals [
• Nystagmus has been described in four affected individuals [
## Clinical Description
Muenke syndrome is characterized by coronal synostosis, and occasionally synostosis of other sutures, abnormal skull shape in those with synostosis, characteristic facies, hearing loss, and strabismus. Additional features can include developmental delay, intellectual disability, epilepsy, intracranial anomalies, brachydactyly, broad thumbs and great toes, and/or clinodactyly. Penetrance is incomplete, and phenotypic variability is considerable even within the same family. Some individuals have minor clinical signs such as macrocephaly and subtle facial findings without craniosynostosis; some have only radiographic features [
Muenke Syndrome: Frequency of Select Features
Bilateral coronal synostosis typically results in brachycephaly, although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly (asymmetry of the skull and face).
Other craniofacial findings typically include temporal bossing, widely spaced eyes, ptosis or proptosis (usually mild), and midface retrusion (usually mild). Rarer craniofacial features include malar flattening, a short nose with anteverted nares and a depressed nasal bridge, deviation of the nasal septum, an overhanging nasal tip, high-arched palate, cleft lip and/or palate, dental malocclusion, mild retrognathia, hypoplastic auricles, and low-set ears.
Children with Muenke syndrome and craniosynostosis can develop hearing loss following a normal newborn hearing screen [E Doherty & M Muenke, personal observation]. Individuals may have recurrent episodes of otitis media treated with myringotomy tube placement [
Compared to normative populations, individuals with Muenke syndrome have also been reported to be at increased risk for developing some behavioral and emotional issues [
Individuals with Muenke syndrome were at increased risk for developing adaptive and executive functioning issues [
The following intracranial anomalies have been reported:
Hippocampus and bilateral medial temporal dysgenesis in one person [
Bilateral lateral ventricular dilatation and a small cerebellum in one person [
Porencephalic cyst of the occipital horn of left ventricle and absence of the corpus callosum in one person [
Epilepsy was reported in 13 individuals with Muenke syndrome by
One individual had a cranial nerve VI deficit leading to paralytic strabismus [
Strabismus is the most common ocular finding in Muenke syndrome. Children with Muenke syndrome also have a higher incidence of anisometropia, downward lateral canthal dystopia, and amblyopia [
Ptosis of the upper eyelids has been described in 13 affected individuals [
Nystagmus has been described in four affected individuals [
• The following intracranial anomalies have been reported:
• Hippocampus and bilateral medial temporal dysgenesis in one person [
• Bilateral lateral ventricular dilatation and a small cerebellum in one person [
• Porencephalic cyst of the occipital horn of left ventricle and absence of the corpus callosum in one person [
• Hippocampus and bilateral medial temporal dysgenesis in one person [
• Bilateral lateral ventricular dilatation and a small cerebellum in one person [
• Porencephalic cyst of the occipital horn of left ventricle and absence of the corpus callosum in one person [
• Epilepsy was reported in 13 individuals with Muenke syndrome by
• One individual had a cranial nerve VI deficit leading to paralytic strabismus [
• Hippocampus and bilateral medial temporal dysgenesis in one person [
• Bilateral lateral ventricular dilatation and a small cerebellum in one person [
• Porencephalic cyst of the occipital horn of left ventricle and absence of the corpus callosum in one person [
• Strabismus is the most common ocular finding in Muenke syndrome. Children with Muenke syndrome also have a higher incidence of anisometropia, downward lateral canthal dystopia, and amblyopia [
• Ptosis of the upper eyelids has been described in 13 affected individuals [
• Nystagmus has been described in four affected individuals [
## Penetrance
Penetrance is reduced. Some individuals heterozygous for the
## Nomenclature
The phrase "Muenke nonsyndromic coronal craniosynostosis" is occasionally used to mean Muenke syndrome. The authors discourage the use of this phrase because it inaccurately implies a "non-genetic" cause of Muenke syndrome.
The term "Adelaide-type craniosynostosis" is no longer used to describe Muenke syndrome.
## Prevalence
The birth prevalence of Muenke syndrome is approximately one in 30,000.
In a prospective study of 214 individuals with craniosynostosis born between 1993 and 2005,
Muenke syndrome is estimated to account for 25%-30% of all genetic causes of craniosynostosis [
## Genetically Related (Allelic) Disorders
Other craniosynostosis phenotypes associated with germline pathogenic variants in
Allelic Craniosynostosis Disorders
Reference sequences:
Other Clinically Distinct Allelic Disorders and Associated
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Reference sequences:
## Differential Diagnosis
Comparison of Muenke Syndrome with Other
Bilateral coronal synostosis
Midface retrusion
Widely spaced eyes
Downslanted palpebral fissures
Strabismus
Highly arched palate
Brachydactyly
Normal intellect
Broad thumbs & great toes
Variable brachydactyly
Ocular proptosis
Medial deviation of thumbs & great toes
Lateral deviation of thumbs & great toes away from other digits
Malformed & fused phalanges
Symphalangism
Mandibular prognathism
Bilateral coronal synostosis
Broad thumbs & great toes
Widely spaced eyes
Downslanted palpebral fissures
Strabismus
Highly arched palate
Hearing loss
Ocular proptosis
Disproportionately severe midface retrusion
Severe, symmetric soft tissue / bony syndactyly of fingers & toes
Lateral deviation of thumbs & great toes
Acneiform eruptions
Bilateral coronal synostosis
Normal extremities
Furrowed palms & soles
Widespread cutis gyrata & acanthosis nigricans
Prominent umbilicus
Moderate intellectual disability
Bilateral coronal synostosis
Normal extremities
Normal intellect
Strabismus
Widely spaced eyes
Hearing deficit (conductive vs sensorineural in Muenke syndrome)
Significant proptosis
Mandibular prognathism
Convex nasal ridge
Malar flattening
Progressive hydrocephalus
Bilateral coronal synostosis
Midface retrusion
Tarsal fusions
Broad great toes
Metatarsal fusions
Abnormal tarsal bones
Medial deviation of great toes
Uni- or bilateral coronal synostosis
Brachycephaly
Facial asymmetry
Midface retrusion
Normal intellect or mild-to-moderate developmental delay
Ptosis
Widely spaced eyes
Strabismus
Downslanted palpebral fissures
High-arched palate
Brachydactyly
Small ear pinna w/prominent crus
Syndactyly of fingers 2-3
Low anterior hairline
Duplication of the distal phalanx of the hallux
See
Jackson-Weiss syndrome is most likely limited to members of the original pedigree.
For an overview of other primary and secondary forms of craniosynostosis, see
• Bilateral coronal synostosis
• Midface retrusion
• Widely spaced eyes
• Downslanted palpebral fissures
• Strabismus
• Highly arched palate
• Brachydactyly
• Normal intellect
• Broad thumbs & great toes
• Variable brachydactyly
• Ocular proptosis
• Medial deviation of thumbs & great toes
• Lateral deviation of thumbs & great toes away from other digits
• Malformed & fused phalanges
• Symphalangism
• Mandibular prognathism
• Bilateral coronal synostosis
• Broad thumbs & great toes
• Widely spaced eyes
• Downslanted palpebral fissures
• Strabismus
• Highly arched palate
• Hearing loss
• Ocular proptosis
• Disproportionately severe midface retrusion
• Severe, symmetric soft tissue / bony syndactyly of fingers & toes
• Lateral deviation of thumbs & great toes
• Acneiform eruptions
• Bilateral coronal synostosis
• Normal extremities
• Furrowed palms & soles
• Widespread cutis gyrata & acanthosis nigricans
• Prominent umbilicus
• Moderate intellectual disability
• Bilateral coronal synostosis
• Normal extremities
• Normal intellect
• Strabismus
• Widely spaced eyes
• Hearing deficit (conductive vs sensorineural in Muenke syndrome)
• Significant proptosis
• Mandibular prognathism
• Convex nasal ridge
• Malar flattening
• Progressive hydrocephalus
• Bilateral coronal synostosis
• Midface retrusion
• Tarsal fusions
• Broad great toes
• Metatarsal fusions
• Abnormal tarsal bones
• Medial deviation of great toes
• Uni- or bilateral coronal synostosis
• Brachycephaly
• Facial asymmetry
• Midface retrusion
• Normal intellect or mild-to-moderate developmental delay
• Ptosis
• Widely spaced eyes
• Strabismus
• Downslanted palpebral fissures
• High-arched palate
• Brachydactyly
• Small ear pinna w/prominent crus
• Syndactyly of fingers 2-3
• Low anterior hairline
• Duplication of the distal phalanx of the hallux
## Management
To establish the extent of disease and needs in an individual diagnosed with Muenke syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Muenke Syndrome
Assessment of suture involvement by skull radiographs or preferably 3D skull CT
Assessment for hydrocephalus w/brain CT or MRI
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Children with Muenke syndrome and craniosynostosis should be referred to a craniofacial clinic with pediatric experience. These individuals benefit most from a multidisciplinary approach to care. A craniofacial clinic associated with a major pediatric medical center usually includes a surgical team (craniofacial surgeon and neurosurgeon), clinical geneticist, ophthalmologist, otolaryngologist, pediatrician, radiologist, psychologist, dentist, audiologist, speech therapist, and social worker. Other disciplines are involved as needed.
Newer approaches being performed include endoscopic strip craniectomy and posterior distraction.
Endoscopic strip craniectomy is typically performed before the affected child reaches age three months. This minimally invasive surgery limits blood loss and has an overall long-term improved symmetry compared to traditional cranial vault remodeling and fronto-orbital advancement.
Posterior distraction (PD) is used to manage individuals with severe brachycephaly or turribrachycephaly. It is a well-planned surgery using distractor devices. PD requires nuanced technical skill and the commitment of both the surgeon and the family several weeks postoperatively. PD has associated risks, yet severe complications are rare [
Following craniosynostosis repair, the need for a second procedure is increased in those with Muenke syndrome compared to those with craniosynostosis without the defining pathogenic variant. The reasons for a second procedure vary by individual and can include the following:
Severe initial clinical presentation requiring a staged repair
Cranial vault abnormalities including temporal bulging and recurrent supraorbital retrusion requiring extracranial contouring (i.e., use of a cement such as calcium phosphate to contour the surface of the skull)
Postoperative increased intracranial pressure (ICP)
Recurrent deformity requiring a second transcranial repair:
The need for a surgical revision for aesthetic reasons (typically temporal bulging) has been reported in multiple series [
According to
Seven of 29 individuals (24.1%) with the
In the report of
However, a study by
In Muenke syndrome a discrepancy between severity of the craniofacial findings (e.g., severe midface retrusion, widely spaced eyes) and neurologic findings (e.g., increased ICP, hydrocephalus, structural brain anomalies, severe developmental delay, or severe intellectual disability) has been noted [
Strabismus surgery/correction is indicated to prevent amblyopia.
Because surgical correction of craniosynostosis is a priority, delay in strabismus surgery in the first two years of life is common; however, earlier correction of strabismus should be considered to achieve binocularity.
In those with proptosis, lubrication for exposure keratopathy is indicated.
Protocol-driven approaches to surveillance currently in use include those of
Recommended Surveillance for Individuals with Muenke Syndrome
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from institution of treatment and preventive measures (particularly in individuals affected with craniosynostosis, hearing loss, developmental delay, and/or cognitive disability). Evaluation includes targeted molecular genetic testing for the
See
Animal models indicate that
Search
• Assessment of suture involvement by skull radiographs or preferably 3D skull CT
• Assessment for hydrocephalus w/brain CT or MRI
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Endoscopic strip craniectomy is typically performed before the affected child reaches age three months. This minimally invasive surgery limits blood loss and has an overall long-term improved symmetry compared to traditional cranial vault remodeling and fronto-orbital advancement.
• Posterior distraction (PD) is used to manage individuals with severe brachycephaly or turribrachycephaly. It is a well-planned surgery using distractor devices. PD requires nuanced technical skill and the commitment of both the surgeon and the family several weeks postoperatively. PD has associated risks, yet severe complications are rare [
• Severe initial clinical presentation requiring a staged repair
• Cranial vault abnormalities including temporal bulging and recurrent supraorbital retrusion requiring extracranial contouring (i.e., use of a cement such as calcium phosphate to contour the surface of the skull)
• Postoperative increased intracranial pressure (ICP)
• Recurrent deformity requiring a second transcranial repair:
• The need for a surgical revision for aesthetic reasons (typically temporal bulging) has been reported in multiple series [
• According to
• Seven of 29 individuals (24.1%) with the
• In the report of
• However, a study by
• The need for a surgical revision for aesthetic reasons (typically temporal bulging) has been reported in multiple series [
• According to
• Seven of 29 individuals (24.1%) with the
• In the report of
• However, a study by
• The need for a surgical revision for aesthetic reasons (typically temporal bulging) has been reported in multiple series [
• According to
• Seven of 29 individuals (24.1%) with the
• In the report of
• However, a study by
• Strabismus surgery/correction is indicated to prevent amblyopia.
• Because surgical correction of craniosynostosis is a priority, delay in strabismus surgery in the first two years of life is common; however, earlier correction of strabismus should be considered to achieve binocularity.
• In those with proptosis, lubrication for exposure keratopathy is indicated.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Muenke syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Muenke Syndrome
Assessment of suture involvement by skull radiographs or preferably 3D skull CT
Assessment for hydrocephalus w/brain CT or MRI
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assessment of suture involvement by skull radiographs or preferably 3D skull CT
• Assessment for hydrocephalus w/brain CT or MRI
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Children with Muenke syndrome and craniosynostosis should be referred to a craniofacial clinic with pediatric experience. These individuals benefit most from a multidisciplinary approach to care. A craniofacial clinic associated with a major pediatric medical center usually includes a surgical team (craniofacial surgeon and neurosurgeon), clinical geneticist, ophthalmologist, otolaryngologist, pediatrician, radiologist, psychologist, dentist, audiologist, speech therapist, and social worker. Other disciplines are involved as needed.
Newer approaches being performed include endoscopic strip craniectomy and posterior distraction.
Endoscopic strip craniectomy is typically performed before the affected child reaches age three months. This minimally invasive surgery limits blood loss and has an overall long-term improved symmetry compared to traditional cranial vault remodeling and fronto-orbital advancement.
Posterior distraction (PD) is used to manage individuals with severe brachycephaly or turribrachycephaly. It is a well-planned surgery using distractor devices. PD requires nuanced technical skill and the commitment of both the surgeon and the family several weeks postoperatively. PD has associated risks, yet severe complications are rare [
Following craniosynostosis repair, the need for a second procedure is increased in those with Muenke syndrome compared to those with craniosynostosis without the defining pathogenic variant. The reasons for a second procedure vary by individual and can include the following:
Severe initial clinical presentation requiring a staged repair
Cranial vault abnormalities including temporal bulging and recurrent supraorbital retrusion requiring extracranial contouring (i.e., use of a cement such as calcium phosphate to contour the surface of the skull)
Postoperative increased intracranial pressure (ICP)
Recurrent deformity requiring a second transcranial repair:
The need for a surgical revision for aesthetic reasons (typically temporal bulging) has been reported in multiple series [
According to
Seven of 29 individuals (24.1%) with the
In the report of
However, a study by
In Muenke syndrome a discrepancy between severity of the craniofacial findings (e.g., severe midface retrusion, widely spaced eyes) and neurologic findings (e.g., increased ICP, hydrocephalus, structural brain anomalies, severe developmental delay, or severe intellectual disability) has been noted [
Strabismus surgery/correction is indicated to prevent amblyopia.
Because surgical correction of craniosynostosis is a priority, delay in strabismus surgery in the first two years of life is common; however, earlier correction of strabismus should be considered to achieve binocularity.
In those with proptosis, lubrication for exposure keratopathy is indicated.
• Endoscopic strip craniectomy is typically performed before the affected child reaches age three months. This minimally invasive surgery limits blood loss and has an overall long-term improved symmetry compared to traditional cranial vault remodeling and fronto-orbital advancement.
• Posterior distraction (PD) is used to manage individuals with severe brachycephaly or turribrachycephaly. It is a well-planned surgery using distractor devices. PD requires nuanced technical skill and the commitment of both the surgeon and the family several weeks postoperatively. PD has associated risks, yet severe complications are rare [
• Severe initial clinical presentation requiring a staged repair
• Cranial vault abnormalities including temporal bulging and recurrent supraorbital retrusion requiring extracranial contouring (i.e., use of a cement such as calcium phosphate to contour the surface of the skull)
• Postoperative increased intracranial pressure (ICP)
• Recurrent deformity requiring a second transcranial repair:
• The need for a surgical revision for aesthetic reasons (typically temporal bulging) has been reported in multiple series [
• According to
• Seven of 29 individuals (24.1%) with the
• In the report of
• However, a study by
• The need for a surgical revision for aesthetic reasons (typically temporal bulging) has been reported in multiple series [
• According to
• Seven of 29 individuals (24.1%) with the
• In the report of
• However, a study by
• The need for a surgical revision for aesthetic reasons (typically temporal bulging) has been reported in multiple series [
• According to
• Seven of 29 individuals (24.1%) with the
• In the report of
• However, a study by
• Strabismus surgery/correction is indicated to prevent amblyopia.
• Because surgical correction of craniosynostosis is a priority, delay in strabismus surgery in the first two years of life is common; however, earlier correction of strabismus should be considered to achieve binocularity.
• In those with proptosis, lubrication for exposure keratopathy is indicated.
## Surveillance
Protocol-driven approaches to surveillance currently in use include those of
Recommended Surveillance for Individuals with Muenke Syndrome
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
## Evaluation of Relatives at Risk
It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from institution of treatment and preventive measures (particularly in individuals affected with craniosynostosis, hearing loss, developmental delay, and/or cognitive disability). Evaluation includes targeted molecular genetic testing for the
See
## Therapies Under Investigation
Animal models indicate that
Search
## Genetic Counseling
Muenke syndrome is inherited in an autosomal dominant manner.
More than half of individuals diagnosed with Muenke syndrome inherited the
A proband with Muenke syndrome may have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband include:
Physical examination and radiographs of the skull, hands, and feet;
Molecular genetic testing for the
Evaluation of the parents may determine that one is heterozygous for the
If the
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with Muenke syndrome may appear to be negative because of subtle or absent clinical findings in a heterozygous parent or failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
If a parent of the proband is affected and/or is known to have the defining
If the
If the parents have not been tested for the
Consideration of molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management,
Generally, in individuals of school age and older who have no developmental issues, developmental delay, hearing loss, craniosynostosis, or other features of Muenke syndrome, the likelihood of Muenke syndrome is quite low, though the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
In a family known to have the pathogenic variant, if craniosynostosis or other craniofacial features (i.e., midface hypoplasia, ocular hypertelorism) are seen on prenatal ultrasound examination, the index of suspicion for Muenke syndrome should be high.
On prenatal ultrasound examination of twins with Muenke syndrome,
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• More than half of individuals diagnosed with Muenke syndrome inherited the
• A proband with Muenke syndrome may have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband include:
• Physical examination and radiographs of the skull, hands, and feet;
• Molecular genetic testing for the
• Evaluation of the parents may determine that one is heterozygous for the
• Physical examination and radiographs of the skull, hands, and feet;
• Molecular genetic testing for the
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with Muenke syndrome may appear to be negative because of subtle or absent clinical findings in a heterozygous parent or failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
• Physical examination and radiographs of the skull, hands, and feet;
• Molecular genetic testing for the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the defining
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Muenke syndrome is inherited in an autosomal dominant manner.
## Risk to Family Members
More than half of individuals diagnosed with Muenke syndrome inherited the
A proband with Muenke syndrome may have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband include:
Physical examination and radiographs of the skull, hands, and feet;
Molecular genetic testing for the
Evaluation of the parents may determine that one is heterozygous for the
If the
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with Muenke syndrome may appear to be negative because of subtle or absent clinical findings in a heterozygous parent or failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
If a parent of the proband is affected and/or is known to have the defining
If the
If the parents have not been tested for the
• More than half of individuals diagnosed with Muenke syndrome inherited the
• A proband with Muenke syndrome may have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband include:
• Physical examination and radiographs of the skull, hands, and feet;
• Molecular genetic testing for the
• Evaluation of the parents may determine that one is heterozygous for the
• Physical examination and radiographs of the skull, hands, and feet;
• Molecular genetic testing for the
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with Muenke syndrome may appear to be negative because of subtle or absent clinical findings in a heterozygous parent or failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
• Physical examination and radiographs of the skull, hands, and feet;
• Molecular genetic testing for the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the defining
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
Consideration of molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management,
Generally, in individuals of school age and older who have no developmental issues, developmental delay, hearing loss, craniosynostosis, or other features of Muenke syndrome, the likelihood of Muenke syndrome is quite low, though the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
In a family known to have the pathogenic variant, if craniosynostosis or other craniofacial features (i.e., midface hypoplasia, ocular hypertelorism) are seen on prenatal ultrasound examination, the index of suspicion for Muenke syndrome should be high.
On prenatal ultrasound examination of twins with Muenke syndrome,
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
•
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
Muenke Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Muenke Syndrome (
The fibroblast growth factor receptor (FGFR) family is a group of receptor tyrosine kinases. FGFRs 1-4 have an extracellular ligand-binding domain containing three immunoglobulin-like loops, a single-pass transmembrane domain, and a split intracellular kinase domain. FGFRs bind fibroblast growth factors (FGFs) and dimerize to affect downstream intracellular signaling [
The genetics of intramembranous bone (skull vault) formation are complex, and the role of FGFR3 is not yet well understood. FGFR3 is detected in coronal suture osteogenic fronts but at lower levels than FGFR1 and FGFR2 [
The
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The fibroblast growth factor receptor (FGFR) family is a group of receptor tyrosine kinases. FGFRs 1-4 have an extracellular ligand-binding domain containing three immunoglobulin-like loops, a single-pass transmembrane domain, and a split intracellular kinase domain. FGFRs bind fibroblast growth factors (FGFs) and dimerize to affect downstream intracellular signaling [
The genetics of intramembranous bone (skull vault) formation are complex, and the role of FGFR3 is not yet well understood. FGFR3 is detected in coronal suture osteogenic fronts but at lower levels than FGFR1 and FGFR2 [
The
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
The authors are indebted to the affected individuals they work with and their families. This work was supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health.
Yonit A Addissie, BA; National Human Genome Research Institute (2016-2023)Nneamaka B Agochukwu, MD; National Human Genome Research Institute (2006-2023)Emily S Doherty, MD, FAAP, FACMG; Carilion Clinic (2006-2023)Kristopher T Kahle, MD, PhD (2023-present)Paul Kruszka, MD, MPH (2016-present)Maximilian Muenke, MD, FACMG (2006-present)Myron Rolle, MD (2023-present)
30 March 2023 (sw) Comprehensive update posted live
10 November 2016 (ma) Comprehensive update posted live
19 June 2014 (me) Comprehensive update posted live
7 December 2010 (me) Comprehensive update posted live
10 May 2006 (me) Review posted live
30 January 2006 (mm) Original submission
• 30 March 2023 (sw) Comprehensive update posted live
• 10 November 2016 (ma) Comprehensive update posted live
• 19 June 2014 (me) Comprehensive update posted live
• 7 December 2010 (me) Comprehensive update posted live
• 10 May 2006 (me) Review posted live
• 30 January 2006 (mm) Original submission
## Acknowledgments
The authors are indebted to the affected individuals they work with and their families. This work was supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health.
## Author History
Yonit A Addissie, BA; National Human Genome Research Institute (2016-2023)Nneamaka B Agochukwu, MD; National Human Genome Research Institute (2006-2023)Emily S Doherty, MD, FAAP, FACMG; Carilion Clinic (2006-2023)Kristopher T Kahle, MD, PhD (2023-present)Paul Kruszka, MD, MPH (2016-present)Maximilian Muenke, MD, FACMG (2006-present)Myron Rolle, MD (2023-present)
## Revision History
30 March 2023 (sw) Comprehensive update posted live
10 November 2016 (ma) Comprehensive update posted live
19 June 2014 (me) Comprehensive update posted live
7 December 2010 (me) Comprehensive update posted live
10 May 2006 (me) Review posted live
30 January 2006 (mm) Original submission
• 30 March 2023 (sw) Comprehensive update posted live
• 10 November 2016 (ma) Comprehensive update posted live
• 19 June 2014 (me) Comprehensive update posted live
• 7 December 2010 (me) Comprehensive update posted live
• 10 May 2006 (me) Review posted live
• 30 January 2006 (mm) Original submission
## References
## Literature Cited
Schema of the FGFR3 protein
The loops represent the three immunoglobulin domains (left to right: IgI, IgII, IgIII). The p.Pro250Arg protein change (indicated with a black dot) is in the linker region between the second and third immunoglobulin domains. The grey boxes following the third immunoglobulin domain are (left to right): transmembrane domain (small grey box); first and second tyrosine kinase domains (2nd and 3rd dark grey boxes, respectively) [
|
[
"NB Agochukwu, BD Solomon, LJ Benson, M Muenke. Talocalcaneal coalition in Muenke syndrome: report of a patient, review of the literature in FGFR-related craniosynostoses, and consideration of mechanism.. Am J Med Genet A. 2013;161A:453-60",
"NB Agochukwu, BD Solomon, M Muenke. Hearing loss in syndromic craniosynostoses: introduction and consideration of mechanisms.. Am J Audiol. 2014a;23:135-41",
"NB Agochukwu, BD Solomon, M Muenke. Hearing loss in syndromic craniosynostoses: otologic manifestations and clinical findings.. Int J Pediatr Otorhinolaryngol. 2014b;78:2037-47",
"NB Agochukwu, BD Solomon, M Muenke. Impact of genetics on the diagnosis and clinical management of syndromic craniosynostoses.. Childs Nerv Syst. 2012;28:1447-63",
"E Arnaud, P Meneses, E Lajeunie, JA Thorne, D Marchac, D Renier. Postoperative mental and morphological outcome for nonsyndromic brachycephaly.. Plast Reconstr Surg 2002;110:6-12",
"N Bannink, M Maliepaard, H Raat, KF Joosten, IM Mathijssen. Obstructive sleep apnea-specific quality of life and behavioral problems in children with syndromic craniosynostosis.. J Dev Behav Pediatr. 2011;32:233-8",
"GS Baynam, J Goldblatt. A child with an FGFR3 mutation, a laterality disorder and an hepatoblastoma: novel associations and possible gene-environment interactions.. Twin Res Hum Genet 2010;13:297-300",
"GA Bellus, K Gaudenz, EH Zackai, LA Clarke, J Szabo, CA Francomano, M Muenke. Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes.. Nat Genet 1996;14:174-6",
"LB Cassileth, SP Bartlett, PM Glat, KW Gripp, M Muenke, EH Zackai, LA Whitaker. Clinical characteristics of patients with unicoronal synostosis and mutations of fibroblast growth factor receptor 3: a preliminary report.. Plast Reconstr Surg 2001;108:1849-54",
"K Chun, AS Teebi, JH Jung, S Kennedy, R Laframboise, WS Meschino, K Nakabayashi, SW Scherer, PN Ray, I Teshima. Genetic analysis of patients with the Saethre-Chotzen phenotype.. Am J Med Genet 2002;110:136-43",
"ML Cunningham, ML Seto, C Ratisoontorn, CL Heike, AV Hing. Syndromic craniosynostosis: from history to hydrogen bonds.. Orthod Craniofac Res. 2007;10:67-81",
"T de Jong, N Bannink, HH Bredero-Boelhouwer, ML van Veelen, MC Bartels, LJ Hoeve, AJ Hoogeboom, EB Wolvius, MH Lequin, JJ van der Meulen, LN van Adrichem, JM Vaandrager, EM Ongkosuwito, KF Joosten, IM Mathijssen. Long-term functional outcome in 167 patients with syndromic craniosynostosis; defining a syndrome-specific risk profile.. J Plast Reconstr Aesthet Surg 2010;63:1635-41",
"T de Jong, IM Mathijssen, AJ Hoogeboom. Additional phenotypic features of Muenke syndrome in 2 Dutch families.. J Craniofac Surg. 2011;22:571-5",
"K Dentino, K Ganjawalla, G Inverso, JB Mulliken, BL Padwa. Upper Airway Length is Predictive of Obstructive Sleep Apnea in Syndromic Craniosynostosis.. J Oral Maxillofac Surg. 2015;73:S20-5",
"MM Didolkar, EN Vinson, AM Gaca. A young patient with polyarthralgia and hearing loss: a case report of Muenke syndrome.. Skeletal Radiol 2009;38:1011-4",
"GD Doumit, J Sidaoui, E Meisler, FA Papay. Squamosal suture craniosynostosis in Muenke syndrome.. J Craniofac Surg. 2014;25:429-31",
"LF Escobar, AK Hiett, A Marnocha. Significant phenotypic variability of Muenke syndrome in identical twins.. Am J Med Genet A. 2009;149A:1273-6",
"WJ Flapper, PJ Anderson, RM Roberts, DJ David. Intellectual outcomes following protocol management in Crouzon, Pfeiffer, and Muenke syndromes.. J Craniofac Surg. 2009;20:1252-5",
"N Funato, K Ohtani, K Ohyama, T Kuroda, M Nakamura. Common regulation of growth arrest and differentiation of osteoblasts by helix-loop-helix factors.. Mol Cell Biol 2001;21:7416-28",
"A Golla, P Lichmer, S von Gernet, A Winterpacht, J Fairley, J Murken, S Schuffenhauer. Phenotypic expression of the fibroblast growth factor receptor 3 (FGFR3) mutation P250R in a large craniosynostosis family.. J Med Genet. 1997;34:683-4",
"PJ Green, FS Walsh, P Doherty. Promiscuity of fibroblast growth factor receptors.. Bioessays 1996;18:639-46",
"S Grosso, MA Farnetani, R Berardi, G Bartalini, M Carpentieri, P Galluzzi, R Mostardini, G Morgese, P Balestri. Medial temporal lobe dysgenesis in Muenke syndrome and hypochondroplasia.. Am J Med Genet A. 2003;120A:88-91",
"GE Hollway, GK Suthers, KM Battese, AM Turner, DJ David, JC Mulley. Deafness due to Pro250Arg mutation of FGFR3.. Lancet. 1998;351:877-8",
"MB Honnebier, DS Cabiling, M Hetlinger, DM McDonald-McGinn, EH Zackai, SP Bartlett. The natural history of patients treated for FGFR3-associated (Muenke-type) craniosynostosis.. Plast Reconstr Surg. 2008;121:919-31",
"J Hughes, NC Nevin, PJ Morrison. Familial craniosynostosis due to Pro250Arg mutation in the fibroblast growth factor receptor 3 gene.. Ulster Med J. 2001;70:47-50",
"OA Ibrahimi, F Zhang, AV Eliseenkova, RJ Linhardt, M Mohammadi. Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity.. Hum Mol Genet 2004;13:69-78",
"S Iseki, AO Wilkie, GM Morriss-Kay. Fgfr1 and Fgfr2 have distinct differentia. Development 1999;126:5611-20",
"SK Jadico, A Huebner, DM McDonald-McGinn, EH Zackai, TL Young. Ocular phenotype correlations in patients with TWIST versus FGFR3 genetic mutations.. J AAPOS. 2006;10:435-44",
"MK Keller, NV Hermann, TA Darvann, P Larsen, HD Hove, L Christensen, M Schwartz, JL Marsh, S Kreiborg. Craniofacial morphology in Muenke syndrome.. J Craniofac Surg 2007;18:374-86",
"P Kruszka, YA Addissie, CM Yarnell, DW Hadley, MJ Guillen Sacoto, P Platte, Y Paelecke, H Collmann, N Snow, T Schweitzer, SA Boyadjiev, C Aravidis, SE Hall, JB Mulliken, T Roscioli, M Muenke. Muenke syndrome: An international multicenter natural history study.. Am J Med Genet A. 2016;170A:918-29",
"E Lajeunie, V El Ghouzzi, M Le Merrer, A Munnich, J Bonaventure, D Renier. Sex related expressivity of the phenotype in coronal craniosynostosis caused by the recurrent P250R FGFR3 mutation.. J Med Genet 1999;36:9-13",
"RB Lowry, EW Jabs, GE Graham, J Gerritsen, J Fleming. Syndrome of coronal craniosynostosis, Klippel-Feil anomaly, and Sprengel shoulder with and without Pro250Arg mutation in the FGFR3 gene.. Am J Med Genet 2001;104:112-9",
"M Maliepaard, IM Mathijssen, J Oosterlaan, JM Okkerse. Intellectual, behavioral, and emotional functioning in children with syndromic craniosynostosis.. Pediatrics. 2014;133:e1608-15",
"SL Mansour, C Li, LD Urness. Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates.. Genes Dev. 2013;27:2320-31",
"SL Mansour, SRF Twigg, RM Freeland, SA Wall, C Li, AOM Wilkie. Hearing loss in a mouse model of Muenke syndrome.. Hum Mol Genet 2009;18:43-50",
"SB Moko, TM Blandin de Chalain. New Zealand Maori family with the pro250arg fibroblast growth factor receptor 3 mutation associated with craniosynostosis.. J Craniomaxillofac Surg 2001;29:22-4",
"DM Moloney, SA Wall, GJ Ashworth, M Oldridge, IA Glass, CA Francomano, M Muenke, AO Wilkie. Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis.. Lancet 1997;349:1059-62",
"GM Morriss-Kay, AOM Wilkie. Growth of the normal skull vault and its alteration in craniosynostosis: Insights from human genetics and experimental studies.. J Anat 2005;207:637-53",
"M Muenke, KW Gripp, DM McDonald-McGinn, K Gaudenz, LA Whitaker, SP Bartlett, RI Markowitz, NH Robin, N Nwokoro, JJ Mulvihill, HW Losken, JB Mulliken, AE Guttmacher, RS Wilroy, LA Clarke, G Hollway, LC Ades, EA Haan, JC Mulley, MM Cohen, GA Bellus, CA Francomano, DM Moloney, SA Wall, AO Wilkie, EH Zackai. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome.. Am J Hum Genet 1997;60:555-64",
"JB Mulliken, D Steinberger, S Kunze, U Muller. Molecular diagnosis of bilateral coronal synostosis.. Plast Reconstr Surg 1999;104:1603-15",
"DM Ornitz, PJ Marie. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease.. Genes Dev 2002;16:1446-65",
"WJ Park, C. Theda, NE Maestri, GA Meyers, JS Fryberg, C Dufresne, MM Cohen, EW Jabs. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome.. Am J Hum Genet 1995;57:321-8",
"MR Passos-Bueno, WR Wilcox, EW Jabs, AL Sertié, LG Alonso, H Kitoh. Clinical spectrum of fibroblast growth factor receptor mutations.. Hum Mutat. 1999;14:115-25",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"SV Rannan-Eliya, IB Taylor, IM De Heer, AM Van Den Ouweland, SA Wall, AO Wilkie. Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis.. Hum Genet 2004;115:200-7",
"D Renier, V El-Ghouzzi, J Bonaventure, M Le Merrer, E Lajeunie. Fibroblast growth factor receptor 3 mutation in nonsyndromic coronal synostosis: clinical spectrum, prevalence, and surgical outcome.. J Neurosurg 2000;92:631-6",
"EB Ridgway, JK Wu, SR Sullivan, S Vasudavan, BL Padwa, GF Rogers, JB Mulliken. Craniofacial growth in patients with FGFR3 Pro250Arg mutation after fronto-orbital advancement in infancy.. J Craniofac Surg. 2011;22:455-61",
"NH Robin. Molecular genetic advances in understanding craniosynostosis.. Plast Reconstr Surg 1999;103:1060-70",
"NH Robin, JA Scott, AR Cohen, JA Goldstein. Nonpenetrance in FGFR3-associated coronal synostosis syndrome.. Am J Med Genet 1998;80:296-7",
"K Rymer, R Shiang, A Hsiung, A Pandya, T Bigdeli, BT Webb, J Rhodes. Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans.. Mol Genet Genomic Med. 2019;7",
"N Salokorpi, L Satanin, I Teterin, JJ Sinikumpu, W Serlo. Posterior vault distraction technique: how I do it.. Childs Nerv Syst. 2021;37:3127-36",
"S Schindler, M Friedrich, H Wagener, B Lorenz, MN Preising. Heterozygous P250L mutation of fibroblast growth factor receptor 3 in a case of isolated craniosynostosis.. J Med Genet 2002;39:764-6",
"PS Shah, K Siriwardena, G Taylor, L Steele, P Ray, S Blaser, D Chitayat. Sudden infant death in a patient with FGFR3 P250R mutation.. Am J Med Genet A. 2006;140:2794-6",
"A Shaw, OB Petersen, LS Chitty. Prenatal diagnosis of craniosynostosis: sonographic features of Muenke syndrome.. J Obstet Gynaecol. 2011;31:770-1",
"A Singh, M Goyal, S Kumar, W Kress, S Kapoor. Phenotypic variability in two families of Muenke syndrome with FGFR3 mutation.. Indian J Pediatr. 2014;81:1230-2",
"GP Thomas, SA Wall, J Jayamohan, SA Magdum, PG Richards, A Wiberg, D Johnson. Lessons learned in posterior cranial vault distraction.. J Craniofac Surg. 2014;25:1721-7",
"GP Thomas, AO Wilkie, PG Richards, SA Wall. FGFR3 P250R mutation increases the risk of reoperation in apparent \"nonsyndromic\" coronal craniosynostosis.. J Craniofac Surg 2005;16:347-52",
"G Tonni, M Panteghini, A Rossi, M Baldi, C Magnani, B Ferrari, M. Lituania. Craniosynostosis: prenatal diagnosis by means of ultrasound and SSSE-MRI. Family series with report of neurodevelopmental outcome and review of the literature.. Arch Gynecol Obstet. 2011;283:909-16",
"A Trusen, M Beissert, H Collmann, K Darge. The pattern of skeletal anomalies in the cervical spine, hands and feet in patients with Saethre-Chotzen syndrome and Muenke-type mutation.. Pediatr Radiol. 2003;33:168-72",
"J van der Meulen, A van den Ouweland, J Hoogeboom. Trigonocephaly in Muenke syndrome.. Am J Med Genet A 2006;140:2493-4",
"A Wiberg, S Magdum, PG Richards, J Jayamohan, SA Wall, D Johnson. Posterior calvarial distraction in craniosynostosis - an evolving technique.. J Craniomaxillofac Surg. 2012;40:799-806",
"AO Wilkie, JC Byren, JA Hurst, J Jayamohan, D Johnson, SJ Knight, T Lester, PG Richards, SR Twigg, SA Wall. Prevalence and complications of single gene and chromosomal disorders in craniosynostosis.. Pediatrics 2010;126:e391-400",
"AOM Wilkie, SF Slaney, M. Oldridge, MD Poole, GJ Ashworth, AD Hockley, RD Hayward, DJ David, LK Pulleyn, P Rutland, S Malcolm, RM Winter, W Reardon. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.. Nat Genet 1995;9:165-72",
"CM Yarnell, YA Addissie, DW Hadley, MJ Guillen Sacoto, NB Agochukwu, RA Hart, EA Wiggs, P Platte, Y Paelecke, H Collmann, T Schweitzer, P Kruszka, M Muenke. Executive Function and Adaptive Behavior in Muenke Syndrome.. J Pediatr. 2015;167:428-34",
"JE Yu, DH Park, SH Yoon. A Korean family with the Muenke syndrome.. J Korean Med Sci 2010;25:1086-9"
] |
10/5/2006
|
30/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
mws
|
mws
|
[
"Hirschsprung Disease – Intellectual Disability Syndrome",
"Hirschsprung Disease-Intellectual Disability Syndrome",
"Zinc finger E-box-binding homeobox 2",
"ZEB2",
"Classic Mowat-Wilson Syndrome"
] |
Classic Mowat-Wilson Syndrome
|
Margaret P Adam, Jessie Conta, Lora JH Bean
|
Summary Classic Mowat-Wilson syndrome (MWS) is characterized by distinctive facial features (widely spaced eyes, broad eyebrows with a medial flare, low-hanging columella, prominent or pointed chin, open-mouth expression, and uplifted earlobes with a central depression), congenital heart defects with predilection for abnormalities of the pulmonary arteries and/or valves, Hirschsprung disease and/or chronic constipation, genitourinary anomalies (particularly hypospadias in males), and hypogenesis or agenesis of the corpus callosum. Most affected individuals have moderate-to-severe intellectual disability. Speech is typically limited to a few words or is absent, with relative preservation of receptive language skills. Growth restriction with microcephaly and epilepsy are also common. Most affected people have a happy demeanor and a wide-based gait that can sometimes be confused with Angelman syndrome. The diagnosis of classic MWS is established in a proband with the typical recognizable dysmorphic facial features and developmental delay / intellectual disability and/or a heterozygous pathogenic variant in Classic MWS is an autosomal dominant disorder caused by a pathogenic variant in
|
## Diagnosis
Formal clinical diagnostic criteria for classic Mowat-Wilson syndrome (MWS) have not been published. However, the facial features are recognizable and, when accompanied by other features of the condition (e.g., Hirschsprung disease and/or chronic constipation, developmental delay / intellectual disability), can establish a clinical diagnosis.
Classic MWS
Typical facial features (see
Widely spaced eyes
Broad eyebrows with a medial flare
Low-hanging columella
Open-mouth expression
Prominent or pointed chin
Uplifted earlobes often with a central depression, described as resembling the shape of "orecchiette pasta" or "red blood corpuscles" (red blood cells)
Growth restriction with microcephaly
Intellectual disability, typically in the moderate to severe range, with severe speech impairment but relative preservation of receptive language skills
Congenital heart defects, particularly abnormalities of the pulmonary arteries and/or valves
Hirschsprung disease and/or chronic constipation
Genitourinary anomalies, particularly hypospadias in males
Epilepsy, including electrical status epilepticus in sleep (ESES)
Wide-based gait
Happy personality
The diagnosis of classic MWS
A heterozygous pathogenic (or likely pathogenic) variant involving
A heterozygous deletion of 2q22.3 involving
Note: (1) Chromosome rearrangements that disrupt
Molecular genetic testing approaches can include a combination of
When the phenotypic findings suggest the diagnosis of classic MWS, molecular genetic testing approaches can include
Note: Larger deletions or duplications of chromosome 2q22.3 that include
For an introduction to CMA click
For an introduction to multigene panels click
When the diagnosis of classic MWS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Classic Mowat-Wilson Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
In one affected individual, classic MWS was caused by a
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Typical facial features (see
• Widely spaced eyes
• Broad eyebrows with a medial flare
• Low-hanging columella
• Open-mouth expression
• Prominent or pointed chin
• Uplifted earlobes often with a central depression, described as resembling the shape of "orecchiette pasta" or "red blood corpuscles" (red blood cells)
• Widely spaced eyes
• Broad eyebrows with a medial flare
• Low-hanging columella
• Open-mouth expression
• Prominent or pointed chin
• Uplifted earlobes often with a central depression, described as resembling the shape of "orecchiette pasta" or "red blood corpuscles" (red blood cells)
• Growth restriction with microcephaly
• Intellectual disability, typically in the moderate to severe range, with severe speech impairment but relative preservation of receptive language skills
• Congenital heart defects, particularly abnormalities of the pulmonary arteries and/or valves
• Hirschsprung disease and/or chronic constipation
• Genitourinary anomalies, particularly hypospadias in males
• Epilepsy, including electrical status epilepticus in sleep (ESES)
• Wide-based gait
• Happy personality
• Widely spaced eyes
• Broad eyebrows with a medial flare
• Low-hanging columella
• Open-mouth expression
• Prominent or pointed chin
• Uplifted earlobes often with a central depression, described as resembling the shape of "orecchiette pasta" or "red blood corpuscles" (red blood cells)
• A heterozygous pathogenic (or likely pathogenic) variant involving
• A heterozygous deletion of 2q22.3 involving
• Note: Larger deletions or duplications of chromosome 2q22.3 that include
• For an introduction to CMA click
• For an introduction to multigene panels click
## Suggestive Findings
Classic MWS
Typical facial features (see
Widely spaced eyes
Broad eyebrows with a medial flare
Low-hanging columella
Open-mouth expression
Prominent or pointed chin
Uplifted earlobes often with a central depression, described as resembling the shape of "orecchiette pasta" or "red blood corpuscles" (red blood cells)
Growth restriction with microcephaly
Intellectual disability, typically in the moderate to severe range, with severe speech impairment but relative preservation of receptive language skills
Congenital heart defects, particularly abnormalities of the pulmonary arteries and/or valves
Hirschsprung disease and/or chronic constipation
Genitourinary anomalies, particularly hypospadias in males
Epilepsy, including electrical status epilepticus in sleep (ESES)
Wide-based gait
Happy personality
• Typical facial features (see
• Widely spaced eyes
• Broad eyebrows with a medial flare
• Low-hanging columella
• Open-mouth expression
• Prominent or pointed chin
• Uplifted earlobes often with a central depression, described as resembling the shape of "orecchiette pasta" or "red blood corpuscles" (red blood cells)
• Widely spaced eyes
• Broad eyebrows with a medial flare
• Low-hanging columella
• Open-mouth expression
• Prominent or pointed chin
• Uplifted earlobes often with a central depression, described as resembling the shape of "orecchiette pasta" or "red blood corpuscles" (red blood cells)
• Growth restriction with microcephaly
• Intellectual disability, typically in the moderate to severe range, with severe speech impairment but relative preservation of receptive language skills
• Congenital heart defects, particularly abnormalities of the pulmonary arteries and/or valves
• Hirschsprung disease and/or chronic constipation
• Genitourinary anomalies, particularly hypospadias in males
• Epilepsy, including electrical status epilepticus in sleep (ESES)
• Wide-based gait
• Happy personality
• Widely spaced eyes
• Broad eyebrows with a medial flare
• Low-hanging columella
• Open-mouth expression
• Prominent or pointed chin
• Uplifted earlobes often with a central depression, described as resembling the shape of "orecchiette pasta" or "red blood corpuscles" (red blood cells)
## Establishing the Diagnosis
The diagnosis of classic MWS
A heterozygous pathogenic (or likely pathogenic) variant involving
A heterozygous deletion of 2q22.3 involving
Note: (1) Chromosome rearrangements that disrupt
Molecular genetic testing approaches can include a combination of
When the phenotypic findings suggest the diagnosis of classic MWS, molecular genetic testing approaches can include
Note: Larger deletions or duplications of chromosome 2q22.3 that include
For an introduction to CMA click
For an introduction to multigene panels click
When the diagnosis of classic MWS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Classic Mowat-Wilson Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
In one affected individual, classic MWS was caused by a
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• A heterozygous pathogenic (or likely pathogenic) variant involving
• A heterozygous deletion of 2q22.3 involving
• Note: Larger deletions or duplications of chromosome 2q22.3 that include
• For an introduction to CMA click
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of classic MWS, molecular genetic testing approaches can include
Note: Larger deletions or duplications of chromosome 2q22.3 that include
For an introduction to CMA click
For an introduction to multigene panels click
• Note: Larger deletions or duplications of chromosome 2q22.3 that include
• For an introduction to CMA click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of classic MWS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Classic Mowat-Wilson Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
In one affected individual, classic MWS was caused by a
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
## Clinical Characteristics
More than 340 individuals with classic Mowat-Wilson syndrome (MWS) have been reported in the medical literature [
Classic Mowat-Wilson Syndrome: Frequency of Select Clinical Features
Adapted from
Head circumference ≥2 standard deviations below the mean for age and sex
Length or height ≥2 standard deviations below the mean for age and sex
Distinctive craniofacial features are a hallmark of classic MWS and, therefore, are one of the most specific findings (see
The facial phenotype evolves and becomes more pronounced with age (
The eyebrows may become heavier, broad, and horizontal.
The nasal tip lengthens and becomes more depressed and the nasal profile becomes more convex.
The columella becomes more pronounced, leading to the appearance of a short philtrum.
The face tends to elongate, and the jaw becomes more prominent.
However, the ear configuration does not change significantly with age, with the exception of the central depression, which is less obvious in adults.
Additional suggestive facial features include the following:
Telecanthus
Deeply set eyes
Wide nasal bridge with prominent and rounded nasal tip
Thick or everted vermilion of the lower lip
Increased posterior angulation of the ears
Other rare craniofacial findings include the following:
Palatal anomalies (bifid uvula, submucous cleft palate, and cleft of the hard palate)
Unicoronal craniosynostosis
Classic MWS growth charts have been published (see
Birth weight and length are typically in the normal range.
Microcephaly (head circumference ≥2 standard deviations [SD] below the mean for age and sex) is most often acquired but can be present at birth.
Short stature (defined as length or height ≥2 SD below the mean for age and sex) typically develops over time, with a mean adult height of 165.1 cm in males and 150.5 cm in females [
Body habitus is frequently lean and slender, with about 30% of affected individuals having a weight below the third centile for age and sex.
Strabismus is the most common finding, present in more than half of affected individuals. Astigmatism and myopia are also common findings. Nystagmus has been described in some individuals, particularly in infancy; it often resolves with age.
About 10% of affected individuals have structural eye anomalies or optic nerve findings, including the following [
Microphthalmia
Iris/retinal colobomas, which sometimes can lead to a suspicion of
Axenfeld anomaly / posterior embryotoxon; at least one affected individual had acquired and progressive anterior iris synechiae [
Ptosis
Congenital or acquired cataract
Retinal aplasia or retinal pigment epithelium atrophy
Optic nerve hypoplasia or atrophy
Abnormalities of the optic nerve disc
Recurrent otitis media, which can cause conductive hearing loss, has been described in about one third of affected individuals. Due to a high pain threshold seen in many affected individuals (see
Sensorineural hearing loss has only rarely been described [
Widely spaced teeth, malpositioned teeth, delayed tooth eruption, malformed teeth, dental crowding, gingival hypertrophy, and/or bruxism have been described [
Structural heart defects are present in almost 60% of individuals with classic MWS, with multiple different types of congenital heart defects reported. The most common findings are septal defects and patent ductus arteriosus. More complex congenital heart defects, however, have been reported and include the following [
Pulmonary stenosis (in ≤20%)
Coarctation of the aorta (in ≤10%)
Bicuspid aortic valve
Aortic valve stenosis
Tetralogy of Fallot
Pulmonary artery sling, with or without congenital tracheal stenosis (<4%). However, this finding is even less common in the general population, and thus pulmonary artery sling alone should prompt the clinician to consider a diagnosis of classic MWS.
Shone complex [
Classic MWS was initially described as a syndromic form of Hirschsprung disease (HSCR); however, only 44% of individuals with classic MWS have biopsy-proven HSCR.
Chronic constipation has been described in about 30% of persons with classic MWS without documented HSCR [
Chronic constipation typically becomes more common with age, likely due to a combination of factors, including insufficient liquid intake, low-fiber diet, and less vigilance in tracking stool output and consistency by caregivers [
Surgical outcomes for HSCR in individuals with classic MWS are generally worse than surgical outcomes for those with nonsyndromic HSCR; complications may include prolonged need for total parenteral nutrition and/or recurrent enterocolitis [
Other GI findings include the following:
Repeated vomiting attacks in about 20% of affected individuals [
Pyloric stenosis in 5% of affected individuals
Dysphagia (rare) [
Kidney anomalies are present in about one quarter of affected individuals and most commonly consist of vesicoureteral reflux and hydronephrosis. Other, less common findings may include duplex kidney, pelvic kidney, and multicystic dysplastic kidney.
About 60% of males have hypospadias, while about 40% have cryptorchidism. Less common findings in males may include bifid scrotum, penile chordee or "webbed penis," micropenis, macro-orchidism, or hydrocele.
Septum of the vagina has been described rarely in females.
Very little has been written regarding pubertal development in classic MWS. One female age 17 years underwent menarche at age 15 years but had inconsistent menstruation. One male underwent normal pubertal development. One male had mildly delayed pubertal development [
A variety of skeletal manifestations have been described in individuals with classic MWS. Among the most common skeletal manifestations are long, slender, tapered fingers. In later childhood and adulthood, the interphalangeal joints may become prominent. Calcaneovalgus deformity of the feet is also common.
Findings seen in up to 50% of affected individuals include the following:
Pectus anomalies (excavatum or carinatum)
Scoliosis
Adducted thumbs
Ulnar deviation of the hands
Mild contractures of the joints and/or camptodactyly
Genu valgus
Pes planus
Long toes with or without long and/or broad halluces
Hallux valgus
Delayed bone age
Syndactyly
Rarely, individuals with MWS have sustained frequent fractures that responded to bisphosphonate therapy [MP Adam, personal observation]. This is most likely a secondary finding resulting from decreased weight-bearing activity.
Neurologic findings are very common in individuals with classic MWS.
Mean age of onset is around three years, although first presentation of seizure as early as age one month and as late as 11 years has been reported [
Multiple seizure types have been described; types most frequently seen are focal and atypical absence seizures. For many individuals, the first seizure is a focal seizure associated with fever.
Up to 25% of affected individuals have seizures that are difficult to control (more so in childhood than in adolescence or adulthood) or refractory to conventional anti-seizure medications.
Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
Electrical status epilepticus during sleep (ESES) has been described in multiple individuals who have undergone overnight EEG studies [
The presence of ESES can negatively affect behavior as well as motor and cognitive function.
Evaluation for ESES should be considered in any affected individual who has experienced regression in cognitive function or motor skills, such as the development of ataxia or dyspraxia.
Seizure activity does not appear to correlate with structural brain anomalies.
Central nervous system anomalies are present in approximately half of individuals who have been imaged. The most common findings are abnormalities of the corpus callosum (i.e., hypoplasia, partial or complete agenesis). A variety of other anomalies, including the following [
Ventricular enlargement (lateral ventricle or ventricular temporal horn)
Abnormalities of the hippocampus
Cortical malformations (polymicrogyria, periventricular heterotopia, focal cortical dysplasia)
Reduction of white matter thickness
Localized signal alterations of the white matter
Posterior fossa malformations (absent or small cerebellar vermis, macrocerebellum)
Large basal ganglia
All individuals with classic MWS have moderate-to-severe intellectual disability, although the results of formal IQ testing have not been reported in most studies. Individuals with pathogenic missense variants may have milder features, including milder cognitive disabilities (see
Receptive language skills are generally more advanced than expressive language skills.
Sign language and communication boards have been used by some affected individuals with limited success.
Mean age of walking is between ages three and four years (range: 23 months to 8 years); some individuals do not achieve ambulation.
The gait is typically wide based with the arms held up and flexed at the elbow.
Adaptive toileting skills (waking at night to urinate, using the toilet) improve with age, although most affected individuals are unable to be completely toilet trained.
Treatment of chronic constipation may help with urinary incontinence (see
Repetitive behaviors
Oral behaviors, including mouthing and/or chewing objects or body parts
Underreaction to pain
Asplenia has been reported in several individuals with classic MWS; one individual had a severe course that included purpura fulminans [
Current data does not suggest that there is a common immunodeficiency phenotype in people with classic MWS. In individuals studied, there is a skewing of T cells away from CD8 differentiation, but this had only a slight effect on immune system function [
However, several affected individuals have required treatment with intravenous immunoglobulin (IVIG) for antibody deficiency leading to recurrent infections [MP Adam, personal observation].
The most common management issue is the rare finding of a difficult airway at the time of intubation [
The following findings have each been described in one affected individual. It is unclear whether these are rare features of MWS or if they represent unrelated co-occurrences.
Congenital tracheal stenosis [
Supernumerary intestinal muscle coat [
It is unknown if life span in individuals with classic MWS is abnormal. One reported individual is alive at age 60 years [MP Adam, personal observation], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
In general, those with a whole-gene deletion are more likely to have earlier onset of epilepsy and are at greater risk for epilepsy that is refractory to multiple medications compared to those in whom a defective protein is likely to be produced [
Missense, splice site, or in-frame pathogenic variants in
The prevalence of MWS has been estimated at 1:50,000-70,000 live births [
• The eyebrows may become heavier, broad, and horizontal.
• The nasal tip lengthens and becomes more depressed and the nasal profile becomes more convex.
• The columella becomes more pronounced, leading to the appearance of a short philtrum.
• The face tends to elongate, and the jaw becomes more prominent.
• Telecanthus
• Deeply set eyes
• Wide nasal bridge with prominent and rounded nasal tip
• Thick or everted vermilion of the lower lip
• Increased posterior angulation of the ears
• Palatal anomalies (bifid uvula, submucous cleft palate, and cleft of the hard palate)
• Unicoronal craniosynostosis
• Microphthalmia
• Iris/retinal colobomas, which sometimes can lead to a suspicion of
• Axenfeld anomaly / posterior embryotoxon; at least one affected individual had acquired and progressive anterior iris synechiae [
• Ptosis
• Congenital or acquired cataract
• Retinal aplasia or retinal pigment epithelium atrophy
• Optic nerve hypoplasia or atrophy
• Abnormalities of the optic nerve disc
• Pulmonary stenosis (in ≤20%)
• Coarctation of the aorta (in ≤10%)
• Bicuspid aortic valve
• Aortic valve stenosis
• Tetralogy of Fallot
• Pulmonary artery sling, with or without congenital tracheal stenosis (<4%). However, this finding is even less common in the general population, and thus pulmonary artery sling alone should prompt the clinician to consider a diagnosis of classic MWS.
• Shone complex [
• Repeated vomiting attacks in about 20% of affected individuals [
• Pyloric stenosis in 5% of affected individuals
• Dysphagia (rare) [
• Pectus anomalies (excavatum or carinatum)
• Scoliosis
• Adducted thumbs
• Ulnar deviation of the hands
• Mild contractures of the joints and/or camptodactyly
• Genu valgus
• Pes planus
• Long toes with or without long and/or broad halluces
• Hallux valgus
• Delayed bone age
• Syndactyly
• Mean age of onset is around three years, although first presentation of seizure as early as age one month and as late as 11 years has been reported [
• Multiple seizure types have been described; types most frequently seen are focal and atypical absence seizures. For many individuals, the first seizure is a focal seizure associated with fever.
• Up to 25% of affected individuals have seizures that are difficult to control (more so in childhood than in adolescence or adulthood) or refractory to conventional anti-seizure medications.
• Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
• In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
• Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
• In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
• Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
• In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
• Electrical status epilepticus during sleep (ESES) has been described in multiple individuals who have undergone overnight EEG studies [
• The presence of ESES can negatively affect behavior as well as motor and cognitive function.
• Evaluation for ESES should be considered in any affected individual who has experienced regression in cognitive function or motor skills, such as the development of ataxia or dyspraxia.
• Seizure activity does not appear to correlate with structural brain anomalies.
• Ventricular enlargement (lateral ventricle or ventricular temporal horn)
• Abnormalities of the hippocampus
• Cortical malformations (polymicrogyria, periventricular heterotopia, focal cortical dysplasia)
• Reduction of white matter thickness
• Localized signal alterations of the white matter
• Posterior fossa malformations (absent or small cerebellar vermis, macrocerebellum)
• Large basal ganglia
• Receptive language skills are generally more advanced than expressive language skills.
• Sign language and communication boards have been used by some affected individuals with limited success.
• Mean age of walking is between ages three and four years (range: 23 months to 8 years); some individuals do not achieve ambulation.
• The gait is typically wide based with the arms held up and flexed at the elbow.
• Adaptive toileting skills (waking at night to urinate, using the toilet) improve with age, although most affected individuals are unable to be completely toilet trained.
• Treatment of chronic constipation may help with urinary incontinence (see
• Repetitive behaviors
• Oral behaviors, including mouthing and/or chewing objects or body parts
• Underreaction to pain
• Congenital tracheal stenosis [
• Supernumerary intestinal muscle coat [
## Clinical Description
More than 340 individuals with classic Mowat-Wilson syndrome (MWS) have been reported in the medical literature [
Classic Mowat-Wilson Syndrome: Frequency of Select Clinical Features
Adapted from
Head circumference ≥2 standard deviations below the mean for age and sex
Length or height ≥2 standard deviations below the mean for age and sex
Distinctive craniofacial features are a hallmark of classic MWS and, therefore, are one of the most specific findings (see
The facial phenotype evolves and becomes more pronounced with age (
The eyebrows may become heavier, broad, and horizontal.
The nasal tip lengthens and becomes more depressed and the nasal profile becomes more convex.
The columella becomes more pronounced, leading to the appearance of a short philtrum.
The face tends to elongate, and the jaw becomes more prominent.
However, the ear configuration does not change significantly with age, with the exception of the central depression, which is less obvious in adults.
Additional suggestive facial features include the following:
Telecanthus
Deeply set eyes
Wide nasal bridge with prominent and rounded nasal tip
Thick or everted vermilion of the lower lip
Increased posterior angulation of the ears
Other rare craniofacial findings include the following:
Palatal anomalies (bifid uvula, submucous cleft palate, and cleft of the hard palate)
Unicoronal craniosynostosis
Classic MWS growth charts have been published (see
Birth weight and length are typically in the normal range.
Microcephaly (head circumference ≥2 standard deviations [SD] below the mean for age and sex) is most often acquired but can be present at birth.
Short stature (defined as length or height ≥2 SD below the mean for age and sex) typically develops over time, with a mean adult height of 165.1 cm in males and 150.5 cm in females [
Body habitus is frequently lean and slender, with about 30% of affected individuals having a weight below the third centile for age and sex.
Strabismus is the most common finding, present in more than half of affected individuals. Astigmatism and myopia are also common findings. Nystagmus has been described in some individuals, particularly in infancy; it often resolves with age.
About 10% of affected individuals have structural eye anomalies or optic nerve findings, including the following [
Microphthalmia
Iris/retinal colobomas, which sometimes can lead to a suspicion of
Axenfeld anomaly / posterior embryotoxon; at least one affected individual had acquired and progressive anterior iris synechiae [
Ptosis
Congenital or acquired cataract
Retinal aplasia or retinal pigment epithelium atrophy
Optic nerve hypoplasia or atrophy
Abnormalities of the optic nerve disc
Recurrent otitis media, which can cause conductive hearing loss, has been described in about one third of affected individuals. Due to a high pain threshold seen in many affected individuals (see
Sensorineural hearing loss has only rarely been described [
Widely spaced teeth, malpositioned teeth, delayed tooth eruption, malformed teeth, dental crowding, gingival hypertrophy, and/or bruxism have been described [
Structural heart defects are present in almost 60% of individuals with classic MWS, with multiple different types of congenital heart defects reported. The most common findings are septal defects and patent ductus arteriosus. More complex congenital heart defects, however, have been reported and include the following [
Pulmonary stenosis (in ≤20%)
Coarctation of the aorta (in ≤10%)
Bicuspid aortic valve
Aortic valve stenosis
Tetralogy of Fallot
Pulmonary artery sling, with or without congenital tracheal stenosis (<4%). However, this finding is even less common in the general population, and thus pulmonary artery sling alone should prompt the clinician to consider a diagnosis of classic MWS.
Shone complex [
Classic MWS was initially described as a syndromic form of Hirschsprung disease (HSCR); however, only 44% of individuals with classic MWS have biopsy-proven HSCR.
Chronic constipation has been described in about 30% of persons with classic MWS without documented HSCR [
Chronic constipation typically becomes more common with age, likely due to a combination of factors, including insufficient liquid intake, low-fiber diet, and less vigilance in tracking stool output and consistency by caregivers [
Surgical outcomes for HSCR in individuals with classic MWS are generally worse than surgical outcomes for those with nonsyndromic HSCR; complications may include prolonged need for total parenteral nutrition and/or recurrent enterocolitis [
Other GI findings include the following:
Repeated vomiting attacks in about 20% of affected individuals [
Pyloric stenosis in 5% of affected individuals
Dysphagia (rare) [
Kidney anomalies are present in about one quarter of affected individuals and most commonly consist of vesicoureteral reflux and hydronephrosis. Other, less common findings may include duplex kidney, pelvic kidney, and multicystic dysplastic kidney.
About 60% of males have hypospadias, while about 40% have cryptorchidism. Less common findings in males may include bifid scrotum, penile chordee or "webbed penis," micropenis, macro-orchidism, or hydrocele.
Septum of the vagina has been described rarely in females.
Very little has been written regarding pubertal development in classic MWS. One female age 17 years underwent menarche at age 15 years but had inconsistent menstruation. One male underwent normal pubertal development. One male had mildly delayed pubertal development [
A variety of skeletal manifestations have been described in individuals with classic MWS. Among the most common skeletal manifestations are long, slender, tapered fingers. In later childhood and adulthood, the interphalangeal joints may become prominent. Calcaneovalgus deformity of the feet is also common.
Findings seen in up to 50% of affected individuals include the following:
Pectus anomalies (excavatum or carinatum)
Scoliosis
Adducted thumbs
Ulnar deviation of the hands
Mild contractures of the joints and/or camptodactyly
Genu valgus
Pes planus
Long toes with or without long and/or broad halluces
Hallux valgus
Delayed bone age
Syndactyly
Rarely, individuals with MWS have sustained frequent fractures that responded to bisphosphonate therapy [MP Adam, personal observation]. This is most likely a secondary finding resulting from decreased weight-bearing activity.
Neurologic findings are very common in individuals with classic MWS.
Mean age of onset is around three years, although first presentation of seizure as early as age one month and as late as 11 years has been reported [
Multiple seizure types have been described; types most frequently seen are focal and atypical absence seizures. For many individuals, the first seizure is a focal seizure associated with fever.
Up to 25% of affected individuals have seizures that are difficult to control (more so in childhood than in adolescence or adulthood) or refractory to conventional anti-seizure medications.
Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
Electrical status epilepticus during sleep (ESES) has been described in multiple individuals who have undergone overnight EEG studies [
The presence of ESES can negatively affect behavior as well as motor and cognitive function.
Evaluation for ESES should be considered in any affected individual who has experienced regression in cognitive function or motor skills, such as the development of ataxia or dyspraxia.
Seizure activity does not appear to correlate with structural brain anomalies.
Central nervous system anomalies are present in approximately half of individuals who have been imaged. The most common findings are abnormalities of the corpus callosum (i.e., hypoplasia, partial or complete agenesis). A variety of other anomalies, including the following [
Ventricular enlargement (lateral ventricle or ventricular temporal horn)
Abnormalities of the hippocampus
Cortical malformations (polymicrogyria, periventricular heterotopia, focal cortical dysplasia)
Reduction of white matter thickness
Localized signal alterations of the white matter
Posterior fossa malformations (absent or small cerebellar vermis, macrocerebellum)
Large basal ganglia
All individuals with classic MWS have moderate-to-severe intellectual disability, although the results of formal IQ testing have not been reported in most studies. Individuals with pathogenic missense variants may have milder features, including milder cognitive disabilities (see
Receptive language skills are generally more advanced than expressive language skills.
Sign language and communication boards have been used by some affected individuals with limited success.
Mean age of walking is between ages three and four years (range: 23 months to 8 years); some individuals do not achieve ambulation.
The gait is typically wide based with the arms held up and flexed at the elbow.
Adaptive toileting skills (waking at night to urinate, using the toilet) improve with age, although most affected individuals are unable to be completely toilet trained.
Treatment of chronic constipation may help with urinary incontinence (see
Repetitive behaviors
Oral behaviors, including mouthing and/or chewing objects or body parts
Underreaction to pain
Asplenia has been reported in several individuals with classic MWS; one individual had a severe course that included purpura fulminans [
Current data does not suggest that there is a common immunodeficiency phenotype in people with classic MWS. In individuals studied, there is a skewing of T cells away from CD8 differentiation, but this had only a slight effect on immune system function [
However, several affected individuals have required treatment with intravenous immunoglobulin (IVIG) for antibody deficiency leading to recurrent infections [MP Adam, personal observation].
The most common management issue is the rare finding of a difficult airway at the time of intubation [
The following findings have each been described in one affected individual. It is unclear whether these are rare features of MWS or if they represent unrelated co-occurrences.
Congenital tracheal stenosis [
Supernumerary intestinal muscle coat [
It is unknown if life span in individuals with classic MWS is abnormal. One reported individual is alive at age 60 years [MP Adam, personal observation], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
• The eyebrows may become heavier, broad, and horizontal.
• The nasal tip lengthens and becomes more depressed and the nasal profile becomes more convex.
• The columella becomes more pronounced, leading to the appearance of a short philtrum.
• The face tends to elongate, and the jaw becomes more prominent.
• Telecanthus
• Deeply set eyes
• Wide nasal bridge with prominent and rounded nasal tip
• Thick or everted vermilion of the lower lip
• Increased posterior angulation of the ears
• Palatal anomalies (bifid uvula, submucous cleft palate, and cleft of the hard palate)
• Unicoronal craniosynostosis
• Microphthalmia
• Iris/retinal colobomas, which sometimes can lead to a suspicion of
• Axenfeld anomaly / posterior embryotoxon; at least one affected individual had acquired and progressive anterior iris synechiae [
• Ptosis
• Congenital or acquired cataract
• Retinal aplasia or retinal pigment epithelium atrophy
• Optic nerve hypoplasia or atrophy
• Abnormalities of the optic nerve disc
• Pulmonary stenosis (in ≤20%)
• Coarctation of the aorta (in ≤10%)
• Bicuspid aortic valve
• Aortic valve stenosis
• Tetralogy of Fallot
• Pulmonary artery sling, with or without congenital tracheal stenosis (<4%). However, this finding is even less common in the general population, and thus pulmonary artery sling alone should prompt the clinician to consider a diagnosis of classic MWS.
• Shone complex [
• Repeated vomiting attacks in about 20% of affected individuals [
• Pyloric stenosis in 5% of affected individuals
• Dysphagia (rare) [
• Pectus anomalies (excavatum or carinatum)
• Scoliosis
• Adducted thumbs
• Ulnar deviation of the hands
• Mild contractures of the joints and/or camptodactyly
• Genu valgus
• Pes planus
• Long toes with or without long and/or broad halluces
• Hallux valgus
• Delayed bone age
• Syndactyly
• Mean age of onset is around three years, although first presentation of seizure as early as age one month and as late as 11 years has been reported [
• Multiple seizure types have been described; types most frequently seen are focal and atypical absence seizures. For many individuals, the first seizure is a focal seizure associated with fever.
• Up to 25% of affected individuals have seizures that are difficult to control (more so in childhood than in adolescence or adulthood) or refractory to conventional anti-seizure medications.
• Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
• In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
• Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
• In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
• Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
• In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
• Electrical status epilepticus during sleep (ESES) has been described in multiple individuals who have undergone overnight EEG studies [
• The presence of ESES can negatively affect behavior as well as motor and cognitive function.
• Evaluation for ESES should be considered in any affected individual who has experienced regression in cognitive function or motor skills, such as the development of ataxia or dyspraxia.
• Seizure activity does not appear to correlate with structural brain anomalies.
• Ventricular enlargement (lateral ventricle or ventricular temporal horn)
• Abnormalities of the hippocampus
• Cortical malformations (polymicrogyria, periventricular heterotopia, focal cortical dysplasia)
• Reduction of white matter thickness
• Localized signal alterations of the white matter
• Posterior fossa malformations (absent or small cerebellar vermis, macrocerebellum)
• Large basal ganglia
• Receptive language skills are generally more advanced than expressive language skills.
• Sign language and communication boards have been used by some affected individuals with limited success.
• Mean age of walking is between ages three and four years (range: 23 months to 8 years); some individuals do not achieve ambulation.
• The gait is typically wide based with the arms held up and flexed at the elbow.
• Adaptive toileting skills (waking at night to urinate, using the toilet) improve with age, although most affected individuals are unable to be completely toilet trained.
• Treatment of chronic constipation may help with urinary incontinence (see
• Repetitive behaviors
• Oral behaviors, including mouthing and/or chewing objects or body parts
• Underreaction to pain
• Congenital tracheal stenosis [
• Supernumerary intestinal muscle coat [
## Craniofacial Features
Distinctive craniofacial features are a hallmark of classic MWS and, therefore, are one of the most specific findings (see
The facial phenotype evolves and becomes more pronounced with age (
The eyebrows may become heavier, broad, and horizontal.
The nasal tip lengthens and becomes more depressed and the nasal profile becomes more convex.
The columella becomes more pronounced, leading to the appearance of a short philtrum.
The face tends to elongate, and the jaw becomes more prominent.
However, the ear configuration does not change significantly with age, with the exception of the central depression, which is less obvious in adults.
Additional suggestive facial features include the following:
Telecanthus
Deeply set eyes
Wide nasal bridge with prominent and rounded nasal tip
Thick or everted vermilion of the lower lip
Increased posterior angulation of the ears
Other rare craniofacial findings include the following:
Palatal anomalies (bifid uvula, submucous cleft palate, and cleft of the hard palate)
Unicoronal craniosynostosis
• The eyebrows may become heavier, broad, and horizontal.
• The nasal tip lengthens and becomes more depressed and the nasal profile becomes more convex.
• The columella becomes more pronounced, leading to the appearance of a short philtrum.
• The face tends to elongate, and the jaw becomes more prominent.
• Telecanthus
• Deeply set eyes
• Wide nasal bridge with prominent and rounded nasal tip
• Thick or everted vermilion of the lower lip
• Increased posterior angulation of the ears
• Palatal anomalies (bifid uvula, submucous cleft palate, and cleft of the hard palate)
• Unicoronal craniosynostosis
## Growth
Classic MWS growth charts have been published (see
Birth weight and length are typically in the normal range.
Microcephaly (head circumference ≥2 standard deviations [SD] below the mean for age and sex) is most often acquired but can be present at birth.
Short stature (defined as length or height ≥2 SD below the mean for age and sex) typically develops over time, with a mean adult height of 165.1 cm in males and 150.5 cm in females [
Body habitus is frequently lean and slender, with about 30% of affected individuals having a weight below the third centile for age and sex.
## Eyes
Strabismus is the most common finding, present in more than half of affected individuals. Astigmatism and myopia are also common findings. Nystagmus has been described in some individuals, particularly in infancy; it often resolves with age.
About 10% of affected individuals have structural eye anomalies or optic nerve findings, including the following [
Microphthalmia
Iris/retinal colobomas, which sometimes can lead to a suspicion of
Axenfeld anomaly / posterior embryotoxon; at least one affected individual had acquired and progressive anterior iris synechiae [
Ptosis
Congenital or acquired cataract
Retinal aplasia or retinal pigment epithelium atrophy
Optic nerve hypoplasia or atrophy
Abnormalities of the optic nerve disc
• Microphthalmia
• Iris/retinal colobomas, which sometimes can lead to a suspicion of
• Axenfeld anomaly / posterior embryotoxon; at least one affected individual had acquired and progressive anterior iris synechiae [
• Ptosis
• Congenital or acquired cataract
• Retinal aplasia or retinal pigment epithelium atrophy
• Optic nerve hypoplasia or atrophy
• Abnormalities of the optic nerve disc
## Ears
Recurrent otitis media, which can cause conductive hearing loss, has been described in about one third of affected individuals. Due to a high pain threshold seen in many affected individuals (see
Sensorineural hearing loss has only rarely been described [
## Dental Findings
Widely spaced teeth, malpositioned teeth, delayed tooth eruption, malformed teeth, dental crowding, gingival hypertrophy, and/or bruxism have been described [
## Cardiovascular Defects
Structural heart defects are present in almost 60% of individuals with classic MWS, with multiple different types of congenital heart defects reported. The most common findings are septal defects and patent ductus arteriosus. More complex congenital heart defects, however, have been reported and include the following [
Pulmonary stenosis (in ≤20%)
Coarctation of the aorta (in ≤10%)
Bicuspid aortic valve
Aortic valve stenosis
Tetralogy of Fallot
Pulmonary artery sling, with or without congenital tracheal stenosis (<4%). However, this finding is even less common in the general population, and thus pulmonary artery sling alone should prompt the clinician to consider a diagnosis of classic MWS.
Shone complex [
• Pulmonary stenosis (in ≤20%)
• Coarctation of the aorta (in ≤10%)
• Bicuspid aortic valve
• Aortic valve stenosis
• Tetralogy of Fallot
• Pulmonary artery sling, with or without congenital tracheal stenosis (<4%). However, this finding is even less common in the general population, and thus pulmonary artery sling alone should prompt the clinician to consider a diagnosis of classic MWS.
• Shone complex [
## Gastrointestinal (GI) Issues
Classic MWS was initially described as a syndromic form of Hirschsprung disease (HSCR); however, only 44% of individuals with classic MWS have biopsy-proven HSCR.
Chronic constipation has been described in about 30% of persons with classic MWS without documented HSCR [
Chronic constipation typically becomes more common with age, likely due to a combination of factors, including insufficient liquid intake, low-fiber diet, and less vigilance in tracking stool output and consistency by caregivers [
Surgical outcomes for HSCR in individuals with classic MWS are generally worse than surgical outcomes for those with nonsyndromic HSCR; complications may include prolonged need for total parenteral nutrition and/or recurrent enterocolitis [
Other GI findings include the following:
Repeated vomiting attacks in about 20% of affected individuals [
Pyloric stenosis in 5% of affected individuals
Dysphagia (rare) [
• Repeated vomiting attacks in about 20% of affected individuals [
• Pyloric stenosis in 5% of affected individuals
• Dysphagia (rare) [
## Kidney Anomalies
Kidney anomalies are present in about one quarter of affected individuals and most commonly consist of vesicoureteral reflux and hydronephrosis. Other, less common findings may include duplex kidney, pelvic kidney, and multicystic dysplastic kidney.
## Genital Anomalies
About 60% of males have hypospadias, while about 40% have cryptorchidism. Less common findings in males may include bifid scrotum, penile chordee or "webbed penis," micropenis, macro-orchidism, or hydrocele.
Septum of the vagina has been described rarely in females.
## Pubertal Development
Very little has been written regarding pubertal development in classic MWS. One female age 17 years underwent menarche at age 15 years but had inconsistent menstruation. One male underwent normal pubertal development. One male had mildly delayed pubertal development [
## Skeletal Findings
A variety of skeletal manifestations have been described in individuals with classic MWS. Among the most common skeletal manifestations are long, slender, tapered fingers. In later childhood and adulthood, the interphalangeal joints may become prominent. Calcaneovalgus deformity of the feet is also common.
Findings seen in up to 50% of affected individuals include the following:
Pectus anomalies (excavatum or carinatum)
Scoliosis
Adducted thumbs
Ulnar deviation of the hands
Mild contractures of the joints and/or camptodactyly
Genu valgus
Pes planus
Long toes with or without long and/or broad halluces
Hallux valgus
Delayed bone age
Syndactyly
Rarely, individuals with MWS have sustained frequent fractures that responded to bisphosphonate therapy [MP Adam, personal observation]. This is most likely a secondary finding resulting from decreased weight-bearing activity.
• Pectus anomalies (excavatum or carinatum)
• Scoliosis
• Adducted thumbs
• Ulnar deviation of the hands
• Mild contractures of the joints and/or camptodactyly
• Genu valgus
• Pes planus
• Long toes with or without long and/or broad halluces
• Hallux valgus
• Delayed bone age
• Syndactyly
## Neurologic Findings
Neurologic findings are very common in individuals with classic MWS.
Mean age of onset is around three years, although first presentation of seizure as early as age one month and as late as 11 years has been reported [
Multiple seizure types have been described; types most frequently seen are focal and atypical absence seizures. For many individuals, the first seizure is a focal seizure associated with fever.
Up to 25% of affected individuals have seizures that are difficult to control (more so in childhood than in adolescence or adulthood) or refractory to conventional anti-seizure medications.
Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
Electrical status epilepticus during sleep (ESES) has been described in multiple individuals who have undergone overnight EEG studies [
The presence of ESES can negatively affect behavior as well as motor and cognitive function.
Evaluation for ESES should be considered in any affected individual who has experienced regression in cognitive function or motor skills, such as the development of ataxia or dyspraxia.
Seizure activity does not appear to correlate with structural brain anomalies.
• Mean age of onset is around three years, although first presentation of seizure as early as age one month and as late as 11 years has been reported [
• Multiple seizure types have been described; types most frequently seen are focal and atypical absence seizures. For many individuals, the first seizure is a focal seizure associated with fever.
• Up to 25% of affected individuals have seizures that are difficult to control (more so in childhood than in adolescence or adulthood) or refractory to conventional anti-seizure medications.
• Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
• In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
• Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
• In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
• Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
• In at least one other individual, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.
• Electrical status epilepticus during sleep (ESES) has been described in multiple individuals who have undergone overnight EEG studies [
• The presence of ESES can negatively affect behavior as well as motor and cognitive function.
• Evaluation for ESES should be considered in any affected individual who has experienced regression in cognitive function or motor skills, such as the development of ataxia or dyspraxia.
• Seizure activity does not appear to correlate with structural brain anomalies.
## Central Nervous System
Central nervous system anomalies are present in approximately half of individuals who have been imaged. The most common findings are abnormalities of the corpus callosum (i.e., hypoplasia, partial or complete agenesis). A variety of other anomalies, including the following [
Ventricular enlargement (lateral ventricle or ventricular temporal horn)
Abnormalities of the hippocampus
Cortical malformations (polymicrogyria, periventricular heterotopia, focal cortical dysplasia)
Reduction of white matter thickness
Localized signal alterations of the white matter
Posterior fossa malformations (absent or small cerebellar vermis, macrocerebellum)
Large basal ganglia
• Ventricular enlargement (lateral ventricle or ventricular temporal horn)
• Abnormalities of the hippocampus
• Cortical malformations (polymicrogyria, periventricular heterotopia, focal cortical dysplasia)
• Reduction of white matter thickness
• Localized signal alterations of the white matter
• Posterior fossa malformations (absent or small cerebellar vermis, macrocerebellum)
• Large basal ganglia
## Psychosocial and Cognitive Development
All individuals with classic MWS have moderate-to-severe intellectual disability, although the results of formal IQ testing have not been reported in most studies. Individuals with pathogenic missense variants may have milder features, including milder cognitive disabilities (see
Receptive language skills are generally more advanced than expressive language skills.
Sign language and communication boards have been used by some affected individuals with limited success.
Mean age of walking is between ages three and four years (range: 23 months to 8 years); some individuals do not achieve ambulation.
The gait is typically wide based with the arms held up and flexed at the elbow.
Adaptive toileting skills (waking at night to urinate, using the toilet) improve with age, although most affected individuals are unable to be completely toilet trained.
Treatment of chronic constipation may help with urinary incontinence (see
Repetitive behaviors
Oral behaviors, including mouthing and/or chewing objects or body parts
Underreaction to pain
• Receptive language skills are generally more advanced than expressive language skills.
• Sign language and communication boards have been used by some affected individuals with limited success.
• Mean age of walking is between ages three and four years (range: 23 months to 8 years); some individuals do not achieve ambulation.
• The gait is typically wide based with the arms held up and flexed at the elbow.
• Adaptive toileting skills (waking at night to urinate, using the toilet) improve with age, although most affected individuals are unable to be completely toilet trained.
• Treatment of chronic constipation may help with urinary incontinence (see
• Repetitive behaviors
• Oral behaviors, including mouthing and/or chewing objects or body parts
• Underreaction to pain
## Immunologic Findings
Asplenia has been reported in several individuals with classic MWS; one individual had a severe course that included purpura fulminans [
Current data does not suggest that there is a common immunodeficiency phenotype in people with classic MWS. In individuals studied, there is a skewing of T cells away from CD8 differentiation, but this had only a slight effect on immune system function [
However, several affected individuals have required treatment with intravenous immunoglobulin (IVIG) for antibody deficiency leading to recurrent infections [MP Adam, personal observation].
## Anesthesia Risk
The most common management issue is the rare finding of a difficult airway at the time of intubation [
## Additional Findings
The following findings have each been described in one affected individual. It is unclear whether these are rare features of MWS or if they represent unrelated co-occurrences.
Congenital tracheal stenosis [
Supernumerary intestinal muscle coat [
• Congenital tracheal stenosis [
• Supernumerary intestinal muscle coat [
## Prognosis
It is unknown if life span in individuals with classic MWS is abnormal. One reported individual is alive at age 60 years [MP Adam, personal observation], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
## Genotype-Phenotype Correlations
In general, those with a whole-gene deletion are more likely to have earlier onset of epilepsy and are at greater risk for epilepsy that is refractory to multiple medications compared to those in whom a defective protein is likely to be produced [
Missense, splice site, or in-frame pathogenic variants in
## Prevalence
The prevalence of MWS has been estimated at 1:50,000-70,000 live births [
## Genetically Related (Allelic) Disorders
Pathogenic variants in
Additionally, pathogenic variants in the penultimate exon of
## Differential Diagnosis
Many of the congenital anomalies seen in classic Mowat-Wilson syndrome (MWS) can be seen as isolated anomalies in an otherwise normal individual. Genetic disorders with overlapping features are summarized in
Genetic Disorders of Interest in the Differential Diagnosis of Classic Mowat-Wilson Syndrome
Iris/retinal colobomas
Congenital heart defects
Cryptorchidism in males
ID
Facial features, incl different ear configurations
Choanal atresia/stenosis
Higher frequency of iris/retinal colobomas than in classic MWS
No HSCR
Nasal configuration
ID
Facial features
Spectrum of congenital anomalies
Hypospadias in males
Microcephaly
ID
Facial features
Higher frequency of cleft palate than in classic MWS
Postaxial polydactyly
2-3 toe syndactyly
HSCR
Microcephaly
ID
Facial features
Spectrum of congenital anomalies
Higher frequency of cleft palate, ptosis, & ocular coloboma than in classic MWS
Significant ID
Mean age of walking: 4-6 yrs
Absent or severely impaired verbal language
Behavioral issues
Stereotypic hand movements
Seizures
Microcephaly
Constipation
Characteristic facial features
PTHS may be assoc w/episodic hyperventilation &/or breath-holding while awake.
Absent speech
Hypopigmentation
Seizures
Microcephaly
Ataxic-like gait
Happy demeanor
AD = autosomal dominant; AR = autosomal recessive; HSCR = Hirschsprung disease; ID = intellectual disability; MOI = mode of inheritance; MWS = Mowat-Wilson syndrome
Smith-Lemli-Opitz syndrome is associated with elevated serum concentration of 7-dehydrocholesterol or an elevated 7-dehydrocholesterol-to-cholesterol ratio.
Angelman syndrome is caused by disruption of maternally imprinted
Other syndromic forms of Hirschsprung disease (HSCR) may also be considered.
• Iris/retinal colobomas
• Congenital heart defects
• Cryptorchidism in males
• ID
• Facial features, incl different ear configurations
• Choanal atresia/stenosis
• Higher frequency of iris/retinal colobomas than in classic MWS
• No HSCR
• Nasal configuration
• ID
• Facial features
• Spectrum of congenital anomalies
• Hypospadias in males
• Microcephaly
• ID
• Facial features
• Higher frequency of cleft palate than in classic MWS
• Postaxial polydactyly
• 2-3 toe syndactyly
• HSCR
• Microcephaly
• ID
• Facial features
• Spectrum of congenital anomalies
• Higher frequency of cleft palate, ptosis, & ocular coloboma than in classic MWS
• Significant ID
• Mean age of walking: 4-6 yrs
• Absent or severely impaired verbal language
• Behavioral issues
• Stereotypic hand movements
• Seizures
• Microcephaly
• Constipation
• Characteristic facial features
• PTHS may be assoc w/episodic hyperventilation &/or breath-holding while awake.
• Absent speech
• Hypopigmentation
• Seizures
• Microcephaly
• Ataxic-like gait
• Happy demeanor
## Management
Clinical management guidelines for Mowat-Wilson syndrome (MWS) have been published [
To establish the extent of disease and needs of an individual diagnosed with classic MWS, the evaluations summarized in
Classic Mowat-Wilson Syndrome: Recommended Evaluations Following Initial Diagnosis
To assess for growth restriction & microcephaly
MWS-specific growth charts have been published.
Referral to GI specialist for eval of possible HSCR &/or primary gut motility issues
Treatment of chronic constipation may improve rates of urinary incontinence.
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Incl screening for presence of findings incl sleep disturbances, ADHD, & anxiety
Consider polysomnogram if concerns about sleep disturbance.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; GI = gastrointestinal; HSCR = Hirschsprung disease; MWS = Mowat-Wilson syndrome; VFSS = videofluoroscopic swallowing study
EEG in awake and asleep state is recommended; consider overnight EEG to evaluate for electric status epilepticus during sleep (ESES), particularly for those with regression of developmental skills or focal neurologic dysfunction, dyspraxia, or ataxia [
Which may include immunoglobulin levels (IgG, IgM, IgA) and T and B cell subsets
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Classic Mowat-Wilson Syndrome: Treatment of Manifestations
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; IVIG = intravenous immunoglobulin therapy; OT = occupational therapy; PT = physical therapy
In one study of 36 individuals with classic MWS and epilepsy, valproic acid was the most effective and most frequently used anti-seizure medication, followed by levetiracetam [
Including administration of pneumococcal vaccine (and other vaccines as indicated); consideration of prophylactic antibiotics in children
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, fractures).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, when necessary.
The specific features present in any given individual typically guide surveillance. Follow up with a cardiologist, gastroenterologist, neurologist, urologist, and developmental pediatrician as clinically indicated is recommended. In addition, the evaluations summarized in
Classic Mowat-Wilson Syndrome: Recommended Surveillance
Every 6 mos for 1st 3 yrs of life, then annually
MWS-specific growth charts have been published.
At least one individual with tantrums and difficulties focusing had worsening aggression after a trial of stimulant medication [
See
Search
• To assess for growth restriction & microcephaly
• MWS-specific growth charts have been published.
• Referral to GI specialist for eval of possible HSCR &/or primary gut motility issues
• Treatment of chronic constipation may improve rates of urinary incontinence.
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Incl screening for presence of findings incl sleep disturbances, ADHD, & anxiety
• Consider polysomnogram if concerns about sleep disturbance.
• Community or
• Social work involvement for parental support
• Home nursing referral
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, fractures).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Every 6 mos for 1st 3 yrs of life, then annually
• MWS-specific growth charts have been published.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with classic MWS, the evaluations summarized in
Classic Mowat-Wilson Syndrome: Recommended Evaluations Following Initial Diagnosis
To assess for growth restriction & microcephaly
MWS-specific growth charts have been published.
Referral to GI specialist for eval of possible HSCR &/or primary gut motility issues
Treatment of chronic constipation may improve rates of urinary incontinence.
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Incl screening for presence of findings incl sleep disturbances, ADHD, & anxiety
Consider polysomnogram if concerns about sleep disturbance.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; GI = gastrointestinal; HSCR = Hirschsprung disease; MWS = Mowat-Wilson syndrome; VFSS = videofluoroscopic swallowing study
EEG in awake and asleep state is recommended; consider overnight EEG to evaluate for electric status epilepticus during sleep (ESES), particularly for those with regression of developmental skills or focal neurologic dysfunction, dyspraxia, or ataxia [
Which may include immunoglobulin levels (IgG, IgM, IgA) and T and B cell subsets
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• To assess for growth restriction & microcephaly
• MWS-specific growth charts have been published.
• Referral to GI specialist for eval of possible HSCR &/or primary gut motility issues
• Treatment of chronic constipation may improve rates of urinary incontinence.
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Incl screening for presence of findings incl sleep disturbances, ADHD, & anxiety
• Consider polysomnogram if concerns about sleep disturbance.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Classic Mowat-Wilson Syndrome: Treatment of Manifestations
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; IVIG = intravenous immunoglobulin therapy; OT = occupational therapy; PT = physical therapy
In one study of 36 individuals with classic MWS and epilepsy, valproic acid was the most effective and most frequently used anti-seizure medication, followed by levetiracetam [
Including administration of pneumococcal vaccine (and other vaccines as indicated); consideration of prophylactic antibiotics in children
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, fractures).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, when necessary.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, fractures).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, fractures).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, fractures).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, when necessary.
## Surveillance
The specific features present in any given individual typically guide surveillance. Follow up with a cardiologist, gastroenterologist, neurologist, urologist, and developmental pediatrician as clinically indicated is recommended. In addition, the evaluations summarized in
Classic Mowat-Wilson Syndrome: Recommended Surveillance
Every 6 mos for 1st 3 yrs of life, then annually
MWS-specific growth charts have been published.
• Every 6 mos for 1st 3 yrs of life, then annually
• MWS-specific growth charts have been published.
## Agents/Circumstances to Avoid
At least one individual with tantrums and difficulties focusing had worsening aggression after a trial of stimulant medication [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Classic Mowat-Wilson syndrome (MWS), an autosomal dominant disorder, is caused by a pathogenic variant (most typically predicted to lead to haploinsufficiency) in
Almost all individuals reported to date have represented simplex cases (i.e., a single occurrence in a family) resulting from a
Most probands reported to date with classic MWS whose parents have undergone molecular genetic testing have the disorder as the result of a
Parents of a proband are not affected.
If the proband appears to be the only affected family member, molecular genetic testing capable of identifying the genetic alteration identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and presumed gonadal mosaicism has been reported [
* A parent with somatic and gonadal mosaicism for a classic MWS-related genetic alteration may be mildly/minimally affected.
Because classic MWS typically occurs as a
Presumed parental gonadal mosaicism has been reported in rare families with recurrence of classic MWS in sibs [
Parents of a proband are not affected with classic MWS but are at risk of having a balanced chromosome rearrangement.
Recommendations for the evaluation of asymptomatic parents of a proband with a chromosome rearrangement include routine karyotyping with additional FISH analysis to determine if a balanced chromosome rearrangement involving the 2q22.3 region is present.
If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with classic MWS.
Prenatal and preimplantation genetic testing require prior identification of the classic MWS-causing genetic alteration in the proband and/or of balanced chromosome rearrangement carrier status in a parent. However, risk to future pregnancies is presumed to be low, as the classic MWS-causing genetic alteration in the proband most likely occurred
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most probands reported to date with classic MWS whose parents have undergone molecular genetic testing have the disorder as the result of a
• Parents of a proband are not affected.
• If the proband appears to be the only affected family member, molecular genetic testing capable of identifying the genetic alteration identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and presumed gonadal mosaicism has been reported [
• * A parent with somatic and gonadal mosaicism for a classic MWS-related genetic alteration may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and presumed gonadal mosaicism has been reported [
• * A parent with somatic and gonadal mosaicism for a classic MWS-related genetic alteration may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and presumed gonadal mosaicism has been reported [
• * A parent with somatic and gonadal mosaicism for a classic MWS-related genetic alteration may be mildly/minimally affected.
• Because classic MWS typically occurs as a
• Presumed parental gonadal mosaicism has been reported in rare families with recurrence of classic MWS in sibs [
• Parents of a proband are not affected with classic MWS but are at risk of having a balanced chromosome rearrangement.
• Recommendations for the evaluation of asymptomatic parents of a proband with a chromosome rearrangement include routine karyotyping with additional FISH analysis to determine if a balanced chromosome rearrangement involving the 2q22.3 region is present.
• If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
• If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with classic MWS.
## Mode of Inheritance
Classic Mowat-Wilson syndrome (MWS), an autosomal dominant disorder, is caused by a pathogenic variant (most typically predicted to lead to haploinsufficiency) in
Almost all individuals reported to date have represented simplex cases (i.e., a single occurrence in a family) resulting from a
## Risk to Family Members – Pathogenic Variant in
Most probands reported to date with classic MWS whose parents have undergone molecular genetic testing have the disorder as the result of a
Parents of a proband are not affected.
If the proband appears to be the only affected family member, molecular genetic testing capable of identifying the genetic alteration identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and presumed gonadal mosaicism has been reported [
* A parent with somatic and gonadal mosaicism for a classic MWS-related genetic alteration may be mildly/minimally affected.
Because classic MWS typically occurs as a
Presumed parental gonadal mosaicism has been reported in rare families with recurrence of classic MWS in sibs [
• Most probands reported to date with classic MWS whose parents have undergone molecular genetic testing have the disorder as the result of a
• Parents of a proband are not affected.
• If the proband appears to be the only affected family member, molecular genetic testing capable of identifying the genetic alteration identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and presumed gonadal mosaicism has been reported [
• * A parent with somatic and gonadal mosaicism for a classic MWS-related genetic alteration may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and presumed gonadal mosaicism has been reported [
• * A parent with somatic and gonadal mosaicism for a classic MWS-related genetic alteration may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental somatic and presumed gonadal mosaicism has been reported [
• * A parent with somatic and gonadal mosaicism for a classic MWS-related genetic alteration may be mildly/minimally affected.
• Because classic MWS typically occurs as a
• Presumed parental gonadal mosaicism has been reported in rare families with recurrence of classic MWS in sibs [
## Risk to Family Members – Chromosome Rearrangement
Parents of a proband are not affected with classic MWS but are at risk of having a balanced chromosome rearrangement.
Recommendations for the evaluation of asymptomatic parents of a proband with a chromosome rearrangement include routine karyotyping with additional FISH analysis to determine if a balanced chromosome rearrangement involving the 2q22.3 region is present.
If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement.
• Parents of a proband are not affected with classic MWS but are at risk of having a balanced chromosome rearrangement.
• Recommendations for the evaluation of asymptomatic parents of a proband with a chromosome rearrangement include routine karyotyping with additional FISH analysis to determine if a balanced chromosome rearrangement involving the 2q22.3 region is present.
• If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
• If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with classic MWS.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with classic MWS.
## Prenatal Testing and Preimplantation Genetic Testing
Prenatal and preimplantation genetic testing require prior identification of the classic MWS-causing genetic alteration in the proband and/or of balanced chromosome rearrangement carrier status in a parent. However, risk to future pregnancies is presumed to be low, as the classic MWS-causing genetic alteration in the proband most likely occurred
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Mowat-Wilson Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Mowat-Wilson Syndrome (
ZEB2 is widely expressed in the developing mouse and plays an important role in the development of the neural crest, consistent with the clinical features of classic Mowat-Wilson syndrome (MWS). ZEB2, like other ΔEF1 family members, interacts with SMAD proteins and functions as a transcriptional repressor in response to TGF-beta signaling [
Studies in animal models may help explain the clinical features of classic MWS:
The vast majority of
Evidence suggests that less severe pathogenic variants result in milder or atypical presentations (see
• The vast majority of
• Evidence suggests that less severe pathogenic variants result in milder or atypical presentations (see
## Molecular Pathogenesis
ZEB2 is widely expressed in the developing mouse and plays an important role in the development of the neural crest, consistent with the clinical features of classic Mowat-Wilson syndrome (MWS). ZEB2, like other ΔEF1 family members, interacts with SMAD proteins and functions as a transcriptional repressor in response to TGF-beta signaling [
Studies in animal models may help explain the clinical features of classic MWS:
The vast majority of
Evidence suggests that less severe pathogenic variants result in milder or atypical presentations (see
• The vast majority of
• Evidence suggests that less severe pathogenic variants result in milder or atypical presentations (see
## Chapter Notes
Margaret P Adam, MD, MS, FAAP, FACMG (2007-present)Lora JH Bean, PhD, FACMG (2007-present)Jessie Conta, MS, LCG (2013-present)Vanessa Rangel Miller, MS, CGC; Emory University (2007-2013)
10 April 2025 (sw) Comprehensive update posted live
25 July 2019 (ha) Comprehensive update posted live
26 November 2013 (me) Comprehensive update posted live
28 March 2007 (me) Review posted live
1 December 2006 (vrm) Original submission
• 10 April 2025 (sw) Comprehensive update posted live
• 25 July 2019 (ha) Comprehensive update posted live
• 26 November 2013 (me) Comprehensive update posted live
• 28 March 2007 (me) Review posted live
• 1 December 2006 (vrm) Original submission
## Author History
Margaret P Adam, MD, MS, FAAP, FACMG (2007-present)Lora JH Bean, PhD, FACMG (2007-present)Jessie Conta, MS, LCG (2013-present)Vanessa Rangel Miller, MS, CGC; Emory University (2007-2013)
## Revision History
10 April 2025 (sw) Comprehensive update posted live
25 July 2019 (ha) Comprehensive update posted live
26 November 2013 (me) Comprehensive update posted live
28 March 2007 (me) Review posted live
1 December 2006 (vrm) Original submission
• 10 April 2025 (sw) Comprehensive update posted live
• 25 July 2019 (ha) Comprehensive update posted live
• 26 November 2013 (me) Comprehensive update posted live
• 28 March 2007 (me) Review posted live
• 1 December 2006 (vrm) Original submission
## References
## Literature Cited
An individual with Mowat-Wilson syndrome at (a) one month, (b) two months, (c) five years, (d) 13 years, (e) 20 years, and (f) 21 years. Note how the typical facial features become more pronounced with time.
|
[] |
28/3/2007
|
10/4/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
myh9
|
myh9
|
[
"Epstein Syndrome",
"Sebastian Syndrome",
"Fechtner Syndrome",
"May-Hegglin Anomaly",
"Myosin-9",
"MYH9",
"MYH9-Related Disease (MYH9-RD)"
] |
Anna Savoia, Alessandro Pecci
|
Summary The diagnosis of
|
In the past, the phenotypes included in
## Diagnosis
No consensus clinical diagnostic criteria for
Manifestations of thrombocytopenia
Easy bruising
Spontaneous mucocutaneous bleeding
Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs)
Sensorineural hearing loss ranging from a slight defect occurring in the elderly to profound deafness that may manifest at a young age
Glomerular nephropathy manifest as proteinuria, with possible evidence of chronic kidney disease
Presenile cataract (occurring in early or middle life)
Thrombocytopenia. Platelet count <150 x 10
Platelet macrocytosis. Extreme platelet macrocytosis present from birth, a hallmark of
Giant platelets (i.e., platelets larger than red blood cells) are invariably present on examination of blood smears of persons with
Moreover, a mean platelet diameter >3.7 μm and/or the finding that >40% of platelets are larger than 3.9 µm (i.e., about half the diameter of a red blood cell) has very good sensitivity and specificity in distinguishing
Note: Electronic cell counters do not recognize the largest platelets of individuals with
Döhle-like bodies. Faint, slightly basophilic inclusion bodies in the cytoplasm of neutrophils (similar to the Döhle bodies that may be found in persons with an infection) are observed on microscopic assessment of a peripheral blood smear after conventional staining (e.g., May-Grünwald-Giemsa).
Note: Döhle-like bodies, present in 42%-84% of individuals with
Typical aggregates of the MYH9 protein in the cytoplasm of neutrophils observed on immunofluorescence staining of a peripheral blood smear:
Are present at birth and throughout the life span;
Can be detected in all individuals with
Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
The diagnosis of
Note: Identification of a heterozygous
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The only
• Manifestations of thrombocytopenia
• Easy bruising
• Spontaneous mucocutaneous bleeding
• Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs)
• Easy bruising
• Spontaneous mucocutaneous bleeding
• Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs)
• Sensorineural hearing loss ranging from a slight defect occurring in the elderly to profound deafness that may manifest at a young age
• Glomerular nephropathy manifest as proteinuria, with possible evidence of chronic kidney disease
• Presenile cataract (occurring in early or middle life)
• Easy bruising
• Spontaneous mucocutaneous bleeding
• Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs)
•
• Thrombocytopenia. Platelet count <150 x 10
• Platelet macrocytosis. Extreme platelet macrocytosis present from birth, a hallmark of
• Giant platelets (i.e., platelets larger than red blood cells) are invariably present on examination of blood smears of persons with
• Moreover, a mean platelet diameter >3.7 μm and/or the finding that >40% of platelets are larger than 3.9 µm (i.e., about half the diameter of a red blood cell) has very good sensitivity and specificity in distinguishing
• Note: Electronic cell counters do not recognize the largest platelets of individuals with
• Thrombocytopenia. Platelet count <150 x 10
• Platelet macrocytosis. Extreme platelet macrocytosis present from birth, a hallmark of
• Giant platelets (i.e., platelets larger than red blood cells) are invariably present on examination of blood smears of persons with
• Moreover, a mean platelet diameter >3.7 μm and/or the finding that >40% of platelets are larger than 3.9 µm (i.e., about half the diameter of a red blood cell) has very good sensitivity and specificity in distinguishing
• Note: Electronic cell counters do not recognize the largest platelets of individuals with
•
• Döhle-like bodies. Faint, slightly basophilic inclusion bodies in the cytoplasm of neutrophils (similar to the Döhle bodies that may be found in persons with an infection) are observed on microscopic assessment of a peripheral blood smear after conventional staining (e.g., May-Grünwald-Giemsa).
• Note: Döhle-like bodies, present in 42%-84% of individuals with
• Typical aggregates of the MYH9 protein in the cytoplasm of neutrophils observed on immunofluorescence staining of a peripheral blood smear:
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Döhle-like bodies. Faint, slightly basophilic inclusion bodies in the cytoplasm of neutrophils (similar to the Döhle bodies that may be found in persons with an infection) are observed on microscopic assessment of a peripheral blood smear after conventional staining (e.g., May-Grünwald-Giemsa).
• Note: Döhle-like bodies, present in 42%-84% of individuals with
• Typical aggregates of the MYH9 protein in the cytoplasm of neutrophils observed on immunofluorescence staining of a peripheral blood smear:
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Thrombocytopenia. Platelet count <150 x 10
• Platelet macrocytosis. Extreme platelet macrocytosis present from birth, a hallmark of
• Giant platelets (i.e., platelets larger than red blood cells) are invariably present on examination of blood smears of persons with
• Moreover, a mean platelet diameter >3.7 μm and/or the finding that >40% of platelets are larger than 3.9 µm (i.e., about half the diameter of a red blood cell) has very good sensitivity and specificity in distinguishing
• Note: Electronic cell counters do not recognize the largest platelets of individuals with
• Döhle-like bodies. Faint, slightly basophilic inclusion bodies in the cytoplasm of neutrophils (similar to the Döhle bodies that may be found in persons with an infection) are observed on microscopic assessment of a peripheral blood smear after conventional staining (e.g., May-Grünwald-Giemsa).
• Note: Döhle-like bodies, present in 42%-84% of individuals with
• Typical aggregates of the MYH9 protein in the cytoplasm of neutrophils observed on immunofluorescence staining of a peripheral blood smear:
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
## Suggestive Findings
Manifestations of thrombocytopenia
Easy bruising
Spontaneous mucocutaneous bleeding
Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs)
Sensorineural hearing loss ranging from a slight defect occurring in the elderly to profound deafness that may manifest at a young age
Glomerular nephropathy manifest as proteinuria, with possible evidence of chronic kidney disease
Presenile cataract (occurring in early or middle life)
Thrombocytopenia. Platelet count <150 x 10
Platelet macrocytosis. Extreme platelet macrocytosis present from birth, a hallmark of
Giant platelets (i.e., platelets larger than red blood cells) are invariably present on examination of blood smears of persons with
Moreover, a mean platelet diameter >3.7 μm and/or the finding that >40% of platelets are larger than 3.9 µm (i.e., about half the diameter of a red blood cell) has very good sensitivity and specificity in distinguishing
Note: Electronic cell counters do not recognize the largest platelets of individuals with
Döhle-like bodies. Faint, slightly basophilic inclusion bodies in the cytoplasm of neutrophils (similar to the Döhle bodies that may be found in persons with an infection) are observed on microscopic assessment of a peripheral blood smear after conventional staining (e.g., May-Grünwald-Giemsa).
Note: Döhle-like bodies, present in 42%-84% of individuals with
Typical aggregates of the MYH9 protein in the cytoplasm of neutrophils observed on immunofluorescence staining of a peripheral blood smear:
Are present at birth and throughout the life span;
Can be detected in all individuals with
Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Manifestations of thrombocytopenia
• Easy bruising
• Spontaneous mucocutaneous bleeding
• Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs)
• Easy bruising
• Spontaneous mucocutaneous bleeding
• Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs)
• Sensorineural hearing loss ranging from a slight defect occurring in the elderly to profound deafness that may manifest at a young age
• Glomerular nephropathy manifest as proteinuria, with possible evidence of chronic kidney disease
• Presenile cataract (occurring in early or middle life)
• Easy bruising
• Spontaneous mucocutaneous bleeding
• Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs)
•
• Thrombocytopenia. Platelet count <150 x 10
• Platelet macrocytosis. Extreme platelet macrocytosis present from birth, a hallmark of
• Giant platelets (i.e., platelets larger than red blood cells) are invariably present on examination of blood smears of persons with
• Moreover, a mean platelet diameter >3.7 μm and/or the finding that >40% of platelets are larger than 3.9 µm (i.e., about half the diameter of a red blood cell) has very good sensitivity and specificity in distinguishing
• Note: Electronic cell counters do not recognize the largest platelets of individuals with
• Thrombocytopenia. Platelet count <150 x 10
• Platelet macrocytosis. Extreme platelet macrocytosis present from birth, a hallmark of
• Giant platelets (i.e., platelets larger than red blood cells) are invariably present on examination of blood smears of persons with
• Moreover, a mean platelet diameter >3.7 μm and/or the finding that >40% of platelets are larger than 3.9 µm (i.e., about half the diameter of a red blood cell) has very good sensitivity and specificity in distinguishing
• Note: Electronic cell counters do not recognize the largest platelets of individuals with
•
• Döhle-like bodies. Faint, slightly basophilic inclusion bodies in the cytoplasm of neutrophils (similar to the Döhle bodies that may be found in persons with an infection) are observed on microscopic assessment of a peripheral blood smear after conventional staining (e.g., May-Grünwald-Giemsa).
• Note: Döhle-like bodies, present in 42%-84% of individuals with
• Typical aggregates of the MYH9 protein in the cytoplasm of neutrophils observed on immunofluorescence staining of a peripheral blood smear:
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Döhle-like bodies. Faint, slightly basophilic inclusion bodies in the cytoplasm of neutrophils (similar to the Döhle bodies that may be found in persons with an infection) are observed on microscopic assessment of a peripheral blood smear after conventional staining (e.g., May-Grünwald-Giemsa).
• Note: Döhle-like bodies, present in 42%-84% of individuals with
• Typical aggregates of the MYH9 protein in the cytoplasm of neutrophils observed on immunofluorescence staining of a peripheral blood smear:
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Thrombocytopenia. Platelet count <150 x 10
• Platelet macrocytosis. Extreme platelet macrocytosis present from birth, a hallmark of
• Giant platelets (i.e., platelets larger than red blood cells) are invariably present on examination of blood smears of persons with
• Moreover, a mean platelet diameter >3.7 μm and/or the finding that >40% of platelets are larger than 3.9 µm (i.e., about half the diameter of a red blood cell) has very good sensitivity and specificity in distinguishing
• Note: Electronic cell counters do not recognize the largest platelets of individuals with
• Döhle-like bodies. Faint, slightly basophilic inclusion bodies in the cytoplasm of neutrophils (similar to the Döhle bodies that may be found in persons with an infection) are observed on microscopic assessment of a peripheral blood smear after conventional staining (e.g., May-Grünwald-Giemsa).
• Note: Döhle-like bodies, present in 42%-84% of individuals with
• Typical aggregates of the MYH9 protein in the cytoplasm of neutrophils observed on immunofluorescence staining of a peripheral blood smear:
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Are present at birth and throughout the life span;
• Can be detected in all individuals with
• Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
## Establishing the Diagnosis
The diagnosis of
Note: Identification of a heterozygous
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The only
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The only
## Clinical Characteristics
Presence and severity of a spontaneous
Hearing loss is usually bilateral. Once diagnosed, hearing loss frequently progresses over time, although it can remain stable in a minority of affected individuals. Earlier-onset hearing loss often progresses more rapidly and may result in severe-to-profound deafness [
Hearing loss interferes with activities of daily living in 90% of individuals who have an abnormal audiometric examination [
The mean age at onset is 27 years. Of those who develop renal disease, 72% are diagnosed before age 35 years. In most individuals with nephropathy, kidney damage is progressive and evolves to end-stage renal disease (ESRD). Among those with nephropathy, the overall annual rate for progression to ESRD is 6.79 per 100 affected persons. After a median follow up of 36 months, 64% of 61 individuals with nephropathy developed chronic kidney disease and 43% developed ESRD [
Observed genotype-phenotype correlations are discussed in this section. (See Molecular Genetics,
Individuals with pathogenic variants involving the head domain of the MYH9 protein have more severe thrombocytopenia compared to those with pathogenic variants affecting the tail domain.
The risk of developing kidney damage, hearing loss, and cataract also depends on the specific
Pathogenic variants in the codon for arginine residue 702 (located in the short functional SH1 helix of the head domain) are associated with the most severe phenotype. Individuals with Arg702 substitutions present with severe thrombocytopenia (platelet count usually <50 x 10
The
Pathogenic variants encoding the residues at the interface between the SH3-like motif and the upper 50-kd subdomain of the head domain or those resulting in substitutions of the arginine residue 1165 are associated with a high risk for hearing loss (all are expected to develop hearing loss before age 60 years) and a low risk for nephropathy and cataract.
The
To date, no significant genotype-phenotype correlations have been identified for the occurrence of elevated liver enzyme levels [
Penetrance is complete for the following congenital findings:
Platelet macrocytosis with giant platelets
Aggregates of the MYH9 proteins in neutrophils
Except for a very few individuals in whom platelet count was just above the conventional cut-off value for thrombocytopenia (150 x 10
Expressivity varies for onset and severity of sensorineural deafness, glomerular nephropathy, presenile cataract, and alterations of liver enzymes.
In the past, the conditions now collectively referred to as
Modified from Table 1 in
DFNA17 = autosomal-dominant deafness 17; SNHL = sensorineural hearing loss
• Pathogenic variants in the codon for arginine residue 702 (located in the short functional SH1 helix of the head domain) are associated with the most severe phenotype. Individuals with Arg702 substitutions present with severe thrombocytopenia (platelet count usually <50 x 10
• The
• Pathogenic variants encoding the residues at the interface between the SH3-like motif and the upper 50-kd subdomain of the head domain or those resulting in substitutions of the arginine residue 1165 are associated with a high risk for hearing loss (all are expected to develop hearing loss before age 60 years) and a low risk for nephropathy and cataract.
• The
• Platelet macrocytosis with giant platelets
• Aggregates of the MYH9 proteins in neutrophils
## Clinical Description
Presence and severity of a spontaneous
Hearing loss is usually bilateral. Once diagnosed, hearing loss frequently progresses over time, although it can remain stable in a minority of affected individuals. Earlier-onset hearing loss often progresses more rapidly and may result in severe-to-profound deafness [
Hearing loss interferes with activities of daily living in 90% of individuals who have an abnormal audiometric examination [
The mean age at onset is 27 years. Of those who develop renal disease, 72% are diagnosed before age 35 years. In most individuals with nephropathy, kidney damage is progressive and evolves to end-stage renal disease (ESRD). Among those with nephropathy, the overall annual rate for progression to ESRD is 6.79 per 100 affected persons. After a median follow up of 36 months, 64% of 61 individuals with nephropathy developed chronic kidney disease and 43% developed ESRD [
## Genotype-Phenotype Correlations
Observed genotype-phenotype correlations are discussed in this section. (See Molecular Genetics,
Individuals with pathogenic variants involving the head domain of the MYH9 protein have more severe thrombocytopenia compared to those with pathogenic variants affecting the tail domain.
The risk of developing kidney damage, hearing loss, and cataract also depends on the specific
Pathogenic variants in the codon for arginine residue 702 (located in the short functional SH1 helix of the head domain) are associated with the most severe phenotype. Individuals with Arg702 substitutions present with severe thrombocytopenia (platelet count usually <50 x 10
The
Pathogenic variants encoding the residues at the interface between the SH3-like motif and the upper 50-kd subdomain of the head domain or those resulting in substitutions of the arginine residue 1165 are associated with a high risk for hearing loss (all are expected to develop hearing loss before age 60 years) and a low risk for nephropathy and cataract.
The
To date, no significant genotype-phenotype correlations have been identified for the occurrence of elevated liver enzyme levels [
• Pathogenic variants in the codon for arginine residue 702 (located in the short functional SH1 helix of the head domain) are associated with the most severe phenotype. Individuals with Arg702 substitutions present with severe thrombocytopenia (platelet count usually <50 x 10
• The
• Pathogenic variants encoding the residues at the interface between the SH3-like motif and the upper 50-kd subdomain of the head domain or those resulting in substitutions of the arginine residue 1165 are associated with a high risk for hearing loss (all are expected to develop hearing loss before age 60 years) and a low risk for nephropathy and cataract.
• The
## Penetrance
Penetrance is complete for the following congenital findings:
Platelet macrocytosis with giant platelets
Aggregates of the MYH9 proteins in neutrophils
Except for a very few individuals in whom platelet count was just above the conventional cut-off value for thrombocytopenia (150 x 10
Expressivity varies for onset and severity of sensorineural deafness, glomerular nephropathy, presenile cataract, and alterations of liver enzymes.
• Platelet macrocytosis with giant platelets
• Aggregates of the MYH9 proteins in neutrophils
## Nomenclature
In the past, the conditions now collectively referred to as
Modified from Table 1 in
DFNA17 = autosomal-dominant deafness 17; SNHL = sensorineural hearing loss
## Prevalence
## Genetically Related (Allelic) Disorders
In addition to
## Differential Diagnosis
The differential diagnosis of
If the genetic origin of thrombocytopenia is not obvious because a family history is absent or unclear, the following findings on microscopic evaluation of peripheral blood slides are a simple and effective way to distinguish individuals with
Platelets are significantly larger in persons with
More than 40% of platelets >3.9 µm (i.e., about half the diameter of a red blood cell) distinguishes
Assay of immunofluorescence staining of MYH9 protein distribution in neutrophils can also be used to differentiate
Note: All congenital macrothrombocytopenias are very rare disorders.
Inherited Macrothrombocytopenias in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; NA = not applicable; RT = related thrombocytopenia; THC6 = thrombocytopenia 6; XL = X-linked
Platelet defects have not been described in Alport syndrome. Therefore, whenever nephropathies are associated with macrothrombocytopenia,
• Platelets are significantly larger in persons with
• More than 40% of platelets >3.9 µm (i.e., about half the diameter of a red blood cell) distinguishes
## Acquired Thrombocytopenia
If the genetic origin of thrombocytopenia is not obvious because a family history is absent or unclear, the following findings on microscopic evaluation of peripheral blood slides are a simple and effective way to distinguish individuals with
Platelets are significantly larger in persons with
More than 40% of platelets >3.9 µm (i.e., about half the diameter of a red blood cell) distinguishes
Assay of immunofluorescence staining of MYH9 protein distribution in neutrophils can also be used to differentiate
• Platelets are significantly larger in persons with
• More than 40% of platelets >3.9 µm (i.e., about half the diameter of a red blood cell) distinguishes
## Inherited Thrombocytopenia
Note: All congenital macrothrombocytopenias are very rare disorders.
Inherited Macrothrombocytopenias in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; NA = not applicable; RT = related thrombocytopenia; THC6 = thrombocytopenia 6; XL = X-linked
## Hereditary Nephritis
Platelet defects have not been described in Alport syndrome. Therefore, whenever nephropathies are associated with macrothrombocytopenia,
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Assessment of bleeding history incl spontaneous & provoked bleeding episodes
Complete blood count to evaluate for anemia
Use of standardized questionnaires (e.g., ISTH Bleeding Assessment Tool
In persons w/anemia, serum concentration of iron & ferritin to evaluate for iron deficiency
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase; ISTH = International Society on Thrombosis and Haemostasis; MOI = mode of inheritance; SNHL = sensorineural hearing loss
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Multidisciplinary management by different specialists including hematologists or internists with expertise in hemostasis, nephrologists, otolaryngologists, and ophthalmologists is recommended.
Treatment of Manifestations in Individuals with
Treatments incl local measures, transfusion of platelet concentrates, eltrombopag, antifibrinolytics drugs, desmopressin.
See
Treatments should be administered by hematologist or internist w/expertise in hemostasis.
Thrombocytopenia cannot be prevented.
Education re drugs that affect platelet function to prevent bleeding (See
Oral contraceptives to prevent or control menorrhagia
Regular dental care to prevent gum bleeding
Treatments incl hearing aids, cochlear implantation.
See
See
Treatments should be administered by audiologist/otolaryngologist.
Treatments incl angiotensin converting enzyme inhibitors &/or angiotensin receptor blockers, dialysis, kidney transplantation.
See
Treatments should be administered by nephrologist.
SNHL = sensorineural hearing loss
A recent retrospective case series from a single center reported 11 consecutive surgical procedures in individuals with
The need for prophylactic intervention in preparation for surgery or other invasive procedures (including platelet transfusion, short-term eltrombopag, and/or empiric use of antifibrinolytics drugs or desmopressin) should be established based on the type of procedure, the individual's previous history of bleeding, and platelet count before the procedure.
Regular dental care and good oral hygiene are essential to prevent gingival bleeding.
Recommended Surveillance for Individuals with
Microscopic assessment of platelet count
Note: Electronic cell counters do not recognize the largest platelets of persons w/
Assessment of person's bleeding history through standardized questionnaires (e.g., ISTH Bleeding Assessment Tool)
Blood count to screen for anemia
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase; ISTH = International Society on Thrombosis and Haemostasis; SNHL = sensorineural hearing loss
Drugs that inhibit platelet function include:
Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
Drugs that may reduce platelet count include oncologic treatments and some antibiotics.
Antithrombotic drugs (such as heparin or oral anticoagulants) should be prescribed with caution and after a careful assessment of the risk-to-benefit ratio, as in patients affected with other forms of thrombocytopenia.
It is appropriate to clarify the status of all first-degree relatives of an affected individual in order to establish: (1) appropriate management (including follow-up
Evaluations to clarify the status of at-risk family members include:
Examination of peripheral blood smear to search for platelet macrocytosis, assessment of platelet count, and immunofluorescence search for aggregates of the MYH9 protein;
Molecular genetic testing if the
See
Deliveries should be managed as they are in women with other forms of thrombocytopenia. (Note that
Search
• Assessment of bleeding history incl spontaneous & provoked bleeding episodes
• Complete blood count to evaluate for anemia
• Use of standardized questionnaires (e.g., ISTH Bleeding Assessment Tool
• In persons w/anemia, serum concentration of iron & ferritin to evaluate for iron deficiency
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
• Treatments incl local measures, transfusion of platelet concentrates, eltrombopag, antifibrinolytics drugs, desmopressin.
• See
• Treatments should be administered by hematologist or internist w/expertise in hemostasis.
• Thrombocytopenia cannot be prevented.
• Education re drugs that affect platelet function to prevent bleeding (See
• Oral contraceptives to prevent or control menorrhagia
• Regular dental care to prevent gum bleeding
• Treatments incl hearing aids, cochlear implantation.
• See
• See
• Treatments should be administered by audiologist/otolaryngologist.
• Treatments incl angiotensin converting enzyme inhibitors &/or angiotensin receptor blockers, dialysis, kidney transplantation.
• See
• Treatments should be administered by nephrologist.
• Microscopic assessment of platelet count
• Note: Electronic cell counters do not recognize the largest platelets of persons w/
• Assessment of person's bleeding history through standardized questionnaires (e.g., ISTH Bleeding Assessment Tool)
• Blood count to screen for anemia
• Drugs that inhibit platelet function include:
• Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
• Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
• Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
• Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
• Drugs that may reduce platelet count include oncologic treatments and some antibiotics.
• Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
• Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
• Examination of peripheral blood smear to search for platelet macrocytosis, assessment of platelet count, and immunofluorescence search for aggregates of the MYH9 protein;
• Molecular genetic testing if the
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Assessment of bleeding history incl spontaneous & provoked bleeding episodes
Complete blood count to evaluate for anemia
Use of standardized questionnaires (e.g., ISTH Bleeding Assessment Tool
In persons w/anemia, serum concentration of iron & ferritin to evaluate for iron deficiency
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase; ISTH = International Society on Thrombosis and Haemostasis; MOI = mode of inheritance; SNHL = sensorineural hearing loss
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Assessment of bleeding history incl spontaneous & provoked bleeding episodes
• Complete blood count to evaluate for anemia
• Use of standardized questionnaires (e.g., ISTH Bleeding Assessment Tool
• In persons w/anemia, serum concentration of iron & ferritin to evaluate for iron deficiency
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
Multidisciplinary management by different specialists including hematologists or internists with expertise in hemostasis, nephrologists, otolaryngologists, and ophthalmologists is recommended.
Treatment of Manifestations in Individuals with
Treatments incl local measures, transfusion of platelet concentrates, eltrombopag, antifibrinolytics drugs, desmopressin.
See
Treatments should be administered by hematologist or internist w/expertise in hemostasis.
Thrombocytopenia cannot be prevented.
Education re drugs that affect platelet function to prevent bleeding (See
Oral contraceptives to prevent or control menorrhagia
Regular dental care to prevent gum bleeding
Treatments incl hearing aids, cochlear implantation.
See
See
Treatments should be administered by audiologist/otolaryngologist.
Treatments incl angiotensin converting enzyme inhibitors &/or angiotensin receptor blockers, dialysis, kidney transplantation.
See
Treatments should be administered by nephrologist.
SNHL = sensorineural hearing loss
A recent retrospective case series from a single center reported 11 consecutive surgical procedures in individuals with
The need for prophylactic intervention in preparation for surgery or other invasive procedures (including platelet transfusion, short-term eltrombopag, and/or empiric use of antifibrinolytics drugs or desmopressin) should be established based on the type of procedure, the individual's previous history of bleeding, and platelet count before the procedure.
Regular dental care and good oral hygiene are essential to prevent gingival bleeding.
• Treatments incl local measures, transfusion of platelet concentrates, eltrombopag, antifibrinolytics drugs, desmopressin.
• See
• Treatments should be administered by hematologist or internist w/expertise in hemostasis.
• Thrombocytopenia cannot be prevented.
• Education re drugs that affect platelet function to prevent bleeding (See
• Oral contraceptives to prevent or control menorrhagia
• Regular dental care to prevent gum bleeding
• Treatments incl hearing aids, cochlear implantation.
• See
• See
• Treatments should be administered by audiologist/otolaryngologist.
• Treatments incl angiotensin converting enzyme inhibitors &/or angiotensin receptor blockers, dialysis, kidney transplantation.
• See
• Treatments should be administered by nephrologist.
## Thrombocytopenia and/or Bleeding Tendency
A recent retrospective case series from a single center reported 11 consecutive surgical procedures in individuals with
The need for prophylactic intervention in preparation for surgery or other invasive procedures (including platelet transfusion, short-term eltrombopag, and/or empiric use of antifibrinolytics drugs or desmopressin) should be established based on the type of procedure, the individual's previous history of bleeding, and platelet count before the procedure.
Regular dental care and good oral hygiene are essential to prevent gingival bleeding.
## Sensorineural Hearing Loss
## Nephropathy
## Cataracts
## Surveillance
Recommended Surveillance for Individuals with
Microscopic assessment of platelet count
Note: Electronic cell counters do not recognize the largest platelets of persons w/
Assessment of person's bleeding history through standardized questionnaires (e.g., ISTH Bleeding Assessment Tool)
Blood count to screen for anemia
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase; ISTH = International Society on Thrombosis and Haemostasis; SNHL = sensorineural hearing loss
• Microscopic assessment of platelet count
• Note: Electronic cell counters do not recognize the largest platelets of persons w/
• Assessment of person's bleeding history through standardized questionnaires (e.g., ISTH Bleeding Assessment Tool)
• Blood count to screen for anemia
## Agents/Circumstances to Avoid
Drugs that inhibit platelet function include:
Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
Drugs that may reduce platelet count include oncologic treatments and some antibiotics.
Antithrombotic drugs (such as heparin or oral anticoagulants) should be prescribed with caution and after a careful assessment of the risk-to-benefit ratio, as in patients affected with other forms of thrombocytopenia.
• Drugs that inhibit platelet function include:
• Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
• Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
• Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
• Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
• Drugs that may reduce platelet count include oncologic treatments and some antibiotics.
• Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
• Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
## Bleeding Tendency
Drugs that inhibit platelet function include:
Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
Drugs that may reduce platelet count include oncologic treatments and some antibiotics.
Antithrombotic drugs (such as heparin or oral anticoagulants) should be prescribed with caution and after a careful assessment of the risk-to-benefit ratio, as in patients affected with other forms of thrombocytopenia.
• Drugs that inhibit platelet function include:
• Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
• Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
• Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
• Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
• Drugs that may reduce platelet count include oncologic treatments and some antibiotics.
• Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;
• Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.
## Hearing Loss
## Nephropathy
## Cataract
## Elevation of Liver Enzymes
## Evaluation of Relatives at Risk
It is appropriate to clarify the status of all first-degree relatives of an affected individual in order to establish: (1) appropriate management (including follow-up
Evaluations to clarify the status of at-risk family members include:
Examination of peripheral blood smear to search for platelet macrocytosis, assessment of platelet count, and immunofluorescence search for aggregates of the MYH9 protein;
Molecular genetic testing if the
See
• Examination of peripheral blood smear to search for platelet macrocytosis, assessment of platelet count, and immunofluorescence search for aggregates of the MYH9 protein;
• Molecular genetic testing if the
## Pregnancy Management
Deliveries should be managed as they are in women with other forms of thrombocytopenia. (Note that
## Therapies Under Investigation
Search
## Genetic Counseling
Approximately 65% of probands diagnosed with
An individual with
If neither parent of the proband is known to have
Molecular genetic testing for the
If the causative pathogenic variant has not been identified in the proband or a mild phenotype resulting from potential somatic mosaicism is suspected in a parent, appropriate hematologic testing (e.g., evaluation of platelet number and size and distribution of the MYH9 protein in neutrophils; see
If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Both germline mosaicism and somatic mosaicism including the germline have been reported [
Note: A parent with somatic mosaicism for an
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. A sib who inherits an
If the proband has a known
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Approximately 65% of probands diagnosed with
• An individual with
• If neither parent of the proband is known to have
• Molecular genetic testing for the
• If the causative pathogenic variant has not been identified in the proband or a mild phenotype resulting from potential somatic mosaicism is suspected in a parent, appropriate hematologic testing (e.g., evaluation of platelet number and size and distribution of the MYH9 protein in neutrophils; see
• Molecular genetic testing for the
• If the causative pathogenic variant has not been identified in the proband or a mild phenotype resulting from potential somatic mosaicism is suspected in a parent, appropriate hematologic testing (e.g., evaluation of platelet number and size and distribution of the MYH9 protein in neutrophils; see
• If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Both germline mosaicism and somatic mosaicism including the germline have been reported [
• Note: A parent with somatic mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Both germline mosaicism and somatic mosaicism including the germline have been reported [
• Note: A parent with somatic mosaicism for an
• The family history of some individuals diagnosed with
• Molecular genetic testing for the
• If the causative pathogenic variant has not been identified in the proband or a mild phenotype resulting from potential somatic mosaicism is suspected in a parent, appropriate hematologic testing (e.g., evaluation of platelet number and size and distribution of the MYH9 protein in neutrophils; see
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Both germline mosaicism and somatic mosaicism including the germline have been reported [
• Note: A parent with somatic mosaicism for an
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. A sib who inherits an
• If the proband has a known
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
## Risk to Family Members
Approximately 65% of probands diagnosed with
An individual with
If neither parent of the proband is known to have
Molecular genetic testing for the
If the causative pathogenic variant has not been identified in the proband or a mild phenotype resulting from potential somatic mosaicism is suspected in a parent, appropriate hematologic testing (e.g., evaluation of platelet number and size and distribution of the MYH9 protein in neutrophils; see
If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Both germline mosaicism and somatic mosaicism including the germline have been reported [
Note: A parent with somatic mosaicism for an
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. A sib who inherits an
If the proband has a known
• Approximately 65% of probands diagnosed with
• An individual with
• If neither parent of the proband is known to have
• Molecular genetic testing for the
• If the causative pathogenic variant has not been identified in the proband or a mild phenotype resulting from potential somatic mosaicism is suspected in a parent, appropriate hematologic testing (e.g., evaluation of platelet number and size and distribution of the MYH9 protein in neutrophils; see
• Molecular genetic testing for the
• If the causative pathogenic variant has not been identified in the proband or a mild phenotype resulting from potential somatic mosaicism is suspected in a parent, appropriate hematologic testing (e.g., evaluation of platelet number and size and distribution of the MYH9 protein in neutrophils; see
• If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Both germline mosaicism and somatic mosaicism including the germline have been reported [
• Note: A parent with somatic mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Both germline mosaicism and somatic mosaicism including the germline have been reported [
• Note: A parent with somatic mosaicism for an
• The family history of some individuals diagnosed with
• Molecular genetic testing for the
• If the causative pathogenic variant has not been identified in the proband or a mild phenotype resulting from potential somatic mosaicism is suspected in a parent, appropriate hematologic testing (e.g., evaluation of platelet number and size and distribution of the MYH9 protein in neutrophils; see
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Both germline mosaicism and somatic mosaicism including the germline have been reported [
• Note: A parent with somatic mosaicism for an
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. A sib who inherits an
• If the proband has a known
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Clinica Medica III IRCCS Policlinico
San Matteo Foundation
Piazzale Golgi, 2
Pavia 27100
Italy
•
•
•
•
•
•
•
•
•
•
•
•
•
• Clinica Medica III IRCCS Policlinico
• San Matteo Foundation
• Piazzale Golgi, 2
• Pavia 27100
• Italy
•
## Molecular Genetics
MYH9-Related Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MYH9-Related Disease (
Pathogenesis of the manifestations of
NMMIIA is dispensable for megakaryocyte production and maturation, but has a key role in the extension of proplatelets. In fact, megakaryocytes of individuals with
Kidney damage is thought to mainly result from defective function of the podocytes, highly specialized epithelial cells of the renal glomerular filtration barrier. Investigations of mouse models of
The mechanisms of hearing loss are poorly understood. However, the hearing defect is likely to derive from alteration of the functions of the hair cells of the cochlea of the inner ear – that is, the cells specialized in converting the sound stimulus into electric signals directed to the brain.
Pathogenesis of the other phenotypes of
The spectrum of the
Moreover, almost 70% of affected individuals have pathogenic variants involving only six residues: Ser96 or Arg702 of the head domain; and Arg1165, Asp1424, Glu1841, or Arg1933 of the tail domain [
Notable
NHT = nonhelical tailpiece; SH3/MD i = interface between the SH3-like motif and the motor domain
Variants listed in the table have been provided by the authors.
See
## Molecular Pathogenesis
Pathogenesis of the manifestations of
NMMIIA is dispensable for megakaryocyte production and maturation, but has a key role in the extension of proplatelets. In fact, megakaryocytes of individuals with
Kidney damage is thought to mainly result from defective function of the podocytes, highly specialized epithelial cells of the renal glomerular filtration barrier. Investigations of mouse models of
The mechanisms of hearing loss are poorly understood. However, the hearing defect is likely to derive from alteration of the functions of the hair cells of the cochlea of the inner ear – that is, the cells specialized in converting the sound stimulus into electric signals directed to the brain.
Pathogenesis of the other phenotypes of
The spectrum of the
Moreover, almost 70% of affected individuals have pathogenic variants involving only six residues: Ser96 or Arg702 of the head domain; and Arg1165, Asp1424, Glu1841, or Arg1933 of the tail domain [
Notable
NHT = nonhelical tailpiece; SH3/MD i = interface between the SH3-like motif and the motor domain
Variants listed in the table have been provided by the authors.
See
## Chapter Notes
Alessandro Pecci works as a physician and researcher at the IRCCS Policlinico San Matteo Foundation and the University of Pavia, Pavia, Italy. His research interests focus on hemostasis and thrombosis, ranging from clinical to basic research. He is particularly interested in clinical aspects, management and pathogenetic mechanisms of inherited thrombocytopenias. Email:
Carlo L Balduini, MD; University of Pavia (2008-2015)Alessandro Pecci, MD, PhD (2015-present)Anna Savoia, PhD (2008-present)
18 February 2021 (bp) Comprehensive update posted live
16 July 2015 (me) Comprehensive update posted live
5 April 2011 (me) Comprehensive update posted live
25 June 2009 (cd) Revision: deletion/duplication analysis available clinically
20 November 2008 (me) Review posted live
9 July 2008 (as) Original submission
• 18 February 2021 (bp) Comprehensive update posted live
• 16 July 2015 (me) Comprehensive update posted live
• 5 April 2011 (me) Comprehensive update posted live
• 25 June 2009 (cd) Revision: deletion/duplication analysis available clinically
• 20 November 2008 (me) Review posted live
• 9 July 2008 (as) Original submission
## Author Notes
Alessandro Pecci works as a physician and researcher at the IRCCS Policlinico San Matteo Foundation and the University of Pavia, Pavia, Italy. His research interests focus on hemostasis and thrombosis, ranging from clinical to basic research. He is particularly interested in clinical aspects, management and pathogenetic mechanisms of inherited thrombocytopenias. Email:
## Author History
Carlo L Balduini, MD; University of Pavia (2008-2015)Alessandro Pecci, MD, PhD (2015-present)Anna Savoia, PhD (2008-present)
## Revision History
18 February 2021 (bp) Comprehensive update posted live
16 July 2015 (me) Comprehensive update posted live
5 April 2011 (me) Comprehensive update posted live
25 June 2009 (cd) Revision: deletion/duplication analysis available clinically
20 November 2008 (me) Review posted live
9 July 2008 (as) Original submission
• 18 February 2021 (bp) Comprehensive update posted live
• 16 July 2015 (me) Comprehensive update posted live
• 5 April 2011 (me) Comprehensive update posted live
• 25 June 2009 (cd) Revision: deletion/duplication analysis available clinically
• 20 November 2008 (me) Review posted live
• 9 July 2008 (as) Original submission
## References
## Literature Cited
|
[
"K Althaus, A. Greinacher. MYH9-related platelet disorders.. Semin Thromb Hemost 2009;35:189-203",
"CL Balduini, P Noris, S Belletti, P Spedini, G Gamba. In vitro and in vivo effects of desmopressin on platelet function.. Haematologica. 1999;84:891-6",
"R Favier, A DiFeo, N Hezard, M Fabre, P Bedossa, JA Martignetti. A new feature of the MYH9-related syndrome: chronic transaminase elevation.. Hepatology. 2013;57:1288-9",
"R Fernandez-Prado, SM Carriazo-Julio, R Torra, A Ortiz, MV Perez-Gomez. MYH9-related disease: it does exist, may be more frequent than you think and requires specific therapy.. Clin Kidney J. 2019;12:488-93",
"E Fewings, M Ziemer, K Hörtnagel, K Reicherter, A Larionov, J Redman, MA Goldgraben, A Pepler, T Hearn, H Firth, T Ha, J Schaller, DJ Adams, E Rytina, M van Steensel, M Tischkowitz. Malta (MYH9 associated elastin aggregation) syndrome: germline variants in MYH9 cause rare sweat duct proliferations and irregular elastin ggregations.. J Invest Dermatol. 2019;139:2238-2241.e6",
"J Futterer, A Dalby, GC Lowe, B Johnson, MA Simpson, J Motwani, M Williams, SP Watson, NV Morgan. Mutation in GNE is associated with severe congenital thrombocytopenia.. Blood. 2018;132:1855-8",
"A Greinacher, A Pecci, S Kunishima, K Althaus, P Nurden, CL Balduini, T Bakchoul. Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders.. J Thromb Haemost. 2017;15:1511-21",
"P Gresele, D De Rocco, L Bury, T Fierro, AM Mezzasoma, A Pecci, A Savoia. Apparent genotype-phenotype mismatch in a patient with MYH9-related disease: when the exception proves the rule.. Thromb Haemost. 2013;110:618-20",
"P Gresele, S Orsini, P Noris, E Falcinelli, MC Alessi, L Bury, M Borhany, C Santoro, AC Glembotsky, AR Cid, A Tosetto, E De Candia, P Fontana, G Guglielmini, A Pecci. Validation of the ISTH/SSC bleeding assessment tool for inherited platelet disorders: a communication from the Platelet Physiology SSC.. J Thromb Haemost. 2020;18:732-39",
"K Kitamura, K Yoshida, Y Shiraishi, K Chiba, H Tanaka, K Furukawa, S Miyano, S Ogawa, S. Kunishima. Normal neutrophil myosin IIA localization in an immunofluorescence analysis can rule out MYH9 disorders.. J Thromb Haemost. 2013;11:2071-3",
"S Kunishima, K Kitamura, T Matsumoto, T Sekine, H. Saito. Somatic mosaicism in MYH9 disorders: the need to carefully evaluate apparently healthy parents.. Br J Haematol. 2014;165:885-7",
"S Kunishima, T Matsushita, M Hamaguchi, H Saito. Identification and characterization of the first large deletion of the MYH9 gene associated with MYH9 disorders.. Eur J Haematol. 2008;80:540-4",
"S Kunishima, T Matsushita, T Kojima, M Sako, F Kimura, EK Jo, C Inoue, T Kamiya, H Saito. Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A (NMMHCA) in MYH9 disorders: association of subcellular localization with MYH9 mutations.. Lab Invest. 2003;83:115-22",
"S Kunishima, T Matsushita, T Yoshihara, Y Nakase, K Yokoi, M Hamaguchi, H Saito. First description of somatic mosaicism in MYH9 disorders.. Br J Haematol. 2005;128:360-5",
"S Kunishima, K Takaki, Y Ito, H. Saito. Germinal mosaicism in MYH9 disorders: a family with two affected siblings of normal parents.. Br J Haematol. 2009;145:260-2",
"AK Lalwani, JA Goldstein, MJ Kelley, W Luxford, CM Castelein, AN Mhatre. Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9.. Am J Hum Genet. 2000;67:1121-8",
"P Noris, G Biino, A Pecci, E Civaschi, A Savoia, M Seri, F Melazzini, G Loffredo, G Russo, V Bozzi, LD Notarangelo, P Gresele, PG Heller, N Pujol-Moix, S Kunishima, M Cattaneo, J Bussel, E De Candia, C Cagioni, U Ramenghi, S Barozzi, F Fabris, CL Balduini. Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders.. Blood. 2014a;124:e4-e10",
"P Noris, N Schlegel, C Klersy, PG Heller, E Civaschi, N Pujol-Moix, F Fabris, R Favier, P Gresele, V Latger-Cannard, A Cuker, P Nurden, A Greinacher, M Cattaneo, E De Candia, A Pecci, MF Hurtaud-Roux, AC Glembotsky, E Muñiz-Diaz, ML Randi, N Trillot, L Bury, T Lecompte, C Marconi, A Savoia, CL Balduini, S Bayart, A Bauters, S Benabdallah-Guedira, F Boehlen, JY Borg, R Bottega, J Bussel, D De Rocco, E de Maistre, M Faleschini, E Falcinelli, S Ferrari, A Ferster, T Fierro, D Fleury, P Fontana, C James, F Lanza, V Le Cam Duchez, G Loffredo, P Magini, D Martin-Coignard, F Menard, S Mercier, A Mezzasoma, P Minuz, I Nichele, LD Notarangelo, T Pippucci, GM Podda, C Pouymayou, A Rigouzzo, B Royer, P Sie, V Siguret, C Trichet, A Tucci, B Saposnik, D Veneri. Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia.. Haematologica. 2014b;99:1387-94",
"S Orsini, P Noris, L Bury, PG Heller, C Santoro, RA Kadir, NC Butta, E Falcinelli, AR Cid, F Fabris, M Fouassier, K Miyazaki, ML Lozano, P Zúñiga, C Flaujac, GM Podda, N Bermejo, R Favier, Y Henskens, E De Maistre, E De Candia, AD Mumford, GN Ozdemir, I Eker, P Nurden, S Bayart, MP Lambert, J Bussel, B Zieger, A Tosetto, F Melazzini, AC Glembotsky, A Pecci, M Cattaneo, N Schlegel, P Gresele. Bleeding risk of surgery and its prevention in patients with inherited platelet disorders.. Haematologica. 2017;102:1192-1203",
"K Pal, R Nowak, N Billington, R Liu, A Ghosh, JR Sellers, VM Fowler. Megakaryocyte migration defects due to nonmuscle myosin IIA mutations underlie thrombocytopenia in MYH9-related disease.. Blood. 2020;135:1887-98",
"A Pecci, G Biino, T Fierro, V Bozzi, A Mezzasoma, P Noris, U Ramenghi, G Loffredo, F Fabris, S Momi, U Magrini, M Pirastu, A Savoia, C Balduini, P Gresele. Alteration of liver enzymes is a feature of the MYH9-related disease syndrome.. PLoS One. 2012;7",
"A Pecci, A Granata, CE Fiore, CL Balduini. Renin-angiotensin system blockade is effective in reducing proteinuria of individuals with progressive nephropathy caused by MYH9 mutations (Fechtner-Epstein syndrome).. Nephrol Dial Transplant. 2008;23:2690-2",
"A Pecci, P Gresele, C Klersy, A Savoia, P Noris, T Fierro, V Bozzi, AM Mezzasoma, F Melazzini, CL Balduini. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations.. Blood. 2010;116:5832-7",
"A Pecci, C Klersy, P Gresele, KJ Lee, D De Rocco, V Bozzi, G Russo, PG Heller, G Loffredo, M Ballmaier, F Fabris, E Beggiato, WH Kahr, N Pujol-Moix, H Platokouki, C Van Geet, P Noris, P Yerram, C Hermans, B Gerber, M Economou, M De Groot, B Zieger, E De Candia, V Fraticelli, R Kersseboom, GB Piccoli, S Zimmermann, T Fierro, AC Glembotsky, F Vianello, C Zaninetti, E Nicchia, C Güthner, C Baronci, M Seri, PJ Knight, CL Balduini, A Savoia. MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations.. Hum Mutat. 2014a;35:236-47",
"A Pecci, X Ma, A Savoia, RS Adelstein. MYH9: Structure, functions and role of non-muscle myosin IIA in human disease.. Gene. 2018;664:152-167",
"A Pecci, EJ Verver, N Schlegel, P Canzi, CM Boccio, H Platokouki, E Krause, M Benazzo, V Topsakal, A Greinacher. Cochlear implantation is safe and effective in patients with MYH9-related disease.. Orphanet J Rare Dis. 2014b;9:100",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"B Saposnik, S Binard, O Fenneteau, A Nurden, P Nurden, MF Hurtaud-Roux, N Schlegel. French MYH9 networka. Mutation spectrum and genotype-phenotype correlations in a large French cohort of MYH9-related disorders.. Mol Genet Genomic Med. 2014;2:297-312",
"A Savoia, D De Rocco, E Panza, V Bozzi, R Scandellari, G Loffredo, A Mumford, PG Heller, P Noris, MR De Groot, M Giani, P Freddi, F Scognamiglio, S Riondino, N Pujol-Moix, F Fabris, M Seri, CL Balduini, A Pecci. Heavy chain myosin 9-related disease (MYH9-RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder.. Thromb Haemost. 2010;103:826-32",
"S Sivapalaratnam, SK Westbury, JC Stephens, D Greene, K Downes, AM Kelly, C Lentaigne, WJ Astle, EG Huizinga, P Nurden, S Papadia, K Peerlinck, CJ Penkett, DJ Perry, C Roughley, I Simeoni, K Stirrups, DP Hart, RC Tait, AD Mumford, MA Laffan, K Freson, WH Ouwehand, S Kunishima, E Turro. Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia.. Blood. 2017;129:520-4",
"T Sekine, M Konno, S Sasaki, S Moritani, T Miura, WS Wong, H Nishio, T Nishiguchi, MY Ohuchi, S Tsuchiya, T Matsuyama, H Kanegane, K Ida, K Miura, Y Harita, M Hattori, S Horita, T Igarashi, H Saito, S Kunishima. Patients with Epstein-Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease.. Kidney Int. 2010;78:207-14",
"M Seri, A Pecci, F Di Bari, R Cusano, M Savino, E Panza, A Nigro, P Noris, S Gangarossa, B Rocca, P Gresele, N Bizzaro, P Malatesta, PA Koivisto, I Longo, R Musso, C Pecoraro, A Iolascon, U Magrini, J Rodriguez Soriano, A Renieri, GM Ghiggeri, R Ravazzolo, CL Balduini, A Savoia. MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness.. Medicine (Baltimore) 2003;82:203-15",
"P Vassallo, SK Westbury, AD Mumford. FLNA variants associated with disorders of platelet number or function.. Platelets. 2020;31:1097-100",
"E Verver, A Pecci, D De Rocco, S Ryhänen, S Barozzi, H Kunst, V Topsakal, A. Savoia. R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17.. Clin Genet. 2015;88:85-9",
"EJJ Verver, V Topsakal, HPM Kunst, PLM Huygen, PG Heller, N Pujol-Moix, A Savoia, M Benazzo, T Fierro, W Grolman, P Gresele, A Pecci. NMMHC-IIA mutation predicts severity and progression of sensorineural hearing loss in patients with MYH9-related disease.. Ear Hear. 2016;37:112-20",
"C Zaninetti, S Barozzi, V Bozzi, P Gresele, CL Balduini, A Pecci. Eltrombopag in preparation for surgery in patients with severe MYH9-related thrombocytopenia.. Am J Hematol. 2019;94:E199-E201",
"C Zaninetti, P Gresele, A Bertomoro, C Klersy, E De Candia, D Veneri, S Barozzi, T Fierro, MA Alberelli, V Musella, P Noris, F Fabris, CL Balduini, A Pecci. Eltrombopag for the treatment of inherited thrombocytopenias: a phase II clinical trial.. Haematologica. 2020;105:820-8"
] |
20/11/2008
|
18/2/2021
|
25/6/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
myhre
|
myhre
|
[
"Myhre-LAPS Syndrome",
"Laryngotracheal Stenosis, Arthropathy, Prognathism, and Short Stature (LAPS) Syndrome",
"Myhre-LAPS Syndrome",
"Mothers against decapentaplegic homolog 4",
"SMAD4",
"Myhre Syndrome"
] |
Myhre Syndrome
|
Angela E Lin, Nicola Brunetti-Pierri, Mark E Lindsay, Lisa A Schimmenti, Lois J Starr
|
Summary Myhre syndrome is a multisystem progressive connective tissue disorder that often results in significant complications. The highly distinctive (and often severe) findings of joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin usually occur spontaneously. Some proliferation such as abnormal scarring or adhesions may follow trauma, invasive medical procedures, or surgery. Effusions of the heart, airways, lungs, uterus, and peritoneum may occur and can progress to fibrosis. Most affected individuals have characteristic facial features (short palpebral fissures, deeply set eyes, maxillary underdevelopment, short philtrum, thin vermilion of the upper lip, narrow mouth, and prognathism) and developmental delay / cognitive disability, typically in the mild-to-moderate range. Neurobehavioral issues may include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and/or anxiety. Although immunoglobulin (Ig) G and IgA deficiency are rare, affected individuals can experience recurrent infections (including otitis media, sinusitis, mastoiditis, or croup). Hearing loss can progress over time. Growth may be impaired in early life. Most adolescents develop obesity. Eye findings can include refractive errors, astigmatism, corectopia, and optic nerve anomalies. Gastrointestinal (GI) issues may include gastroesophageal reflux disease, constipation, and encopresis. Less commonly, stenosis of the GI tract, Hirschsprung disease, and/or metabolic dysfunction-associated liver disease may be observed. The diagnosis of Myhre syndrome is established in a proband with characteristic clinical findings and a heterozygous (typically recurrent) pathogenic variant in Myhre syndrome is an autosomal dominant disorder typically caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for Myhre syndrome have been published.
Myhre syndrome
Short stature (height is significantly less than predicted mid-parental height) with compact body habitus
Characteristic facial features (See
Conductive and mixed hearing loss
Respiratory difficulties, usually due to restrictive thorax or, infrequently, multilevel airway stenosis (including choanal, subglottic, laryngotracheal, and/or bronchial)
Progressively stiff, thickened skin and subcutaneous tissue
Limited range of motion of the joints with occasional contractures
Effusions involving the heart, airways, lungs, uterus, and peritoneum, which may progress to fibrosis
Mild-to-moderate intellectual disability
Autism spectrum disorder or neurodivergent behaviors
Severe constipation and/or encopresis
Premature puberty
Aortic narrowing, such as typical juxtaductal aortic coarctation, diffuse long-segment aortic hypoplasia, or segmental stenosis (branch arteries)
Congenital heart defects (See
Pericardial involvement ranging from transient effusion to chronic severe constrictive pericarditis
Restrictive cardiomyopathy and diastolic dysfunction
Pulmonary hypertension
Thickened calvarium
Shortened long bones
Enlarged (tall) or flattened (platyspondyly) vertebrae with shortened pedicles
Cervical vertebral fusion
Hypoplastic iliac wings
Absent or extra ribs
Small exostoses and/or enostoses (bone islands)
The diagnosis of Myhre syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and imaging findings suggest the diagnosis of Myhre syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of Myhre syndrome has not been considered, genomic testing may be used.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Myhre Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No exon or whole-gene deletions/duplications have been reported. However, these are not expected to occur since all variants detected so far result in disease by a gain-of-function mechanism (see
• Short stature (height is significantly less than predicted mid-parental height) with compact body habitus
• Characteristic facial features (See
• Conductive and mixed hearing loss
• Respiratory difficulties, usually due to restrictive thorax or, infrequently, multilevel airway stenosis (including choanal, subglottic, laryngotracheal, and/or bronchial)
• Progressively stiff, thickened skin and subcutaneous tissue
• Limited range of motion of the joints with occasional contractures
• Effusions involving the heart, airways, lungs, uterus, and peritoneum, which may progress to fibrosis
• Mild-to-moderate intellectual disability
• Autism spectrum disorder or neurodivergent behaviors
• Severe constipation and/or encopresis
• Premature puberty
•
• Aortic narrowing, such as typical juxtaductal aortic coarctation, diffuse long-segment aortic hypoplasia, or segmental stenosis (branch arteries)
• Congenital heart defects (See
• Pericardial involvement ranging from transient effusion to chronic severe constrictive pericarditis
• Restrictive cardiomyopathy and diastolic dysfunction
• Pulmonary hypertension
• Aortic narrowing, such as typical juxtaductal aortic coarctation, diffuse long-segment aortic hypoplasia, or segmental stenosis (branch arteries)
• Congenital heart defects (See
• Pericardial involvement ranging from transient effusion to chronic severe constrictive pericarditis
• Restrictive cardiomyopathy and diastolic dysfunction
• Pulmonary hypertension
• Thickened calvarium
• Shortened long bones
• Enlarged (tall) or flattened (platyspondyly) vertebrae with shortened pedicles
• Cervical vertebral fusion
• Hypoplastic iliac wings
• Absent or extra ribs
• Small exostoses and/or enostoses (bone islands)
• Thickened calvarium
• Shortened long bones
• Enlarged (tall) or flattened (platyspondyly) vertebrae with shortened pedicles
• Cervical vertebral fusion
• Hypoplastic iliac wings
• Absent or extra ribs
• Small exostoses and/or enostoses (bone islands)
• Aortic narrowing, such as typical juxtaductal aortic coarctation, diffuse long-segment aortic hypoplasia, or segmental stenosis (branch arteries)
• Congenital heart defects (See
• Pericardial involvement ranging from transient effusion to chronic severe constrictive pericarditis
• Restrictive cardiomyopathy and diastolic dysfunction
• Pulmonary hypertension
• Thickened calvarium
• Shortened long bones
• Enlarged (tall) or flattened (platyspondyly) vertebrae with shortened pedicles
• Cervical vertebral fusion
• Hypoplastic iliac wings
• Absent or extra ribs
• Small exostoses and/or enostoses (bone islands)
• For an introduction to multigene panels click
## Suggestive Findings
Myhre syndrome
Short stature (height is significantly less than predicted mid-parental height) with compact body habitus
Characteristic facial features (See
Conductive and mixed hearing loss
Respiratory difficulties, usually due to restrictive thorax or, infrequently, multilevel airway stenosis (including choanal, subglottic, laryngotracheal, and/or bronchial)
Progressively stiff, thickened skin and subcutaneous tissue
Limited range of motion of the joints with occasional contractures
Effusions involving the heart, airways, lungs, uterus, and peritoneum, which may progress to fibrosis
Mild-to-moderate intellectual disability
Autism spectrum disorder or neurodivergent behaviors
Severe constipation and/or encopresis
Premature puberty
Aortic narrowing, such as typical juxtaductal aortic coarctation, diffuse long-segment aortic hypoplasia, or segmental stenosis (branch arteries)
Congenital heart defects (See
Pericardial involvement ranging from transient effusion to chronic severe constrictive pericarditis
Restrictive cardiomyopathy and diastolic dysfunction
Pulmonary hypertension
Thickened calvarium
Shortened long bones
Enlarged (tall) or flattened (platyspondyly) vertebrae with shortened pedicles
Cervical vertebral fusion
Hypoplastic iliac wings
Absent or extra ribs
Small exostoses and/or enostoses (bone islands)
• Short stature (height is significantly less than predicted mid-parental height) with compact body habitus
• Characteristic facial features (See
• Conductive and mixed hearing loss
• Respiratory difficulties, usually due to restrictive thorax or, infrequently, multilevel airway stenosis (including choanal, subglottic, laryngotracheal, and/or bronchial)
• Progressively stiff, thickened skin and subcutaneous tissue
• Limited range of motion of the joints with occasional contractures
• Effusions involving the heart, airways, lungs, uterus, and peritoneum, which may progress to fibrosis
• Mild-to-moderate intellectual disability
• Autism spectrum disorder or neurodivergent behaviors
• Severe constipation and/or encopresis
• Premature puberty
•
• Aortic narrowing, such as typical juxtaductal aortic coarctation, diffuse long-segment aortic hypoplasia, or segmental stenosis (branch arteries)
• Congenital heart defects (See
• Pericardial involvement ranging from transient effusion to chronic severe constrictive pericarditis
• Restrictive cardiomyopathy and diastolic dysfunction
• Pulmonary hypertension
• Aortic narrowing, such as typical juxtaductal aortic coarctation, diffuse long-segment aortic hypoplasia, or segmental stenosis (branch arteries)
• Congenital heart defects (See
• Pericardial involvement ranging from transient effusion to chronic severe constrictive pericarditis
• Restrictive cardiomyopathy and diastolic dysfunction
• Pulmonary hypertension
• Thickened calvarium
• Shortened long bones
• Enlarged (tall) or flattened (platyspondyly) vertebrae with shortened pedicles
• Cervical vertebral fusion
• Hypoplastic iliac wings
• Absent or extra ribs
• Small exostoses and/or enostoses (bone islands)
• Thickened calvarium
• Shortened long bones
• Enlarged (tall) or flattened (platyspondyly) vertebrae with shortened pedicles
• Cervical vertebral fusion
• Hypoplastic iliac wings
• Absent or extra ribs
• Small exostoses and/or enostoses (bone islands)
• Aortic narrowing, such as typical juxtaductal aortic coarctation, diffuse long-segment aortic hypoplasia, or segmental stenosis (branch arteries)
• Congenital heart defects (See
• Pericardial involvement ranging from transient effusion to chronic severe constrictive pericarditis
• Restrictive cardiomyopathy and diastolic dysfunction
• Pulmonary hypertension
• Thickened calvarium
• Shortened long bones
• Enlarged (tall) or flattened (platyspondyly) vertebrae with shortened pedicles
• Cervical vertebral fusion
• Hypoplastic iliac wings
• Absent or extra ribs
• Small exostoses and/or enostoses (bone islands)
## Establishing the Diagnosis
The diagnosis of Myhre syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and imaging findings suggest the diagnosis of Myhre syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of Myhre syndrome has not been considered, genomic testing may be used.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Myhre Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No exon or whole-gene deletions/duplications have been reported. However, these are not expected to occur since all variants detected so far result in disease by a gain-of-function mechanism (see
• For an introduction to multigene panels click
## Option 1
When the phenotypic and imaging findings suggest the diagnosis of Myhre syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of Myhre syndrome has not been considered, genomic testing may be used.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Myhre Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No exon or whole-gene deletions/duplications have been reported. However, these are not expected to occur since all variants detected so far result in disease by a gain-of-function mechanism (see
## Clinical Characteristics
Myhre syndrome is a multisystem progressive connective tissue disorder that often results in significant complications. The highly distinctive (and often severe) findings of joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin may occur spontaneously or following trauma, invasive medical procedures, or surgery. In most, short stature and hearing loss also develop over time.
To date, more than 200 affected individuals with a molecularly confirmed diagnosis of Myhre syndrome have been reported [
Myhre Syndrome: Frequency of Select Features
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HSCR = Hirschsprung disease; Ig = immunoglobulin; VPI = velopharyngeal insufficiency
Length or height that is more than two standard deviations below the mean for age and sex.
Short stature is more common in those whose pathogenic variant involves codon 500 (see
Usually unresponsive to bronchodilator therapy
Typically due to a restrictive thorax
Short palpebral fissures (See
Deeply set eyes
Maxillary underdevelopment
Short philtrum
Narrow mouth
Thin vermilion of the upper lip (See
Small and/or widely spaced teeth
Prognathism
While cleft lip and palate is rare, velopharyngeal insufficiency is common.
Most affected individuals have shortened long bones.
Adult height is expected to be more than two standard deviations below what is predicted by parental heights in more than 80% of affected individuals, particularly in those who have a pathogenic variant at codon position 500 (see
Although head circumference is rarely greater than or equal to two standard deviations above the mean for age and sex, it is commonly proportionally greater than height ("relative macrocephaly").
Although Myhre syndrome-specific growth charts have not been developed, growth is expected to be at the lower end or below the typical growth charts for weight and length/height for infants and children.
Overweight (BMI >25, or >99th centile) may begin in adolescence and is found in most adults.
Choking, coughing, and/or dysphagia
Mild-to-severe constipation
Duodenal atresia
Late-onset and congenital pyloric stenosis; less commonly stenosis may involve the duodenum, jejunum, and anus.
Protein-losing enteropathy associated with right heart failure and restrictive cardiomyopathy (Patient 1 in
Hirschsprung disease
Abnormal liver function tests can suggest a pattern of metabolic dysfunction-associated steatotic liver disease (MASLD); however, this is an emerging observation.
In 47 individuals with confirmed Myhre syndrome evaluated at Massachusetts General Hospital [
Atrial septal defect or ventricular septal defect
Patent ductus arteriosus
Tetralogy of Fallot
Obstructive defects of the left heart, such as juxtaductal aortic coarctation, long-segment aortic narrowing, aortic valve stenosis, mitral valve stenosis, and multiple levels of obstruction. These are more common than obstructive defects of the right side, such as valvar and branch pulmonary artery stenosis.
Visceral vascular stenoses (in celiac, superior mesenteric, inferior mesenteric, and/or renal arteries)
Restrictive cardiomyopathy, a lethal condition, can be difficult to diagnose without cardiac catheterization to assess hemodynamics.
While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamic impairment, they differ in their pathogenesis and treatment (see
Other findings can include the following:
Restrictive pulmonary disease, often associated with restrictive thorax
"Asthma" that does not always respond to bronchodilator therapy, as in typical reactive airway disease
Interstitial lung disease and severe pulmonary fibrosis on autopsy [
Abnormal sleep, most often associated with autism. In some instances, a sleep study may reveal obstructive sleep apnea.
Sleep apnea
Proliferative fibrosis / abnormal scarring can occur following trauma or surgery. Some individuals develop hypertrophic, keloid-like scars. In addition to the skin, proliferation can also involve the large airways (trachea and bronchi) and the serosal surfaces of the heart, lungs, and peritoneum.
Small hands and feet with brachydactyly, found in most individuals (See
Clinodactyly
Syndactyly of the toes, usually 2-3
Scoliosis
Absence of normal lumbar lordosis and straight spine
Sacral dimple, sometimes associated with a tethered spinal cord
Bony fractures, which may be associated with childhood activities and/or trauma
Leg pain involving the calf, which can be severe. Pain is not relieved with standard analgesics and is poorly understood. It can be associated with lower spinal cord compression.
Characteristic radiographic findings in affected individuals are listed in
Hearing loss is predominantly conductive or mixed; affected individuals most often have a history of bilateral myringotomy tube placement.
The underlying etiology of the hearing loss is often unclear or unknown and may require inner ear imaging to diagnose structural anomalies, although this is thought to be rare.
Glucose intolerance in adults may be more common than the few reports of diabetes. One teenage girl had hyperinsulinism and an impaired glucose tolerance test, which may indicate insulin resistance [
Genotype-phenotype correlations are still emerging [
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
LAPS (
The prevalence of Myhre syndrome is unknown. A rough estimate of the prevalence is 1:900,000 individuals.
• Short palpebral fissures (See
• Deeply set eyes
• Maxillary underdevelopment
• Short philtrum
• Narrow mouth
• Thin vermilion of the upper lip (See
• Small and/or widely spaced teeth
• Prognathism
• Most affected individuals have shortened long bones.
• Adult height is expected to be more than two standard deviations below what is predicted by parental heights in more than 80% of affected individuals, particularly in those who have a pathogenic variant at codon position 500 (see
• Although head circumference is rarely greater than or equal to two standard deviations above the mean for age and sex, it is commonly proportionally greater than height ("relative macrocephaly").
• Although Myhre syndrome-specific growth charts have not been developed, growth is expected to be at the lower end or below the typical growth charts for weight and length/height for infants and children.
• Overweight (BMI >25, or >99th centile) may begin in adolescence and is found in most adults.
• Choking, coughing, and/or dysphagia
• Mild-to-severe constipation
• Duodenal atresia
• Late-onset and congenital pyloric stenosis; less commonly stenosis may involve the duodenum, jejunum, and anus.
• Protein-losing enteropathy associated with right heart failure and restrictive cardiomyopathy (Patient 1 in
• Hirschsprung disease
• Abnormal liver function tests can suggest a pattern of metabolic dysfunction-associated steatotic liver disease (MASLD); however, this is an emerging observation.
• Atrial septal defect or ventricular septal defect
• Patent ductus arteriosus
• Tetralogy of Fallot
• Obstructive defects of the left heart, such as juxtaductal aortic coarctation, long-segment aortic narrowing, aortic valve stenosis, mitral valve stenosis, and multiple levels of obstruction. These are more common than obstructive defects of the right side, such as valvar and branch pulmonary artery stenosis.
• Visceral vascular stenoses (in celiac, superior mesenteric, inferior mesenteric, and/or renal arteries)
• Atrial septal defect or ventricular septal defect
• Patent ductus arteriosus
• Tetralogy of Fallot
• Obstructive defects of the left heart, such as juxtaductal aortic coarctation, long-segment aortic narrowing, aortic valve stenosis, mitral valve stenosis, and multiple levels of obstruction. These are more common than obstructive defects of the right side, such as valvar and branch pulmonary artery stenosis.
• Visceral vascular stenoses (in celiac, superior mesenteric, inferior mesenteric, and/or renal arteries)
• Restrictive cardiomyopathy, a lethal condition, can be difficult to diagnose without cardiac catheterization to assess hemodynamics.
• While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamic impairment, they differ in their pathogenesis and treatment (see
• Restrictive cardiomyopathy, a lethal condition, can be difficult to diagnose without cardiac catheterization to assess hemodynamics.
• While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamic impairment, they differ in their pathogenesis and treatment (see
• Atrial septal defect or ventricular septal defect
• Patent ductus arteriosus
• Tetralogy of Fallot
• Obstructive defects of the left heart, such as juxtaductal aortic coarctation, long-segment aortic narrowing, aortic valve stenosis, mitral valve stenosis, and multiple levels of obstruction. These are more common than obstructive defects of the right side, such as valvar and branch pulmonary artery stenosis.
• Visceral vascular stenoses (in celiac, superior mesenteric, inferior mesenteric, and/or renal arteries)
• Restrictive cardiomyopathy, a lethal condition, can be difficult to diagnose without cardiac catheterization to assess hemodynamics.
• While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamic impairment, they differ in their pathogenesis and treatment (see
• Restrictive pulmonary disease, often associated with restrictive thorax
• "Asthma" that does not always respond to bronchodilator therapy, as in typical reactive airway disease
• Interstitial lung disease and severe pulmonary fibrosis on autopsy [
• Abnormal sleep, most often associated with autism. In some instances, a sleep study may reveal obstructive sleep apnea.
• Sleep apnea
• Small hands and feet with brachydactyly, found in most individuals (See
• Clinodactyly
• Syndactyly of the toes, usually 2-3
• Scoliosis
• Absence of normal lumbar lordosis and straight spine
• Sacral dimple, sometimes associated with a tethered spinal cord
• Bony fractures, which may be associated with childhood activities and/or trauma
• Leg pain involving the calf, which can be severe. Pain is not relieved with standard analgesics and is poorly understood. It can be associated with lower spinal cord compression.
• Hearing loss is predominantly conductive or mixed; affected individuals most often have a history of bilateral myringotomy tube placement.
• The underlying etiology of the hearing loss is often unclear or unknown and may require inner ear imaging to diagnose structural anomalies, although this is thought to be rare.
## Clinical Description
Myhre syndrome is a multisystem progressive connective tissue disorder that often results in significant complications. The highly distinctive (and often severe) findings of joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin may occur spontaneously or following trauma, invasive medical procedures, or surgery. In most, short stature and hearing loss also develop over time.
To date, more than 200 affected individuals with a molecularly confirmed diagnosis of Myhre syndrome have been reported [
Myhre Syndrome: Frequency of Select Features
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HSCR = Hirschsprung disease; Ig = immunoglobulin; VPI = velopharyngeal insufficiency
Length or height that is more than two standard deviations below the mean for age and sex.
Short stature is more common in those whose pathogenic variant involves codon 500 (see
Usually unresponsive to bronchodilator therapy
Typically due to a restrictive thorax
Short palpebral fissures (See
Deeply set eyes
Maxillary underdevelopment
Short philtrum
Narrow mouth
Thin vermilion of the upper lip (See
Small and/or widely spaced teeth
Prognathism
While cleft lip and palate is rare, velopharyngeal insufficiency is common.
Most affected individuals have shortened long bones.
Adult height is expected to be more than two standard deviations below what is predicted by parental heights in more than 80% of affected individuals, particularly in those who have a pathogenic variant at codon position 500 (see
Although head circumference is rarely greater than or equal to two standard deviations above the mean for age and sex, it is commonly proportionally greater than height ("relative macrocephaly").
Although Myhre syndrome-specific growth charts have not been developed, growth is expected to be at the lower end or below the typical growth charts for weight and length/height for infants and children.
Overweight (BMI >25, or >99th centile) may begin in adolescence and is found in most adults.
Choking, coughing, and/or dysphagia
Mild-to-severe constipation
Duodenal atresia
Late-onset and congenital pyloric stenosis; less commonly stenosis may involve the duodenum, jejunum, and anus.
Protein-losing enteropathy associated with right heart failure and restrictive cardiomyopathy (Patient 1 in
Hirschsprung disease
Abnormal liver function tests can suggest a pattern of metabolic dysfunction-associated steatotic liver disease (MASLD); however, this is an emerging observation.
In 47 individuals with confirmed Myhre syndrome evaluated at Massachusetts General Hospital [
Atrial septal defect or ventricular septal defect
Patent ductus arteriosus
Tetralogy of Fallot
Obstructive defects of the left heart, such as juxtaductal aortic coarctation, long-segment aortic narrowing, aortic valve stenosis, mitral valve stenosis, and multiple levels of obstruction. These are more common than obstructive defects of the right side, such as valvar and branch pulmonary artery stenosis.
Visceral vascular stenoses (in celiac, superior mesenteric, inferior mesenteric, and/or renal arteries)
Restrictive cardiomyopathy, a lethal condition, can be difficult to diagnose without cardiac catheterization to assess hemodynamics.
While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamic impairment, they differ in their pathogenesis and treatment (see
Other findings can include the following:
Restrictive pulmonary disease, often associated with restrictive thorax
"Asthma" that does not always respond to bronchodilator therapy, as in typical reactive airway disease
Interstitial lung disease and severe pulmonary fibrosis on autopsy [
Abnormal sleep, most often associated with autism. In some instances, a sleep study may reveal obstructive sleep apnea.
Sleep apnea
Proliferative fibrosis / abnormal scarring can occur following trauma or surgery. Some individuals develop hypertrophic, keloid-like scars. In addition to the skin, proliferation can also involve the large airways (trachea and bronchi) and the serosal surfaces of the heart, lungs, and peritoneum.
Small hands and feet with brachydactyly, found in most individuals (See
Clinodactyly
Syndactyly of the toes, usually 2-3
Scoliosis
Absence of normal lumbar lordosis and straight spine
Sacral dimple, sometimes associated with a tethered spinal cord
Bony fractures, which may be associated with childhood activities and/or trauma
Leg pain involving the calf, which can be severe. Pain is not relieved with standard analgesics and is poorly understood. It can be associated with lower spinal cord compression.
Characteristic radiographic findings in affected individuals are listed in
Hearing loss is predominantly conductive or mixed; affected individuals most often have a history of bilateral myringotomy tube placement.
The underlying etiology of the hearing loss is often unclear or unknown and may require inner ear imaging to diagnose structural anomalies, although this is thought to be rare.
Glucose intolerance in adults may be more common than the few reports of diabetes. One teenage girl had hyperinsulinism and an impaired glucose tolerance test, which may indicate insulin resistance [
• Short palpebral fissures (See
• Deeply set eyes
• Maxillary underdevelopment
• Short philtrum
• Narrow mouth
• Thin vermilion of the upper lip (See
• Small and/or widely spaced teeth
• Prognathism
• Most affected individuals have shortened long bones.
• Adult height is expected to be more than two standard deviations below what is predicted by parental heights in more than 80% of affected individuals, particularly in those who have a pathogenic variant at codon position 500 (see
• Although head circumference is rarely greater than or equal to two standard deviations above the mean for age and sex, it is commonly proportionally greater than height ("relative macrocephaly").
• Although Myhre syndrome-specific growth charts have not been developed, growth is expected to be at the lower end or below the typical growth charts for weight and length/height for infants and children.
• Overweight (BMI >25, or >99th centile) may begin in adolescence and is found in most adults.
• Choking, coughing, and/or dysphagia
• Mild-to-severe constipation
• Duodenal atresia
• Late-onset and congenital pyloric stenosis; less commonly stenosis may involve the duodenum, jejunum, and anus.
• Protein-losing enteropathy associated with right heart failure and restrictive cardiomyopathy (Patient 1 in
• Hirschsprung disease
• Abnormal liver function tests can suggest a pattern of metabolic dysfunction-associated steatotic liver disease (MASLD); however, this is an emerging observation.
• Atrial septal defect or ventricular septal defect
• Patent ductus arteriosus
• Tetralogy of Fallot
• Obstructive defects of the left heart, such as juxtaductal aortic coarctation, long-segment aortic narrowing, aortic valve stenosis, mitral valve stenosis, and multiple levels of obstruction. These are more common than obstructive defects of the right side, such as valvar and branch pulmonary artery stenosis.
• Visceral vascular stenoses (in celiac, superior mesenteric, inferior mesenteric, and/or renal arteries)
• Atrial septal defect or ventricular septal defect
• Patent ductus arteriosus
• Tetralogy of Fallot
• Obstructive defects of the left heart, such as juxtaductal aortic coarctation, long-segment aortic narrowing, aortic valve stenosis, mitral valve stenosis, and multiple levels of obstruction. These are more common than obstructive defects of the right side, such as valvar and branch pulmonary artery stenosis.
• Visceral vascular stenoses (in celiac, superior mesenteric, inferior mesenteric, and/or renal arteries)
• Restrictive cardiomyopathy, a lethal condition, can be difficult to diagnose without cardiac catheterization to assess hemodynamics.
• While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamic impairment, they differ in their pathogenesis and treatment (see
• Restrictive cardiomyopathy, a lethal condition, can be difficult to diagnose without cardiac catheterization to assess hemodynamics.
• While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamic impairment, they differ in their pathogenesis and treatment (see
• Atrial septal defect or ventricular septal defect
• Patent ductus arteriosus
• Tetralogy of Fallot
• Obstructive defects of the left heart, such as juxtaductal aortic coarctation, long-segment aortic narrowing, aortic valve stenosis, mitral valve stenosis, and multiple levels of obstruction. These are more common than obstructive defects of the right side, such as valvar and branch pulmonary artery stenosis.
• Visceral vascular stenoses (in celiac, superior mesenteric, inferior mesenteric, and/or renal arteries)
• Restrictive cardiomyopathy, a lethal condition, can be difficult to diagnose without cardiac catheterization to assess hemodynamics.
• While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamic impairment, they differ in their pathogenesis and treatment (see
• Restrictive pulmonary disease, often associated with restrictive thorax
• "Asthma" that does not always respond to bronchodilator therapy, as in typical reactive airway disease
• Interstitial lung disease and severe pulmonary fibrosis on autopsy [
• Abnormal sleep, most often associated with autism. In some instances, a sleep study may reveal obstructive sleep apnea.
• Sleep apnea
• Small hands and feet with brachydactyly, found in most individuals (See
• Clinodactyly
• Syndactyly of the toes, usually 2-3
• Scoliosis
• Absence of normal lumbar lordosis and straight spine
• Sacral dimple, sometimes associated with a tethered spinal cord
• Bony fractures, which may be associated with childhood activities and/or trauma
• Leg pain involving the calf, which can be severe. Pain is not relieved with standard analgesics and is poorly understood. It can be associated with lower spinal cord compression.
• Hearing loss is predominantly conductive or mixed; affected individuals most often have a history of bilateral myringotomy tube placement.
• The underlying etiology of the hearing loss is often unclear or unknown and may require inner ear imaging to diagnose structural anomalies, although this is thought to be rare.
## Genotype-Phenotype Correlations
Genotype-phenotype correlations are still emerging [
## Nomenclature
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
LAPS (
## Prevalence
The prevalence of Myhre syndrome is unknown. A rough estimate of the prevalence is 1:900,000 individuals.
## Genetically Related (Allelic) Disorders
Other phenotypes known to be associated with germline pathogenic variants in
AD = autosomal dominant; MOI = mode of inheritance
Hereditary hemorrhagic telangiectasia (HHT) and Myhre syndrome have opposing phenotypes consistent with
## Differential Diagnosis
The disorders that most closely resemble Myhre syndrome are the other acromelic dysplasias – geleophysic dysplasia, acromicric dysplasia, and Weill-Marchesani syndrome – which share the findings of thickened skin, short stature, short hands, and stiff joints [
Disorders of Interest in the Differential Diagnosis of Myhre Syndrome
IUGR
Short stature
Brachydactyly
Joint stiffness
Distinctive lens abnormalities
No hearing loss
IUGR
Short stature
Short hands & feet
Progressive joint limitation & contractures
Progressive cardiac valvar thickening
Thickened skin
Hepatomegaly
Distinctive facial features
Delayed bone age
IUGR
Short stature
Brachydactyly
Joint stiffness
Thickened skin
Characteristic external notch of 5th metacarpal & internal notch of femoral head
No hearing loss
Less frequent congenital cardiac anomalies
No calvarial thickening
Stiff skin
Stiff joints
Skin has rock-hard involvement.
Not dysmorphic
Few cardiovascular features
No calvarial thickening
IUGR
Short stature
Relatively large head
Constrictive pericarditis
Restrictive cardiomyopathy
Hearing loss
Shorter stature
Small tongue
No calvarial thickening
AD = autosomal dominant; AR = autosomal recessive; IUGR = intrauterine growth restriction; MOI = mode of inheritance
The ocular manifestations of Weill-Marchesani syndrome, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness.
Major findings are likely to be present in the first year of life. Cardiac, airway, and pulmonary involvement result in death before age five years in approximately 33% of individuals with geleophysic dysplasia.
• IUGR
• Short stature
• Brachydactyly
• Joint stiffness
• Distinctive lens abnormalities
• No hearing loss
• IUGR
• Short stature
• Short hands & feet
• Progressive joint limitation & contractures
• Progressive cardiac valvar thickening
• Thickened skin
• Hepatomegaly
• Distinctive facial features
• Delayed bone age
• IUGR
• Short stature
• Brachydactyly
• Joint stiffness
• Thickened skin
• Characteristic external notch of 5th metacarpal & internal notch of femoral head
• No hearing loss
• Less frequent congenital cardiac anomalies
• No calvarial thickening
• Stiff skin
• Stiff joints
• Skin has rock-hard involvement.
• Not dysmorphic
• Few cardiovascular features
• No calvarial thickening
• IUGR
• Short stature
• Relatively large head
• Constrictive pericarditis
• Restrictive cardiomyopathy
• Hearing loss
• Shorter stature
• Small tongue
• No calvarial thickening
## Management
Although formal evidence-based clinical management guidelines for Myhre syndrome have not yet been published, expert consensus recommendations provide pragmatic clinical guidance (Table 5 in
To establish the extent of disease and needs in an individual diagnosed with Myhre syndrome, the evaluations summarized in
Myhre Syndrome: Recommended Evaluations Following Initial Diagnosis
Physical exam for evidence of cleft lip & palate
Assessment for velopharyngeal insufficiency
To incl motor, adaptive, cognitive, & speech-language evals
Eval for early intervention / special education, ABA therapy
To assess for aortic obstruction & systemic hypertension
Consider referral to nephrologist for those w/systemic hypertension.
In children who are able to complete procedure w/o anesthesia (age 5-10 yrs) or if there is hypertension
Cardiac catheterization may be indicated to document characteristic hemodynamics of restrictive cardiomyopathy & pulmonary hypertension.
Gross motor & fine motor skills
↓ range of motion of joints (OT modifications may be indicated.)
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To assess for strabismus, refractive error, & cataracts
Give special attention to optic nerve.
Assess for degree & type of hearing loss.
Newborn hearing screen may be normal; low threshold for repeat testing.
Consider inner ear imaging for those w/hearing loss.
Obtain baseline serum laboratory tests.
Consider standard coagulation tests.
Evaluate cardiovascular hemodynamics under care of cardiologist & liver specialist.
Consider referral to GI specialist.
Assess need for social work involvement for parental support.
Consider palliative care counseling to support family & affected person when there are serious complications (e.g., cardiopulmonary, airway, or neoplastic involvement).
ABA = applied behavior analysis; ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; GI = gastrointestinal; MOI = mode of inheritance; MRA = magnetic resonance angiography; OT = occupational therapy; PT = physical therapy
When a person is old enough to cooperate with this evaluation.
Intestinal obstruction may contribute to constipation.
Hirschsprung disease has been reported.
Basic chemistry and liver function tests (AST, ALT, etc.), with consideration of adding albumin and total protein in those who have protein-losing enteropathy
Consider obtaining a hemoglobin A1c in those with suggestive signs/symptoms or as a baseline in adolescents and adults.
Which could suggest endometrial cancer
Consider obtaining kidney function tests, such as electrolytes, blood urea nitrogen, creatinine, and cystatin C in those with hypertension or renal artery stenosis.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for Myhre syndrome. Supportive care to improve quality of life, maximize function, and reduce complications is recommended, ideally involving multidisciplinary care by specialists in relevant fields (see
Myhre Syndrome: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Avoid any unnecessary instrumentation, as assoc tissue trauma may induce stenosis & scarring-type tissue response.
Affected persons who are in heart failure should be under care of cardiovascular specialist w/access to transplant center. Cardiac & lung transplantation are assoc w/high risk of mortality.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Minimal instrumentation of GI tract is advised because postoperative adhesions can be fatal.
Approach endoscopy w/caution to avoid airway manipulation, which ↑ risk for tracheal/laryngeal scarring/stenosis.
Noninvasive 3D imaging may be preferred.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
CPAP = continuous positive airway pressure; BiPAP = bilevel positive airway pressure; GI = gastrointestinal; IVIG = intravenous immunoglobulin; PT = physical therapy
Growth hormone therapy is not endorsed because its anabolic action may interact with the activating
All individuals with Myhre syndrome should be under the care of a cardiologist.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g. contractures).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Limiting tissue trauma appears to be the single most important preventive measure. When possible, alternative noninvasive approaches should be pursued during diagnosis and management [
Extreme care with intubation and use of an endotracheal tube without a cuff (or careful monitoring of pressures with a cuff) may help prevent airway stenosis [
Minimize abdominal and pelvic procedures as extensive adhesions may develop postoperatively [
Hysterectomy should be an option of last resort for treatment of menorrhagia as postsurgical fibrosis can occur.
Recognize risk of thickened scars or keloids with ear or other piercings.
Use of orthodontic braces may stimulate gum hypertrophy.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Myhre Syndrome: Recommended Surveillance
Monitor for evidence of respiratory insufficiency & obtain pulse oxygen measurement.
Evaluate for signs/symptoms of upper airway stenosis & sleep apnea.
Low threshold for fasting blood sugar & hemoglobin A1c to assess for diabetes mellitus
Periodic DXA scan to assess bone mineral density
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DXA = dual-energy x-ray absorptiometry; GI = gastrointestinal; MRA = magnetic resonance angiography; OT = occupational therapy; PT = physical therapy
Note that pericardial effusion and restrictive cardiomyopathy may occur at any age and may be clinically asymptomatic [
The decision to use CT angiogram or MRA depends on the age and behavior of individual, the imaging center, and the availability of supportive services ("Child Life") to accomplish without anesthesia.
The exact frequency is based on the presence and degree of aortic disease.
These findings are more common in those with the
Vaccines are endorsed.
Affected individuals should be aggressively counseled not to smoke.
Limiting tissue trauma (injury) appears to be the single most important preventive concept in this disorder to communicate to all health care providers involved in an individual's care (see
Elective tracheal surgery/intubation should be avoided when possible. Tracheal resection is contraindicated.
Growth hormone therapy is
See
The antihypertensive drug losartan is an angiotensin II type 1 receptor blocker. Through this mechanism, it also indirectly antagonizes transforming growth factor beta (TGF-β) signaling. In Myhre syndrome fibroblasts, losartan corrected an extracellular matrix deposition defect [
Search
• Physical exam for evidence of cleft lip & palate
• Assessment for velopharyngeal insufficiency
• To incl motor, adaptive, cognitive, & speech-language evals
• Eval for early intervention / special education, ABA therapy
• To assess for aortic obstruction & systemic hypertension
• Consider referral to nephrologist for those w/systemic hypertension.
• In children who are able to complete procedure w/o anesthesia (age 5-10 yrs) or if there is hypertension
• Cardiac catheterization may be indicated to document characteristic hemodynamics of restrictive cardiomyopathy & pulmonary hypertension.
• Gross motor & fine motor skills
• ↓ range of motion of joints (OT modifications may be indicated.)
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To assess for strabismus, refractive error, & cataracts
• Give special attention to optic nerve.
• Assess for degree & type of hearing loss.
• Newborn hearing screen may be normal; low threshold for repeat testing.
• Consider inner ear imaging for those w/hearing loss.
• Obtain baseline serum laboratory tests.
• Consider standard coagulation tests.
• Evaluate cardiovascular hemodynamics under care of cardiologist & liver specialist.
• Consider referral to GI specialist.
• Assess need for social work involvement for parental support.
• Consider palliative care counseling to support family & affected person when there are serious complications (e.g., cardiopulmonary, airway, or neoplastic involvement).
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Avoid any unnecessary instrumentation, as assoc tissue trauma may induce stenosis & scarring-type tissue response.
• Affected persons who are in heart failure should be under care of cardiovascular specialist w/access to transplant center. Cardiac & lung transplantation are assoc w/high risk of mortality.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Minimal instrumentation of GI tract is advised because postoperative adhesions can be fatal.
• Approach endoscopy w/caution to avoid airway manipulation, which ↑ risk for tracheal/laryngeal scarring/stenosis.
• Noninvasive 3D imaging may be preferred.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g. contractures).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Extreme care with intubation and use of an endotracheal tube without a cuff (or careful monitoring of pressures with a cuff) may help prevent airway stenosis [
• Minimize abdominal and pelvic procedures as extensive adhesions may develop postoperatively [
• Hysterectomy should be an option of last resort for treatment of menorrhagia as postsurgical fibrosis can occur.
• Recognize risk of thickened scars or keloids with ear or other piercings.
• Use of orthodontic braces may stimulate gum hypertrophy.
• Monitor for evidence of respiratory insufficiency & obtain pulse oxygen measurement.
• Evaluate for signs/symptoms of upper airway stenosis & sleep apnea.
• Low threshold for fasting blood sugar & hemoglobin A1c to assess for diabetes mellitus
• Periodic DXA scan to assess bone mineral density
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Myhre syndrome, the evaluations summarized in
Myhre Syndrome: Recommended Evaluations Following Initial Diagnosis
Physical exam for evidence of cleft lip & palate
Assessment for velopharyngeal insufficiency
To incl motor, adaptive, cognitive, & speech-language evals
Eval for early intervention / special education, ABA therapy
To assess for aortic obstruction & systemic hypertension
Consider referral to nephrologist for those w/systemic hypertension.
In children who are able to complete procedure w/o anesthesia (age 5-10 yrs) or if there is hypertension
Cardiac catheterization may be indicated to document characteristic hemodynamics of restrictive cardiomyopathy & pulmonary hypertension.
Gross motor & fine motor skills
↓ range of motion of joints (OT modifications may be indicated.)
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To assess for strabismus, refractive error, & cataracts
Give special attention to optic nerve.
Assess for degree & type of hearing loss.
Newborn hearing screen may be normal; low threshold for repeat testing.
Consider inner ear imaging for those w/hearing loss.
Obtain baseline serum laboratory tests.
Consider standard coagulation tests.
Evaluate cardiovascular hemodynamics under care of cardiologist & liver specialist.
Consider referral to GI specialist.
Assess need for social work involvement for parental support.
Consider palliative care counseling to support family & affected person when there are serious complications (e.g., cardiopulmonary, airway, or neoplastic involvement).
ABA = applied behavior analysis; ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; GI = gastrointestinal; MOI = mode of inheritance; MRA = magnetic resonance angiography; OT = occupational therapy; PT = physical therapy
When a person is old enough to cooperate with this evaluation.
Intestinal obstruction may contribute to constipation.
Hirschsprung disease has been reported.
Basic chemistry and liver function tests (AST, ALT, etc.), with consideration of adding albumin and total protein in those who have protein-losing enteropathy
Consider obtaining a hemoglobin A1c in those with suggestive signs/symptoms or as a baseline in adolescents and adults.
Which could suggest endometrial cancer
Consider obtaining kidney function tests, such as electrolytes, blood urea nitrogen, creatinine, and cystatin C in those with hypertension or renal artery stenosis.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Physical exam for evidence of cleft lip & palate
• Assessment for velopharyngeal insufficiency
• To incl motor, adaptive, cognitive, & speech-language evals
• Eval for early intervention / special education, ABA therapy
• To assess for aortic obstruction & systemic hypertension
• Consider referral to nephrologist for those w/systemic hypertension.
• In children who are able to complete procedure w/o anesthesia (age 5-10 yrs) or if there is hypertension
• Cardiac catheterization may be indicated to document characteristic hemodynamics of restrictive cardiomyopathy & pulmonary hypertension.
• Gross motor & fine motor skills
• ↓ range of motion of joints (OT modifications may be indicated.)
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To assess for strabismus, refractive error, & cataracts
• Give special attention to optic nerve.
• Assess for degree & type of hearing loss.
• Newborn hearing screen may be normal; low threshold for repeat testing.
• Consider inner ear imaging for those w/hearing loss.
• Obtain baseline serum laboratory tests.
• Consider standard coagulation tests.
• Evaluate cardiovascular hemodynamics under care of cardiologist & liver specialist.
• Consider referral to GI specialist.
• Assess need for social work involvement for parental support.
• Consider palliative care counseling to support family & affected person when there are serious complications (e.g., cardiopulmonary, airway, or neoplastic involvement).
## Treatment of Manifestations
There is no cure for Myhre syndrome. Supportive care to improve quality of life, maximize function, and reduce complications is recommended, ideally involving multidisciplinary care by specialists in relevant fields (see
Myhre Syndrome: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Avoid any unnecessary instrumentation, as assoc tissue trauma may induce stenosis & scarring-type tissue response.
Affected persons who are in heart failure should be under care of cardiovascular specialist w/access to transplant center. Cardiac & lung transplantation are assoc w/high risk of mortality.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Minimal instrumentation of GI tract is advised because postoperative adhesions can be fatal.
Approach endoscopy w/caution to avoid airway manipulation, which ↑ risk for tracheal/laryngeal scarring/stenosis.
Noninvasive 3D imaging may be preferred.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
CPAP = continuous positive airway pressure; BiPAP = bilevel positive airway pressure; GI = gastrointestinal; IVIG = intravenous immunoglobulin; PT = physical therapy
Growth hormone therapy is not endorsed because its anabolic action may interact with the activating
All individuals with Myhre syndrome should be under the care of a cardiologist.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g. contractures).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Avoid any unnecessary instrumentation, as assoc tissue trauma may induce stenosis & scarring-type tissue response.
• Affected persons who are in heart failure should be under care of cardiovascular specialist w/access to transplant center. Cardiac & lung transplantation are assoc w/high risk of mortality.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Minimal instrumentation of GI tract is advised because postoperative adhesions can be fatal.
• Approach endoscopy w/caution to avoid airway manipulation, which ↑ risk for tracheal/laryngeal scarring/stenosis.
• Noninvasive 3D imaging may be preferred.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g. contractures).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g. contractures).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g. contractures).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
## Prevention of Secondary Complications
Limiting tissue trauma appears to be the single most important preventive measure. When possible, alternative noninvasive approaches should be pursued during diagnosis and management [
Extreme care with intubation and use of an endotracheal tube without a cuff (or careful monitoring of pressures with a cuff) may help prevent airway stenosis [
Minimize abdominal and pelvic procedures as extensive adhesions may develop postoperatively [
Hysterectomy should be an option of last resort for treatment of menorrhagia as postsurgical fibrosis can occur.
Recognize risk of thickened scars or keloids with ear or other piercings.
Use of orthodontic braces may stimulate gum hypertrophy.
• Extreme care with intubation and use of an endotracheal tube without a cuff (or careful monitoring of pressures with a cuff) may help prevent airway stenosis [
• Minimize abdominal and pelvic procedures as extensive adhesions may develop postoperatively [
• Hysterectomy should be an option of last resort for treatment of menorrhagia as postsurgical fibrosis can occur.
• Recognize risk of thickened scars or keloids with ear or other piercings.
• Use of orthodontic braces may stimulate gum hypertrophy.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Myhre Syndrome: Recommended Surveillance
Monitor for evidence of respiratory insufficiency & obtain pulse oxygen measurement.
Evaluate for signs/symptoms of upper airway stenosis & sleep apnea.
Low threshold for fasting blood sugar & hemoglobin A1c to assess for diabetes mellitus
Periodic DXA scan to assess bone mineral density
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DXA = dual-energy x-ray absorptiometry; GI = gastrointestinal; MRA = magnetic resonance angiography; OT = occupational therapy; PT = physical therapy
Note that pericardial effusion and restrictive cardiomyopathy may occur at any age and may be clinically asymptomatic [
The decision to use CT angiogram or MRA depends on the age and behavior of individual, the imaging center, and the availability of supportive services ("Child Life") to accomplish without anesthesia.
The exact frequency is based on the presence and degree of aortic disease.
These findings are more common in those with the
Vaccines are endorsed.
• Monitor for evidence of respiratory insufficiency & obtain pulse oxygen measurement.
• Evaluate for signs/symptoms of upper airway stenosis & sleep apnea.
• Low threshold for fasting blood sugar & hemoglobin A1c to assess for diabetes mellitus
• Periodic DXA scan to assess bone mineral density
## Agents/Circumstances to Avoid
Affected individuals should be aggressively counseled not to smoke.
Limiting tissue trauma (injury) appears to be the single most important preventive concept in this disorder to communicate to all health care providers involved in an individual's care (see
Elective tracheal surgery/intubation should be avoided when possible. Tracheal resection is contraindicated.
Growth hormone therapy is
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
The antihypertensive drug losartan is an angiotensin II type 1 receptor blocker. Through this mechanism, it also indirectly antagonizes transforming growth factor beta (TGF-β) signaling. In Myhre syndrome fibroblasts, losartan corrected an extracellular matrix deposition defect [
Search
## Genetic Counseling
Myhre syndrome is an autosomal dominant disorder typically caused by a
Most individuals diagnosed with Myhre syndrome have the disorder as the result of a
A few individuals diagnosed with Myhre syndrome have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the
If the parents have not been tested for the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Once the
Note: Severe features (e.g., tetralogy of Fallot with pulmonary atresia, severe growth restriction) have been reported in prenatally diagnosed fetuses not known to be at increased risk of Myhre syndrome [
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with Myhre syndrome have the disorder as the result of a
• A few individuals diagnosed with Myhre syndrome have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
Myhre syndrome is an autosomal dominant disorder typically caused by a
## Risk to Family Members
Most individuals diagnosed with Myhre syndrome have the disorder as the result of a
A few individuals diagnosed with Myhre syndrome have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the
If the parents have not been tested for the
• Most individuals diagnosed with Myhre syndrome have the disorder as the result of a
• A few individuals diagnosed with Myhre syndrome have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Note: Severe features (e.g., tetralogy of Fallot with pulmonary atresia, severe growth restriction) have been reported in prenatally diagnosed fetuses not known to be at increased risk of Myhre syndrome [
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
## Molecular Genetics
Myhre Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Myhre Syndrome (
In contrast, heterozygous
Persons w/this variant are typically not as short in stature.
3 affected women w/this variant developed endometrial cancer [
Highly recurrent pathogenic variant
This variant may be assoc w/↑ risk for pre- & postnatal growth deficiency.
Variants listed in the table have been provided by the authors.
It remains unclear if this specific pathogenic variant is associated with an increased risk of developing neoplasia (see
Note that somatic inactivation of
• Persons w/this variant are typically not as short in stature.
• 3 affected women w/this variant developed endometrial cancer [
• Highly recurrent pathogenic variant
• This variant may be assoc w/↑ risk for pre- & postnatal growth deficiency.
## Molecular Pathogenesis
In contrast, heterozygous
Persons w/this variant are typically not as short in stature.
3 affected women w/this variant developed endometrial cancer [
Highly recurrent pathogenic variant
This variant may be assoc w/↑ risk for pre- & postnatal growth deficiency.
Variants listed in the table have been provided by the authors.
It remains unclear if this specific pathogenic variant is associated with an increased risk of developing neoplasia (see
Note that somatic inactivation of
• Persons w/this variant are typically not as short in stature.
• 3 affected women w/this variant developed endometrial cancer [
• Highly recurrent pathogenic variant
• This variant may be assoc w/↑ risk for pre- & postnatal growth deficiency.
## Chapter Notes
The authors are indebted to the people living with Myhre syndrome and their families who have provided consent, motivation, contributions, and advocacy.
Nicola Brunetti-Pierri, MD (2022-present)Angela E Lin, MD (2017-present)Noralane M Lindor, MD; Mayo Clinic (2017-2022)Mark E Lindsay, MD, PhD (2022-present)Lisa A Schimmenti, MD (2022-present)Lois J Starr, MD, PhD (2017-present)
12 December 2024 (ma) Comprehensive update posted live
24 November 2022 (ma) Comprehensive update posted live
13 April 2017 (bp) Review posted live
11 July 2016 (ljs) Original submission
• 12 December 2024 (ma) Comprehensive update posted live
• 24 November 2022 (ma) Comprehensive update posted live
• 13 April 2017 (bp) Review posted live
• 11 July 2016 (ljs) Original submission
## Author Notes
## Acknowledgments
The authors are indebted to the people living with Myhre syndrome and their families who have provided consent, motivation, contributions, and advocacy.
## Author History
Nicola Brunetti-Pierri, MD (2022-present)Angela E Lin, MD (2017-present)Noralane M Lindor, MD; Mayo Clinic (2017-2022)Mark E Lindsay, MD, PhD (2022-present)Lisa A Schimmenti, MD (2022-present)Lois J Starr, MD, PhD (2017-present)
## Revision History
12 December 2024 (ma) Comprehensive update posted live
24 November 2022 (ma) Comprehensive update posted live
13 April 2017 (bp) Review posted live
11 July 2016 (ljs) Original submission
• 12 December 2024 (ma) Comprehensive update posted live
• 24 November 2022 (ma) Comprehensive update posted live
• 13 April 2017 (bp) Review posted live
• 11 July 2016 (ljs) Original submission
## References
## Literature Cited
The same female with Myhre syndrome at ages seven months, four years, and 16 years (lateral and frontal views). Note the short palpebral fissures, thin vermilion of the upper lip, and maxillary underdevelopment. She required tracheostomy at age 13 years for complete tracheal stenosis, attributed in part to traumatic intubations.
Reported as Patient 5 in
The same female with Myhre syndrome as a newborn and at ages 12 months, 3.5 years, and seven years. Note the mild left-sided facial asymmetry (7th cranial nerve palsy), short palpebral fissures, thin vermilion of the upper lip, and progression of mild prognathism.
Reported as Patient 1 in
Male with Myhre syndrome at age 12 years with mild facial features (mild maxillary underdevelopment and thin vermilion of the upper lip) and finger contractures.
Reported as Patient 4 in
Female with Myhre syndrome at age five years. Note the short palpebral fissures, thin vermilion of the upper and lower lips, left-sided facial palsy, and brachydactyly, with otherwise mild features.
Reported by
The same male with Myhre syndrome at various ages from toddlerhood (lower right corner) to age 19 years (upper left corner).
Two different women with Myhre syndrome at ages 40 years (A) and 50 years (B). The women are shown together in C.
Radiographs of a female with Myhre syndrome at age 14 years
A. Lateral cervical spine shows thickened calvaria and anterior cervical vertebral fusion (arrow) of C2 and C3.
B. Chest radiograph shows broad ribs and vertebrae, and 11 rib pairs.
|
[] |
13/4/2017
|
12/12/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
myo-dystonia
|
myo-dystonia
|
[
"Dystonia 11 (DYT11)",
"DYT-SGCE",
"Dystonia 11 (DYT11)",
"DYT-SGCE",
"Epsilon-sarcoglycan",
"SGCE",
"SGCE Myoclonus-Dystonia"
] |
Deborah Raymond, Rachel Saunders-Pullman, Laurie Ozelius
|
Summary The diagnosis of
|
## Diagnosis
Myoclonus isolated or predominating over dystonia
Prominence of the motor manifestations in the upper body
Absence of truncal dystonia
Positive family history
Onset before age 18 years
Obsessive-compulsive disorder, anxiety-related disorder, or alcohol dependence
Spontaneous remission of limb dystonia during childhood or adolescence
Alcohol responsiveness
Other neurologic manifestation in addition to myoclonus and/or dystonia (except seizures, which may be present in some individuals with
Abnormal brain MRI examination
Neurophysiologic findings that do not support the diagnosis (defined as muscle contractions shorter than 300 ms that can occur in body parts not affected by dystonia)
The diagnosis of
Note: (1)
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Myoclonus isolated or predominating over dystonia
• Prominence of the motor manifestations in the upper body
• Absence of truncal dystonia
• Positive family history
• Onset before age 18 years
• Obsessive-compulsive disorder, anxiety-related disorder, or alcohol dependence
• Spontaneous remission of limb dystonia during childhood or adolescence
• Alcohol responsiveness
• Other neurologic manifestation in addition to myoclonus and/or dystonia (except seizures, which may be present in some individuals with
• Abnormal brain MRI examination
• Neurophysiologic findings that do not support the diagnosis (defined as muscle contractions shorter than 300 ms that can occur in body parts not affected by dystonia)
• For an introduction to multigene panels click
## Suggestive Findings
Myoclonus isolated or predominating over dystonia
Prominence of the motor manifestations in the upper body
Absence of truncal dystonia
Positive family history
Onset before age 18 years
Obsessive-compulsive disorder, anxiety-related disorder, or alcohol dependence
Spontaneous remission of limb dystonia during childhood or adolescence
Alcohol responsiveness
Other neurologic manifestation in addition to myoclonus and/or dystonia (except seizures, which may be present in some individuals with
Abnormal brain MRI examination
Neurophysiologic findings that do not support the diagnosis (defined as muscle contractions shorter than 300 ms that can occur in body parts not affected by dystonia)
• Myoclonus isolated or predominating over dystonia
• Prominence of the motor manifestations in the upper body
• Absence of truncal dystonia
• Positive family history
• Onset before age 18 years
• Obsessive-compulsive disorder, anxiety-related disorder, or alcohol dependence
• Spontaneous remission of limb dystonia during childhood or adolescence
• Alcohol responsiveness
• Other neurologic manifestation in addition to myoclonus and/or dystonia (except seizures, which may be present in some individuals with
• Abnormal brain MRI examination
• Neurophysiologic findings that do not support the diagnosis (defined as muscle contractions shorter than 300 ms that can occur in body parts not affected by dystonia)
## Establishing the Diagnosis
The diagnosis of
Note: (1)
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Clinical Characteristics
While most affected adults report a dramatic response of myoclonus to ingestion of alcohol [
The myoclonic jerks typical of
Approximately half of affected individuals (54%) have focal or segmental dystonia that manifests as cervical dystonia and/or writer's cramp [
The involuntary movements are frequently precipitated or worsened by active movements of the affected body parts. Other factors eliciting or enhancing the movements include stress [
Tremor (postural or other) may be a feature in a subset of individuals [
Psychiatric comorbidities have been reported. One systematic analysis of 307 participants with pathogenic variants in
Other neurologic signs and symptoms including dementia and ataxia are rare in
Although spontaneous remission of
Multiple studies support a different disease mechanism for
No genotype-phenotype correlations have been identified.
Reduced penetrance on maternal transmission of the disease allele has been observed, suggesting that maternal genomic imprinting of
Consistent with this hypothesis, two studies demonstrated both paternal transmission of an
Because about 5% of affected individuals inherit the
"Myoclonus-dystonia" is the term used for individuals with an
Little is known about the prevalence of
• Consistent with this hypothesis, two studies demonstrated both paternal transmission of an
• Because about 5% of affected individuals inherit the
## Clinical Description
While most affected adults report a dramatic response of myoclonus to ingestion of alcohol [
The myoclonic jerks typical of
Approximately half of affected individuals (54%) have focal or segmental dystonia that manifests as cervical dystonia and/or writer's cramp [
The involuntary movements are frequently precipitated or worsened by active movements of the affected body parts. Other factors eliciting or enhancing the movements include stress [
Tremor (postural or other) may be a feature in a subset of individuals [
Psychiatric comorbidities have been reported. One systematic analysis of 307 participants with pathogenic variants in
Other neurologic signs and symptoms including dementia and ataxia are rare in
Although spontaneous remission of
Multiple studies support a different disease mechanism for
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
Reduced penetrance on maternal transmission of the disease allele has been observed, suggesting that maternal genomic imprinting of
Consistent with this hypothesis, two studies demonstrated both paternal transmission of an
Because about 5% of affected individuals inherit the
• Consistent with this hypothesis, two studies demonstrated both paternal transmission of an
• Because about 5% of affected individuals inherit the
## Nomenclature
"Myoclonus-dystonia" is the term used for individuals with an
## Prevalence
Little is known about the prevalence of
## Genetically Related (Allelic) Disorders
No other phenotype is known to be associated with intragenic pathogenic variants in
One additional individual with M-D, language delay, dysmorphic features, and a seemingly balanced
## Differential Diagnosis
Myoclonic dystonia 26 (OMIM
Other Genes of Interest in the Differential Diagnosis of
Possible cause of isolated M-D
Often childhood onset
Observed in Mennonite families of Russian origin
High cancer frequency & adverse responses to chemotherapeutic agents assoc w/a common
Ataxia
Progressive intellectual deterioration
Ataxia
Choreoathetosis
Dementia or character changes
Biochemical findings: ↓ serum copper & ceruloplasmin concentrations; ↑ urinary copper excretion
Kayser-Fleischer corneal ring
Ataxia, incoordination, intentional tremor, & dysarthria
Emotional lability, depression, & mild ↓ in intellectual performance over time
↑ frequency & intractability of seizures
Cognitive decline apparent at or soon after onset of seizures
Dysarthria & ataxia appear early; spasticity appears late.
Dramatic & sustained response to levodopa
Typically presents w/gait disturbance, later development of parkinsonism, & diurnal fluctuation of symptoms
Mild ID
Limited upgaze, hypotonia, & OCD
Notable DD & growth delay, seizures, hypotonia, abnormal MRI
Other symptoms may incl genitourinary & gastrointestinal abnormality, vision, hearing, cardiac, & hematologic abnormalities.
Seemingly typical adult-onset M-D reported in 3 families & 2 simplex cases
Alcohol responsiveness & psychiatric comorbidities (5 persons)
Mean onset: age 22 yrs
Latest onset: age 53 yrs
1st symptoms incl progressive ataxia, clumsiness of hands, loss of proprioception, & areflexia.
Cerebellar atrophy
Mild cognitive impairment & skeletal anomalies
Asymmetric pachygyria & dysmorphic basal ganglia on neuroimaging
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnoisis; ID = intellectual disability; Mat = maternal inheritance; M-D = myoclonus-dystonia; MOI = mode of inheritance; OCD = obsessive-compulsive disorder
Because of the association of hypothyroidism with pathogenic variants in
A male with alcohol-responsive M-D who had the typical three-base pair deletion in
For a review of various genetic and secondary forms of dystonia, see
• Possible cause of isolated M-D
• Often childhood onset
• Observed in Mennonite families of Russian origin
• High cancer frequency & adverse responses to chemotherapeutic agents assoc w/a common
• Ataxia
• Progressive intellectual deterioration
• Ataxia
• Choreoathetosis
• Dementia or character changes
• Biochemical findings: ↓ serum copper & ceruloplasmin concentrations; ↑ urinary copper excretion
• Kayser-Fleischer corneal ring
• Ataxia, incoordination, intentional tremor, & dysarthria
• Emotional lability, depression, & mild ↓ in intellectual performance over time
• ↑ frequency & intractability of seizures
• Cognitive decline apparent at or soon after onset of seizures
• Dysarthria & ataxia appear early; spasticity appears late.
• Dramatic & sustained response to levodopa
• Typically presents w/gait disturbance, later development of parkinsonism, & diurnal fluctuation of symptoms
• Mild ID
• Limited upgaze, hypotonia, & OCD
• Notable DD & growth delay, seizures, hypotonia, abnormal MRI
• Other symptoms may incl genitourinary & gastrointestinal abnormality, vision, hearing, cardiac, & hematologic abnormalities.
• Seemingly typical adult-onset M-D reported in 3 families & 2 simplex cases
• Alcohol responsiveness & psychiatric comorbidities (5 persons)
• Mean onset: age 22 yrs
• Latest onset: age 53 yrs
• 1st symptoms incl progressive ataxia, clumsiness of hands, loss of proprioception, & areflexia.
• Cerebellar atrophy
• Mild cognitive impairment & skeletal anomalies
• Asymmetric pachygyria & dysmorphic basal ganglia on neuroimaging
## Management
To establish the extent of disease and needs of an individual diagnosed with
Clinical examination to evaluate the location, severity, and progression of dystonia and the severity and progression of myoclonus. This is best done by a neurologic specialist in movement disorders.
Consultation with a clinical geneticist and/or genetic counselor.
While multiple anti-seizure medications have been reported in case series or individual reports, zonisamide is the first to demonstrate class I evidence of improvement of both myoclonus and dystonia in a double-blind study [
Valproate and levetiracetam may also be used. Topiramate and carbamazepine have been reported to improve myoclonus [
Benzodiazepines, particularly clonazepam, improve mostly myoclonus and tremor [
Anticholinergic medication may improve dystonia [
Improvement of dystonia with L-5-hydroxytryptophan has been reported [
Improvement with both L-dopa [
One individual with
Gamma-hydroxybutyrate [
Note: Although the symptoms of
Stereotactic thalamotomy can improve myoclonus, but caused dysarthria in one individual and mild hemiparesis in another [
As self-treatment with alcohol is common, proper treatment and counseling regarding alcohol abuse may decrease alcohol-related toxicities, particularly in adolescents.
Recommended Surveillance for Individuals with Myoclonus-Dystonia
Use of alcohol to ameliorate symptoms should be avoided due to the risk of alcohol dependence.
See
There is concern about teratogenicity with certain anti-seizure medications that are sometimes used in the treatment of myoclonus-dystonia. These should be avoided in women considering pregnancy or who are known to be pregnant. Discussion of the risks and benefits of using a given anti-seizure drug during pregnancy should ideally take place prior to conception. Women with M-D should be counseled about abstaining from alcohol during pregnancy, particularly during the first trimester, as alcohol negatively affects fetal development.
See
Search
• Clinical examination to evaluate the location, severity, and progression of dystonia and the severity and progression of myoclonus. This is best done by a neurologic specialist in movement disorders.
• Consultation with a clinical geneticist and/or genetic counselor.
• While multiple anti-seizure medications have been reported in case series or individual reports, zonisamide is the first to demonstrate class I evidence of improvement of both myoclonus and dystonia in a double-blind study [
• Valproate and levetiracetam may also be used. Topiramate and carbamazepine have been reported to improve myoclonus [
• Benzodiazepines, particularly clonazepam, improve mostly myoclonus and tremor [
• Anticholinergic medication may improve dystonia [
• Improvement of dystonia with L-5-hydroxytryptophan has been reported [
• Improvement with both L-dopa [
• One individual with
• Gamma-hydroxybutyrate [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with
Clinical examination to evaluate the location, severity, and progression of dystonia and the severity and progression of myoclonus. This is best done by a neurologic specialist in movement disorders.
Consultation with a clinical geneticist and/or genetic counselor.
• Clinical examination to evaluate the location, severity, and progression of dystonia and the severity and progression of myoclonus. This is best done by a neurologic specialist in movement disorders.
• Consultation with a clinical geneticist and/or genetic counselor.
## Treatment of Manifestations
While multiple anti-seizure medications have been reported in case series or individual reports, zonisamide is the first to demonstrate class I evidence of improvement of both myoclonus and dystonia in a double-blind study [
Valproate and levetiracetam may also be used. Topiramate and carbamazepine have been reported to improve myoclonus [
Benzodiazepines, particularly clonazepam, improve mostly myoclonus and tremor [
Anticholinergic medication may improve dystonia [
Improvement of dystonia with L-5-hydroxytryptophan has been reported [
Improvement with both L-dopa [
One individual with
Gamma-hydroxybutyrate [
Note: Although the symptoms of
Stereotactic thalamotomy can improve myoclonus, but caused dysarthria in one individual and mild hemiparesis in another [
• While multiple anti-seizure medications have been reported in case series or individual reports, zonisamide is the first to demonstrate class I evidence of improvement of both myoclonus and dystonia in a double-blind study [
• Valproate and levetiracetam may also be used. Topiramate and carbamazepine have been reported to improve myoclonus [
• Benzodiazepines, particularly clonazepam, improve mostly myoclonus and tremor [
• Anticholinergic medication may improve dystonia [
• Improvement of dystonia with L-5-hydroxytryptophan has been reported [
• Improvement with both L-dopa [
• One individual with
• Gamma-hydroxybutyrate [
## Prevention of Secondary Complications
As self-treatment with alcohol is common, proper treatment and counseling regarding alcohol abuse may decrease alcohol-related toxicities, particularly in adolescents.
## Surveillance
Recommended Surveillance for Individuals with Myoclonus-Dystonia
## Agents/Circumstances to Avoid
Use of alcohol to ameliorate symptoms should be avoided due to the risk of alcohol dependence.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
There is concern about teratogenicity with certain anti-seizure medications that are sometimes used in the treatment of myoclonus-dystonia. These should be avoided in women considering pregnancy or who are known to be pregnant. Discussion of the risks and benefits of using a given anti-seizure drug during pregnancy should ideally take place prior to conception. Women with M-D should be counseled about abstaining from alcohol during pregnancy, particularly during the first trimester, as alcohol negatively affects fetal development.
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most individuals diagnosed with
A proband with M-D may have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). Since the
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
Although most individuals diagnosed with M-D inherited the pathogenic allele from a parent, the family history may appear to be negative because of either the effects of imprinting or failure to recognize the disorder in family members. Since it is possible for affected family members to self-medicate with alcohol, a family history of alcoholism may be indicative of additional affected relatives. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected, the risk to the sibs of inheriting the pathogenic allele is 50%. Expression of the pathogenic
If the
If the
Because of intrafamilial clinical variability, symptomatic sibs may be more or less severely affected than the proband and have different M-D-related findings.
If the proband has a known
If the parents have not been tested for the
If the proband is male, it is likely that all of his children who inherit the pathogenic variant will develop symptoms.
If the proband is female, about 5% of her children who inherit the pathogenic variant will develop symptoms.
Symptomatic offspring of a proband may be more or less severely affected than the proband.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with
• A proband with M-D may have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). Since the
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• Although most individuals diagnosed with M-D inherited the pathogenic allele from a parent, the family history may appear to be negative because of either the effects of imprinting or failure to recognize the disorder in family members. Since it is possible for affected family members to self-medicate with alcohol, a family history of alcoholism may be indicative of additional affected relatives. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected, the risk to the sibs of inheriting the pathogenic allele is 50%. Expression of the pathogenic
• If the
• If the
• If the
• If the
• Because of intrafamilial clinical variability, symptomatic sibs may be more or less severely affected than the proband and have different M-D-related findings.
• If the proband has a known
• If the parents have not been tested for the
• If the
• If the
• If the proband is male, it is likely that all of his children who inherit the pathogenic variant will develop symptoms.
• If the proband is female, about 5% of her children who inherit the pathogenic variant will develop symptoms.
• Symptomatic offspring of a proband may be more or less severely affected than the proband.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
## Risk to Family Members
Most individuals diagnosed with
A proband with M-D may have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). Since the
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
Although most individuals diagnosed with M-D inherited the pathogenic allele from a parent, the family history may appear to be negative because of either the effects of imprinting or failure to recognize the disorder in family members. Since it is possible for affected family members to self-medicate with alcohol, a family history of alcoholism may be indicative of additional affected relatives. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected, the risk to the sibs of inheriting the pathogenic allele is 50%. Expression of the pathogenic
If the
If the
Because of intrafamilial clinical variability, symptomatic sibs may be more or less severely affected than the proband and have different M-D-related findings.
If the proband has a known
If the parents have not been tested for the
If the proband is male, it is likely that all of his children who inherit the pathogenic variant will develop symptoms.
If the proband is female, about 5% of her children who inherit the pathogenic variant will develop symptoms.
Symptomatic offspring of a proband may be more or less severely affected than the proband.
• Most individuals diagnosed with
• A proband with M-D may have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). Since the
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• Although most individuals diagnosed with M-D inherited the pathogenic allele from a parent, the family history may appear to be negative because of either the effects of imprinting or failure to recognize the disorder in family members. Since it is possible for affected family members to self-medicate with alcohol, a family history of alcoholism may be indicative of additional affected relatives. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected, the risk to the sibs of inheriting the pathogenic allele is 50%. Expression of the pathogenic
• If the
• If the
• If the
• If the
• Because of intrafamilial clinical variability, symptomatic sibs may be more or less severely affected than the proband and have different M-D-related findings.
• If the proband has a known
• If the parents have not been tested for the
• If the
• If the
• If the proband is male, it is likely that all of his children who inherit the pathogenic variant will develop symptoms.
• If the proband is female, about 5% of her children who inherit the pathogenic variant will develop symptoms.
• Symptomatic offspring of a proband may be more or less severely affected than the proband.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
PO Box 5801
Bethesda MD 20824
Dystonia Medical Research Foundation
•
•
•
• United Kingdom
•
•
• PO Box 5801
• Bethesda MD 20824
•
•
• Dystonia Medical Research Foundation
•
## Molecular Genetics
SGCE Myoclonus-Dystonia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SGCE Myoclonus-Dystonia (
The sarcoglycan gene family includes alpha, beta, gamma, delta, epsilon, and zeta sarcoglycans. In muscles, these genes encode transmembrane components of the dystrophin-glycoprotein complex, which link the cytoskeleton to the extracellular matrix.
More than 100 pathogenic variants in
Gene deletions in
Of note, while only about 50% of individuals with clinical features of M-D are found to have a pathogenic variant in
## References
## Literature Cited
## Chapter Notes
4 June 2020 (cm) Revision: revised information on
8 August 2019 (sw) Comprehensive update posted live
26 January 2012 (me) Comprehensive update posted live
19 December 2005 (me) Comprehensive update posted live
11 June 2004 (ljo/cd) Revision: testing
21 May 2003 (me) Review posted live
5 May 2003 (ljo) Original submission
• 4 June 2020 (cm) Revision: revised information on
• 8 August 2019 (sw) Comprehensive update posted live
• 26 January 2012 (me) Comprehensive update posted live
• 19 December 2005 (me) Comprehensive update posted live
• 11 June 2004 (ljo/cd) Revision: testing
• 21 May 2003 (me) Review posted live
• 5 May 2003 (ljo) Original submission
## Revision History
4 June 2020 (cm) Revision: revised information on
8 August 2019 (sw) Comprehensive update posted live
26 January 2012 (me) Comprehensive update posted live
19 December 2005 (me) Comprehensive update posted live
11 June 2004 (ljo/cd) Revision: testing
21 May 2003 (me) Review posted live
5 May 2003 (ljo) Original submission
• 4 June 2020 (cm) Revision: revised information on
• 8 August 2019 (sw) Comprehensive update posted live
• 26 January 2012 (me) Comprehensive update posted live
• 19 December 2005 (me) Comprehensive update posted live
• 11 June 2004 (ljo/cd) Revision: testing
• 21 May 2003 (me) Review posted live
• 5 May 2003 (ljo) Original submission
|
[
"F Asmus, LE Hjermind, E Dupont, J Wagenstaller, E Haberlandt, M Munz, TM Strom, T Gasser. Genomic deletion size at the epsilon-sarcoglycan locus determines the clinical phenotype.. Brain. 2007;130:2736-45",
"F Asmus, F Salih, LE Hjermind, K Ostergaard, M Munz, AA Kühn, E Dupont, A Kupsch, T Gasser. Myoclonus-dystonia due to genomic deletions in the epsilon-sarcoglycan gene.. Ann Neurol. 2005;58:792-7",
"F Asmus, A Zimprich, M Naumann, D Berg, M Bertram, A Ceballos-Baumann, R Pruszak-Seel, C Kabus, M Dichgans, S Fuchs, B Muller-Myhsok, T Gasser. Inherited myoclonus-dystonia syndrome: narrowing the 7q21-q31 locus in German families.. Ann Neurol 2001;49:121-4",
"F Asmus, A Zimprich, S Tezenas Du Montcel, C Kabus, G Deuschl, A Kupsch, U Ziemann, M Castro, AA Kuhn, TM Strom, M Vidailhet, KP Bhatia, A Durr, NW Wood, A Brice, T Gasser. Myoclonus-dystonia syndrome: epsilon-sarcoglycan mutations and phenotype.. Ann Neurol 2002;52:489-92",
"A Berardelli, A Curra. Pathophysiology and treatment of cranial dystonia.. Mov Disord. 2002;17:S70-4",
"C Bonnet, MJ Grégoire, M Vibert, E Raffo, B Leheup, P Jonveaux. Cryptic 7q21 and 9p23 deletions in a patient with apparently balanced de novo reciprocal translocation t(7;9)(q21;p23) associated with a dystonia-plus syndrome: paternal deletion of the epsilon-sarcoglycan (SGCE) gene.. J Hum Genet. 2008;53:876-85",
"V Borges, C Aguiar Pde, HB Ferraz, LJ Ozelius. Novel and de novo mutations of the SGCE gene in Brazilian patients with myoclonus-dystonia.. Mov Disord. 2007;22:1208-9",
"SB Bressman, C Sabatti, D Raymond, D de Leon, C Klein, PL Kramer, MF Brin, S Fahn, X Breakefield, LJ Ozelius, NJ Risch. The DYT1 phenotype and guidelines for diagnostic testing.. Neurology 2000;54:1746-52",
"M Carecchio, M Magliozzi, M Copetti, A Ferraris, L Bernardini, M Bonetti, G Defazio, MJ Edwards, I Torrente, F Pellegrini, C Comi, KP Bhatia, EM Valente. Defining the epsilon-sarcoglycan (SGCE) gene phenotypic signature in myoclonus-dystonia: a reappraisal of genetic testing criteria.. Mov Disord. 2013;28:787-94",
"DH Chen, A Méneret, JR Friedman, O Korvatska, A Gad, ES Bonkowski, HA Stessman, D Doummar, C Mignot, M Anheim, S Bernes, MY Davis, N Damon-Perrière, B Degos, D Grabli, D Gras, FM Hisama, KM Mackenzie, PD Swanson, C Tranchant, M Vidailhet, S Winesett, O Trouillard, LM Amendola, MO Dorschner, M Weiss, EE Eichler, A Torkamani, E Roze, TD Bird, WH Raskind. ADCY5-related dyskinesia: broader spectrum and genotype-phenotype correlations.. Neurology. 2015;85:2026-35",
"RC Dale, JJ Nasti, GB Peters. Familial 7q21.3 microdeletion involving epsilon-sarcoglycan causing myoclonus dystonia, cognitive impairment, and psychosis.. Mov Disord. 2011;26:1774-5",
"RJ DeBerardinis, D Conforto, K Russell, J Kaplan, PR Kollros, EH Zackai, BS Emanuel. Myoclonus in a patient with a deletion of the epsilon-sarcoglycan locus on chromosome 7q21.. Am J Med Genet 2003;121A:31-6",
"DO Doheny, MF Brin, CE Morrison, CJ Smith, RH Walker, S Abbasi, B Muller, J Garrels, L Liu, P De Carvalho Aguiar, K Schilling, P Kramer, D De Leon, D Raymond, R Saunders-Pullman, C Klein, SB Bressman, B Schmand, MA Tijssen, LJ Ozelius, JM Silverman. Phenotypic features of myoclonus-dystonia in three kindreds.. Neurology 2002;59:1187-96",
"AG Douglas, G Andreoletti, K Talbot, SR Hammans, J Singh, A Whitney, S Ennis, NC Foulds. ADCY5-related dyskinesia presenting as familial myoclonus-dystonia.. Neurogenetics. 2017;18:111-7",
"AJ Ettinger, G Feng, JR Sanes. Epsilon-sarcoglycan, a broadly expressed homologue of the gene mutated in limb-girdle muscular dystrophy 2D.. J Biol Chem 1997;272:32534-8",
"EM Foncke, RJ Beukers, CC Tijssen, JH Koelman, MA Tijssen. Myoclonus-dystonia and spinocerebellar ataxia type 14 presenting with similar phenotypes: trunk tremor, myoclonus, and dystonia.. Parkinsonism Relat Disord. 2010;16:288-9",
"EM Foncke, C Klein, JH Koelman, PL Kramer, K Schilling, B Muller, J Garrels, P de Carvalho Aguiar, L Liu, A de Froe, JD Speelman, LJ Ozelius, MA Tijssen. Hereditary myoclonus-dystonia associated with epilepsy.. Neurology 2003;60:1988-90",
"SJ Frucht, Y Bordelon, WH Houghton, D Reardan. A pilot tolerability and efficacy trial of sodium oxybate in ethanol-responsive movement disorders.. Mov Disord 2005;20:1330-7",
"T Gasser. Inherited myoclonus-dystonia syndrome.. Adv Neurol 1998;78:325-34",
"T Gasser, B Bereznai, B Muller, R Pruszak-Seel, R Damrich, G Deuschl, WH Oertel. Linkage studies in alcohol-responsive myoclonic dystonia.. Mov Disord 1996;11:363-70",
"JT Geiger, AB Schindler, C Blauwendraat, HS Singer, SW Scholz. TUBB2B mutation in an adult patient with myoclonus-dystonia.. Case Rep Neurol. 2017;9:216-21",
"MC Gerrits, EM Foncke, JH Koelman, MA Tijssen. Pediatric writer's cramp in myoclonus-dystonia: maternal imprinting hides positive family history.. Eur J Paediatr Neurol. 2009;13:178-80",
"CG Goetz, SS Horn. Treatment of tremor and dystonia.. Neurol Clin 2001;19:129-44",
"M Grabowski, A Zimprich, B Lorenz-Depiereux, V Kalscheuer, F Asmus, T Gasser, T Meitinger, TM Strom. The epsilon-sarcoglycan gene (SGCE), mutated in myoclonus-dystonia syndrome, is maternally imprinted.. Eur J Hum Genet. 2003;11:138-44",
"F Graziola, F Stregapede, L Travaglini, G Garone, M Verardo, L Bosco, S Pro, E Bertini, P Curatolo, F Vigevano, A Capuano. A novel KCTD17 mutation is associated with childhood early-onset hyperkinetic movement disorder.. Parkinsonism Relat Disord. 2019;61:4-6",
"DA Grimes, F Han, AE Lang, P St George-Hyssop, L Racacho, DE Bulman. A novel locus for inherited myoclonus-dystonia on 18p11.. Neurology 2002;59:1183-6",
"JL Groen, K Ritz, H Jalalzadeh, SM van der Salm, A Jongejan, OR Mook, MA Haagmans, AH Zwinderman, MM Motazacker, RC Hennekam, F Baas, MA Tijssen. RELN rare variants in myoclonus-dystonia.. Mov Disord. 2015;30:415-9",
"A Grünewald, A Djarmati, K Lohmann-Hedrich, K Farrell, JA Zeller, N Allert, F Papengut, B Petersen, V Fung, CM Sue, D O'Sullivan, N Mahant, A Kupsch, RS Chuang, K Wiegers, H Pawlack, J Hagenah, LJ Ozelius, U Stephani, R Schuit, AE Lang, J Volkmann, A Münchau, C Klein. Myoclonus-dystonia: significance of large SGCE deletions.. Hum Mutat. 2008;29:331-2",
"E Guettard, MF Portnoi, K Lohmann-Hedrich, B Keren, S Rossignol, S Winkler, I El Kamel, S Leu, E Apartis, M Vidailhet, C Klein, E Roze. Myoclonus-dystonia due to maternal uniparental disomy.. Arch Neurol. 2008;65:1380-5",
"E Hainque, M Vidailhet, N Cozic, F Charbonnier-Beaupel, S Thobois, C Tranchant, V Brochard, G Glibert, S Drapier, E Mutez, A Doe De Maindreville, T Lebouvier, C Hubsch, B Degos, C Bonnet, D Grabli, AP Legrand, A Méneret, JP Azulay, A Bissery, N Zahr, F Clot, A Mallet, S Dupont, E Apartis, JC Corvol, E Roze. A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia.. Neurology. 2016;86:1729-35",
"F Han, AE Lang, L Racacho, DE Bulman, DA Grimes. Mutations in the epsilon-sarcoglycan gene found to be uncommon in seven myoclonus-dystonia families.. Neurology 2003;61:244-6",
"F Han, L Racacho, AE Lang, DE Bulman, DA Grimes. Refinement of the DYT15 locus in myoclonus dystonia.. Mov Disord. 2007;22:888-92",
"K Haugarvoll, C Tzoulis, GT Tran, B Karlsen, BA Engelsen, PM Knappskog, LA Bindoff. Myoclonus-dystonia and epilepsy in a family with a novel epsilon-sarcoglycan mutation.. J Neurol. 2014;261:358-62",
"K Hedrich, EM Meyer, B Schule, N Kock, P de Carvalho Aguiar, K Wiegers, JH Koelman, J Garrels, R Durr, L Liu, E Schwinger, LJ Ozelius, B Landwehrmeyer, AJ Stoessl, MA Tijssen, C Klein. Myoclonus-dystonia: detection of novel, recurrent, and de novo SGCE mutations.. Neurology 2004;62:1229-31",
"P Hemati, A Revah-Politi, H Bassan, S Petrovski, CG Bilancia, K Ramsey, NG Griffin, L Bier, MT Cho, M Rosello, SA Lynch, S Colombo, A Weber, M Haug, EL Heinzen, TT Sands, V Narayanan, M Primiano, VS Aggarwal, F Millan, SG Sattler-Holtrop, A Caro-Llopis, N Pillar, J Baker, R Freedman, HY Kroes, S Sacharow, N Stong, P Lapunzina, MC Schneider, NJ Mendelsohn, A Singleton, V Loik Ramey, K Wou, A Kuzminsky, S Monfort, M Weiss, S Doyle, A Iglesias, F Martinez, F Mckenzie, C Orellana, KLI van Gassen, M Palomares, L Bazak, A Lee, A Bircher, L Basel-Vanagaite, M Hafström, G Houge. C4RCD Research Group; DDD study, Goldstein DB, Anyane-Yeboa K. Refining the phenotype associated with GNB1 mutations: clinical data on 18 newly identified patients and review of the literature.. Am J Med Genet A. 2018;176:2259-75",
"LE Hjermind, LM Werdelin, H Eiberg, B Krag-Olsen, E Dupont, SA Sorensen. A novel mutation in the epsilon-sarcoglycan gene causing myoclonus-dystonia syndrome.. Neurology 2003;60:1536-9",
"HF Jones, H Morales-Briceno, K Barwick. Myoclonus-dystonia caused by GNB1 mutation responsive to deep brain stimulation.. Mov Disord. 2019;34:1079-80",
"C Klein, L Liu, D Doheny, N Kock, B Muller, P de Carvalho Aguiar, J Leung, D de Leon, SB Bressman, J Silverman, C Smith, F Danisi, C Morrison, RH Walker, M Velickovic, E Schwinger, PL Kramer, XO Breakefield, MF Brin, LJ Ozelius. Epsilon-sarcoglycan mutations found in combination with other dystonia gene mutations.. Ann Neurol 2002;52:675-9",
"N Kock, M Kasten, B Schule, K Hedrich, K Wiegers, K Kabakci, J Hagenah, PP Pramstaller, MF Nitschke, A Munchau, J Sperner, C Klein. Clinical and genetic features of myoclonus-dystonia in 3 cases: a video presentation.. Mov Disord 2004;19:231-4",
"Z Kosutzka, S Tisch, C Bonnet, M Ruiz, E Hainque, ML Welter, F Viallet, C Karachi, S Navarro, M Jahanshahi, S Rivaud-Pechoux, D Grabli, E Roze, M Vidailhet. Long-term GPi-DBS improves motor features in myoclonus-dystonia and enhances social adjustment.. Mov Disord. 2019;34:87-94",
"M Kyllerman, L Forsgren, G Sanner, G Holmgren, J Wahlstrom, U Drugge. Alcohol-responsive myoclonic dystonia in a large family: dominant inheritance and phenotypic variation.. Mov Disord 1990;5:270-9",
"AE Lang. Essential myoclonus and myoclonic dystonia.. Mov Disord 1997;12:127",
"V Leuzzi, C Carducci, C Carducci, F Cardona, C Artiola, I Antonozzi. Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome.. Neurology 2002;59:1241-3",
"A Levy, AE Lang. Ataxia-telangiectasia: a review of movement disorders, clinical features, and genotype correlations.. Mov Disord. 2018;33:1238-47",
"K Lohmann, I Masuho, DN Patil, H Baumann, E Hebert, S Steinrücke, D Trujillano, NK Skamangas, V Dobricic, I Hüning, G Gillessen-Kaesbach, A Westenberger, D Savic-Pavicevic, A Münchau, G Oprea, C Klein, A Rolfs, KA Martemyanov. Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans.. Hum Mol Genet. 2017;26:1078-86",
"AY Luciano, HA Jinnah, RF Pfeiffer, DD Truong, MA Nance, MS LeDoux. Treatment of myoclonus-dystonia syndrome with tetrabenazine. Parkinsonism Relat Disord 2014;20:1423-6",
"MS Luciano, L Ozelius, K Sims, D Raymond, L Liu, R Saunders-Pullman. Responsiveness to levodopa in epsilon-sarcoglycan deletions.. Mov Disord. 2009;24:425-8",
"A Marcé-Grau, M Correa, MI Vanegas, T Muñoz-Ruiz, S Ferrer-Aparicio, H Baide, A Macaya, B Pérez-Dueñas. Childhood onset progressive myoclonic dystonia due to a de novo KCTD17 splicing mutation.. Parkinsonism Relat Disord. 2019;61:7-9",
"L Maréchal, G Raux, C Dumanchin, G Lefebvre, E Deslandre, C Girard, D Campion, D Parain, T Frebourg, D Hannequin. Severe myoclonus-dystonia syndrome associated with a novel epsilon-sarcoglycan gene truncating mutation.. Am J Med Genet 2003;119B:114-7",
"EM McNally, CT Ly, LM Kunkel. Human epsilon-sarcoglycan is highly related to alpha-sarcoglycan (adhalin), the limb girdle muscular dystrophy 2D gene.. FEBS Lett 1998;422:27-32",
"NE Mencacci, I Rubio-Agusti, A Zdebik, F Asmus, MH Ludtmann, M Ryten, V Plagnol, AK Hauser, S Bandres-Ciga, C Bettencourt, P Forabosco, D Hughes, MM Soutar, K Peall, HR Morris, D Trabzuni, M Tekman, HC Stanescu, R Kleta, M Carecchio, G Zorzi, N Nardocci, B Garavaglia, E Lohmann, A Weissbach, C Klein, J Hardy, AM Pittman, T Foltynie, AY Abramov, T Gasser, KP Bhatia, NW Wood. A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia.. Am J Hum Genet. 2015;96:938-47",
"B Müller, K Hedrich, N Kock, N Dragasevic, M Svetel, J Garrels, O Landt, M Nitschke, PP Pramstaller, W Reik, E Schwinger, J Sperner, L Ozelius, V Kostic, C Klein. Evidence that paternal expression of the epsilon-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia.. Am J Hum Genet 2002;71:1303-11",
"TG Nygaard, D Raymond, C Chen, I Nishino, PE Greene, D Jennings, GA Heiman, C Klein, RJ Saunders-Pullman, P Kramer, LJ Ozelius, SB Bressman. Localization of a gene for myoclonus-dystonia to chromosome 7q21-q31.. Ann Neurol 1999;46:794-8",
"S O'Riordan, LJ Ozelius, P de Carvalho Aguiar, M Hutchinson, M King, T Lynch. Inherited myoclonus-dystonia and epilepsy: further evidence of an association?. Mov Disord. 2004;19:1456-9",
"IS Park, JS Kim, JY An, YI Kim, KS Lee. Excellent response to oral zolpidem in a sporadic case of the myoclonus dystonia syndrome.. Mov Disord. 2009;24:2172-3",
"KJ Peall, JM Dijk, R Saunders-Pullman, YE Dreissen, I van Loon, D Cath, MA Kurian, MJ Owen, EM Foncke, HR Morris, T Gasser, S Bressman, F Asmus, MA Tijssen. Psychiatric disorders, myoclonus dystonia and SGCE: an international study.. Ann Clin Transl Neurol. 2015;3:4-11",
"KJ Peall, MA Kurian, M Wardle, AJ Waite, T Hedderly, JP Lin, M Smith, A Whone, H Pall, C White, A Lux, PE Jardine, B Lynch, G Kirov, S O'Riordan, M Samuel, T Lynch, MD King, PF Chinnery, TT Warner, DJ Blake, MJ Owen, HR Morris. SGCE and myoclonus dystonia: motor characteristics, diagnostic criteria and clinical predictors of genotype.. J Neurol. 2014;261:2296-304",
"S Petrovski, S Küry, CT Myers, K Anyane-Yeboa, B Cogné, M Bialer, F Xia, P Hemati, J Riviello, M Mehaffey, T Besnard, E Becraft, A Wadley, AR Politi, S Colombo, X Zhu, Z Ren, I Andrews, T Dudding-Byth, AL Schneider, G Wallace, ABI Rosen, S Schelley, GM Enns, P Corre, J Dalton, S Mercier, X Latypova, S Schmitt, E Guzman, C Moore, L Bier, EL Heinzen, P Karachunski, N Shur, T Grebe, A Basinger, JM Nguyen, S Bézieau, K Wierenga, JA Bernstein, IE Scheffer, JA Rosenfeld, HC Mefford, B Isidor, DB Goldstein. Germline de novo mutations in GNB1 cause severe neurodevelopmental disability, hypotonia, and seizures.. Am J Hum Genet 2016;98:1001-10",
"A Priori, L Bertolasi, A Pesenti, A Cappellari, S Barbieri. Gamma-hydroxybutyric acid for alcohol-sensitive myoclonus with dystonia.. Neurology 2000;54:1706",
"T Popa, P Milani, A Richard, C Hubsch, V Brochard, C Tranchant, A Sadnicka, J Rothwell, M Vidailhet, S Meunier, E Roze. The neurophysiological features of myoclonus-dystonia and differentiation from other dystonias.. JAMA Neurol. 2014;71:612-9",
"NP Quinn. Essential myoclonus and myoclonic dystonia.. Mov Disord 1996;11:119-24",
"NP Quinn, JC Rothwell, PD Thompson, CD Marsden. Hereditary myoclonic dystonia, hereditary torsion dystonia and hereditary essential myoclonus: an area of confusion.. Adv Neurol 1988;50:391-401",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"D Raymond, R Saunders-Pullman, P de Carvalho Aguiar, B Schule, N Kock, J Friedman, J Harris, B Ford, S Frucht, GA Heiman, D Jennings, D Doheny, MF Brin, D de Leon Brin, T Multhaupt-Buell, AE Lang, R Kurlan, C Klein, L Ozelius, S Bressman. Phenotypic spectrum and sex effects in eleven myoclonus-dystonia families with epsilon-sarcoglycan mutations.. Mov Disord. 2008;23:588-92",
"K Ritz, MC Gerrits, EM Foncke, F van Ruissen, C van der Linden, MD Vergouwen, BR Bloem, W Vandenberghe, R Crols, JD Speelman, F Baas, MA Tijssen. Myoclonus-dystonia: clinical and genetic evaluation of a large cohort.. J Neurol Neurosurg Psychiatry. 2009;80:653-8",
"K Ritz, BD van Schaik, ME Jakobs, AH van Kampen, E Aronica, MA Tijssen, F Baas. SGCE isoform characterization and expression in human brain: implications for myoclonus-dystonia pathogenesis?. Eur J Hum Genet. 2011;19:438-44",
"E Roze, E Apartis, F Clot, N Dorison, S Thobois, L Guyant-Marechal, C Tranchant, P Damier, D Doummar, N Bahi-Buisson, N André-Obadia, D Maltete, A Echaniz-Laguna, Y Pereon, Y Beaugendre, S Dupont, T De Greslan, CP Jedynak, G Ponsot, JC Dussaule, A Brice, A Dürr, M Vidailhet. Myoclonus-dystonia: clinical and electrophysiologic pattern related to SGCE mutations.. Neurology. 2008;70:1010-6",
"E Roze, AE Lang, M Vidailhet. Myoclonus-dystonia: classification, phenomenology, pathogenesis, and treatment.. Curr Opin Neurol. 2018;31:484-90",
"E Roze, M Vidailhet, C Hubsch, S Navarro, D Grabli. Pallidal stimulation for myoclonus-dystonia: Ten years' outcome in two patients.. Mov Disord. 2015;30:871-2",
"H Sanjari Moghaddam, A Tafakhori, H Darvish, J Mahmoudi-Gharaei, F Jamali, V Aghamollaii. Treatment of myoclonus-dystonia with carbamazepine.. Parkinsonism Relat Disord. 2018;53:116-7",
"R Saunders-Pullman, D Raymond, AJ Stoessl, D Hobson, K Nakamura, S Pullman, D Lefton, MS Okun, R Uitti, R Sachdev, K Stanley, M San Luciano, J Hagenah, R Gatti, LJ Ozelius, SB Bressman. Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites.. Neurology. 2012;78:649-57",
"K Scheidtmann, F Muller, E Hartmann, E Koenig. Familial myoclonus-dystonia syndrome associated with panic attacks.. Nervenarzt 2000;71:839-42",
"B Schüle, N Kock, M Svetel, N Dragasevic, K Hedrich, P De Carvalho Aguiar, L Liu, K Kabakci, J Garrels, EM Meyer, I Berisavac, E Schwinger, PL Kramer, LJ Ozelius, C Klein, V Kostic. Genetic heterogeneity in ten families with myoclonus-dystonia.. J Neurol Neurosurg Psychiatry 2004;75:1181-5",
"MB Sheridan, A Bytyci Telegrafi, V Stinnett, CC Umeh, Z Mari, TM Dawson, J Bodurtha, DA Batista. Myoclonus-dystonia and Silver-Russell syndrome resulting from maternal uniparental disomy of chromosome 7.. Clin Genet. 2013;84:368-72",
"Z Stark, MM Ryan, DL Bruno, T Burgess, R Savarirayan. Atypical Silver-Russell phenotype resulting from maternal uniparental disomy of chromosome 7.. Am J Med Genet A. 2010;152A:2342-5",
"S Steinrücke, K Lohmann, A Domingo, A Rolfs, T Bäumer, J Spiegler, C Hartmann, A. Münchau. Novel GNB1 missense mutation in a patient with generalized dystonia, hypotonia, and intellectual disability.. Neurol Genet. 2016;2",
"O Suchowersky, JL Davis. Thalamic surgery for essential myoclonus results in clinical but not functional improvement.. Mov Disord 2000;15:332",
"S Tezenas du Montcel, F Clot, M Vidailhet, E Roze, P Damier, CP Jedynak, A Camuzat, A Lagueny, L Vercueil, D Doummar, L Guyant-Maréchal, JL Houeto, G Ponsot, S Thobois, MA Cournelle, A Durr, F Durif, B Echenne, D Hannequin, C Tranchant, A Brice. Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes.. J Med Genet. 2006;43:394-400",
"T Trottenberg, W Meissner, C Kabus, G Arnold, T Funk, KM Einhaupl, A Kupsch. Neurostimulation of the ventral intermediate thalamic nucleus in inherited myoclonus-dystonia syndrome.. Mov Disord 2001;16:769-71",
"EM Valente, MJ Edwards, P Mir, A DiGiorgio, S Salvi, M Davis, N Russo, M Bozi, HT Kim, G Pennisi, N Quinn, B Dallapiccola, KP Bhatia. The epsilon-sarcoglycan gene in myoclonic syndromes.. Neurology 2005;64:737-9",
"M Vidailhet, J Tassin, F Durif, A Nivelon-Chevallier, Y Agid, A Brice, A Durr. A major locus for several phenotypes of myoclonus—dystonia on chromosome 7q.. Neurology 2001;56:1213-6",
"J Xiao, SR Vemula, Y Xue, MM Khan, FA Carlisle, AJ Waite, DJ Blake, I Dragatsis, Y Zhao, MS LeDoux. Role of major and brain-specific Sgce isoforms in the pathogenesis of myoclonus-dystonia syndrome.. Neurobiol Dis. 2017;98:52-65",
"YQ Zhang, JW Wang, YP Wang, XH Zhang, JP Li. Thalamus stimulation for myoclonus dystonia syndrome: five cases and long-term follow-up.. World Neurosurg. 2019;122:e933-9",
"A Zimprich, M Grabowski, F Asmus, M Naumann, D Berg, M Bertram, K Scheidtmann, P Kern, J Winkelmann, B Muller-Myhsok, L Riedel, M Bauer, T Muller, M Castro, T Meitinger, TM Strom, T Gasser. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome.. Nat Genet 2001;29:66-9"
] |
21/5/2003
|
8/8/2019
|
4/6/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
myodef-sda
|
myodef-sda
|
[
"Iron-Sulfur Cluster Deficiency Myopathy",
"Myopathy with Deficiency of Succinate Dehydrogenase and Aconitase",
"Myopathy with Exercise Intolerance, Swedish Type",
"Myopathy with Deficiency of Succinate Dehydrogenase and Aconitase",
"Myopathy with Exercise Intolerance, Swedish Type",
"Iron-Sulfur Cluster Deficiency Myopathy",
"Iron-sulfur cluster assembly enzyme ISCU, mitochondrial",
"ISCU",
"Myopathy with Deficiency of ISCU"
] |
Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Fanny Mochel, Ronald G Haller
|
Summary Myopathy with deficiency of ISCU, a mitochondrial myopathy, is classically characterized by lifelong exercise intolerance in which minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles; episodes of more profound exercise intolerance associated with rhabdomyolysis, myoglobinuria, and weakness that may be severe; and typically full recovery of muscle strength between episodes of rhabdomyolysis. Affected individuals usually have near-normal strength; they can have large calves. The diagnosis of myopathy with deficiency of ISCU is established in a proband by the identification of biallelic pathogenic variants in Myopathy with deficiency of ISCU is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased are possible if the pathogenic variants in the family have been identified.
|
## Diagnosis
Myopathy with deficiency of ISCU (i.e., iron-sulfur cluster assembly enzyme ISCU), a mitochondrial myopathy,
Lifelong exercise intolerance in which minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles
Episodes of more profound exercise intolerance associated with rhabdomyolysis, myoglobinuria, and weakness that may be severe
Typically, full recovery of muscle strength between episodes of rhabdomyolysis and usually near-normal strength
In some individuals, large calves
Elevated blood lactate concentration (i.e., >2 mmol/L) at rest
Blood lactate and pyruvate concentrations increase steeply at low levels of exercise, with increases in pyruvate higher and peak lactate-to-pyruvate concentrations lower than in persons with mitochondrial defects restricted to the respiratory chain.
Decreased peak levels of oxygen utilization, typically one third or less than that of healthy persons. Reported values in affected persons are 10-12 mL O
The diagnosis of myopathy with deficiency of ISCU
Molecular testing approaches can include
Sequence analysis of ISCU is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
Targeted analysis for the pathogenic variant
For an introduction to multigene panels click
Molecular Genetic Testing Used in Myopathy with Deficiency of ISCU
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Most affected individuals tested to date are homozygous for
Pathogenic variant
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Diagnosis classically has required histochemical and biochemical assessment of a muscle biopsy, most commonly the quadriceps, gastrocnemius, biceps, or deltoid muscle to identify a characteristic deficiency of proteins containing iron-sulfur clusters. However, molecular genetic testing has superseded muscle biopsy in most cases. Characteristic findings on muscle biopsy include the following.
Multiple iron-sulfur cluster-containing proteins including the tricarboxylic acid cycle enzymes succinate dehydrogenase (complex II) and mitochondrial aconitase; and
Respiratory chain complexes which contain iron-sulfur clusters (i.e., complex I and III) [
• Lifelong exercise intolerance in which minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles
• Episodes of more profound exercise intolerance associated with rhabdomyolysis, myoglobinuria, and weakness that may be severe
• Typically, full recovery of muscle strength between episodes of rhabdomyolysis and usually near-normal strength
• In some individuals, large calves
• Elevated blood lactate concentration (i.e., >2 mmol/L) at rest
• Blood lactate and pyruvate concentrations increase steeply at low levels of exercise, with increases in pyruvate higher and peak lactate-to-pyruvate concentrations lower than in persons with mitochondrial defects restricted to the respiratory chain.
• Decreased peak levels of oxygen utilization, typically one third or less than that of healthy persons. Reported values in affected persons are 10-12 mL O
• Sequence analysis of ISCU is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• Targeted analysis for the pathogenic variant
• Multiple iron-sulfur cluster-containing proteins including the tricarboxylic acid cycle enzymes succinate dehydrogenase (complex II) and mitochondrial aconitase; and
• Respiratory chain complexes which contain iron-sulfur clusters (i.e., complex I and III) [
## Suggestive Findings
Myopathy with deficiency of ISCU (i.e., iron-sulfur cluster assembly enzyme ISCU), a mitochondrial myopathy,
Lifelong exercise intolerance in which minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles
Episodes of more profound exercise intolerance associated with rhabdomyolysis, myoglobinuria, and weakness that may be severe
Typically, full recovery of muscle strength between episodes of rhabdomyolysis and usually near-normal strength
In some individuals, large calves
Elevated blood lactate concentration (i.e., >2 mmol/L) at rest
Blood lactate and pyruvate concentrations increase steeply at low levels of exercise, with increases in pyruvate higher and peak lactate-to-pyruvate concentrations lower than in persons with mitochondrial defects restricted to the respiratory chain.
Decreased peak levels of oxygen utilization, typically one third or less than that of healthy persons. Reported values in affected persons are 10-12 mL O
• Lifelong exercise intolerance in which minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles
• Episodes of more profound exercise intolerance associated with rhabdomyolysis, myoglobinuria, and weakness that may be severe
• Typically, full recovery of muscle strength between episodes of rhabdomyolysis and usually near-normal strength
• In some individuals, large calves
• Elevated blood lactate concentration (i.e., >2 mmol/L) at rest
• Blood lactate and pyruvate concentrations increase steeply at low levels of exercise, with increases in pyruvate higher and peak lactate-to-pyruvate concentrations lower than in persons with mitochondrial defects restricted to the respiratory chain.
• Decreased peak levels of oxygen utilization, typically one third or less than that of healthy persons. Reported values in affected persons are 10-12 mL O
## Establishing the Diagnosis
The diagnosis of myopathy with deficiency of ISCU
Molecular testing approaches can include
Sequence analysis of ISCU is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
Targeted analysis for the pathogenic variant
For an introduction to multigene panels click
Molecular Genetic Testing Used in Myopathy with Deficiency of ISCU
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Most affected individuals tested to date are homozygous for
Pathogenic variant
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Diagnosis classically has required histochemical and biochemical assessment of a muscle biopsy, most commonly the quadriceps, gastrocnemius, biceps, or deltoid muscle to identify a characteristic deficiency of proteins containing iron-sulfur clusters. However, molecular genetic testing has superseded muscle biopsy in most cases. Characteristic findings on muscle biopsy include the following.
Multiple iron-sulfur cluster-containing proteins including the tricarboxylic acid cycle enzymes succinate dehydrogenase (complex II) and mitochondrial aconitase; and
Respiratory chain complexes which contain iron-sulfur clusters (i.e., complex I and III) [
• Sequence analysis of ISCU is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• Targeted analysis for the pathogenic variant
• Multiple iron-sulfur cluster-containing proteins including the tricarboxylic acid cycle enzymes succinate dehydrogenase (complex II) and mitochondrial aconitase; and
• Respiratory chain complexes which contain iron-sulfur clusters (i.e., complex I and III) [
## Molecular Genetic Testing
Molecular testing approaches can include
Sequence analysis of ISCU is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
Targeted analysis for the pathogenic variant
For an introduction to multigene panels click
Molecular Genetic Testing Used in Myopathy with Deficiency of ISCU
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Most affected individuals tested to date are homozygous for
Pathogenic variant
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Sequence analysis of ISCU is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• Targeted analysis for the pathogenic variant
## Muscle Biopsy
Diagnosis classically has required histochemical and biochemical assessment of a muscle biopsy, most commonly the quadriceps, gastrocnemius, biceps, or deltoid muscle to identify a characteristic deficiency of proteins containing iron-sulfur clusters. However, molecular genetic testing has superseded muscle biopsy in most cases. Characteristic findings on muscle biopsy include the following.
Multiple iron-sulfur cluster-containing proteins including the tricarboxylic acid cycle enzymes succinate dehydrogenase (complex II) and mitochondrial aconitase; and
Respiratory chain complexes which contain iron-sulfur clusters (i.e., complex I and III) [
• Multiple iron-sulfur cluster-containing proteins including the tricarboxylic acid cycle enzymes succinate dehydrogenase (complex II) and mitochondrial aconitase; and
• Respiratory chain complexes which contain iron-sulfur clusters (i.e., complex I and III) [
## Clinical Characteristics
Symptoms of exercise intolerance in myopathy with deficiency of ISCU are typically present from childhood. Episodes of rhabdomyolysis and myoglobinuria usually occur during or after the second decade of life and are usually triggered by sustained or recurrent physical activity. Episodes of rhabdomyolysis with myoglobinuria may result in renal failure and associated metabolic crises that in some instances have been fatal [
Affected individuals are generally able to minimize or avoid episodes of rhabdomyolysis by moderating physical activity.
For further information on the
Homozygosity for the common pathogenic splice site variant results in a mitochondrial disorder restricted to skeletal muscle with characteristic features of severe exercise intolerance. Although data are limited, reported individuals who are compound heterozygotes for the common pathogenic splice site variant and a novel pathogenic missense variant have had a more severe muscle phenotype with weakness and cardiomyopathy [
Originally myopathy with deficiency of ISCU was described primarily in individuals of northern Swedish ancestry. Three non-Swedish individuals have been reported: one individual of Norwegian ancestry who was homozygous for the common intronic g.7044G>C pathogenic variant [
The carrier rate in northern Sweden has been estimated at 1:188 [
## Clinical Description
Symptoms of exercise intolerance in myopathy with deficiency of ISCU are typically present from childhood. Episodes of rhabdomyolysis and myoglobinuria usually occur during or after the second decade of life and are usually triggered by sustained or recurrent physical activity. Episodes of rhabdomyolysis with myoglobinuria may result in renal failure and associated metabolic crises that in some instances have been fatal [
Affected individuals are generally able to minimize or avoid episodes of rhabdomyolysis by moderating physical activity.
For further information on the
## Genotype-Phenotype Correlations
Homozygosity for the common pathogenic splice site variant results in a mitochondrial disorder restricted to skeletal muscle with characteristic features of severe exercise intolerance. Although data are limited, reported individuals who are compound heterozygotes for the common pathogenic splice site variant and a novel pathogenic missense variant have had a more severe muscle phenotype with weakness and cardiomyopathy [
## Prevalence
Originally myopathy with deficiency of ISCU was described primarily in individuals of northern Swedish ancestry. Three non-Swedish individuals have been reported: one individual of Norwegian ancestry who was homozygous for the common intronic g.7044G>C pathogenic variant [
The carrier rate in northern Sweden has been estimated at 1:188 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The clinical features of lifelong exercise intolerance, low oxidative capacity with impaired mitochondrial extraction of available oxygen from blood, and a hyperkinetic circulation in exercise are mimicked by other mitochondrial myopathies [
Elevated blood lactate concentration at rest and marked increases in blood lactate concentration relative to workload are also typical of other mitochondrial myopathies. High levels of pyruvate relative to lactate may differentiate ISCU myopathy from other mitochondrial myopathies [
Episodes of myoglobinuria also have been described in other mitochondrial myopathies, although less commonly than in myopathy with deficiency of ISCU.
## Management
To establish the extent of disease and needs in an individual diagnosed with myopathy with deficiency of ISCU, the following evaluations are recommended:
Consideration of cardiac evaluation in an affected individual who has at least one pathogenic variant that is
No special evaluations in an affected individual who is homozygous for the common Swedish pathogenic splice site variant
Consultation with a clinical geneticist and/or genetic counselor
No specific therapy currently exists for this disorder.
The major management goal is to prevent episodes of rhabdomyolysis and myoglobinuria. Anecdotal evidence suggests that this goal may be achieved by avoiding sustained fatiguing physical exertion.
The major secondary complications are those attributable to rhabdomyolysis and myoglobinuria, including renal failure and hyperkalemia. Management is similar to that for other causes of rhabdomyolysis including monitoring of renal and electrolyte status, maintenance of intravascular volume and urinary output, urine alkalinization, and institution of dialysis when needed [
Avoid sustained fatiguing physical exertion.
See
Antisense oligonucleotides that induce skipping of the aberrant splice site produced by the pathogenic variant have restored normal mRNA splicing in fibroblasts from affected individuals [
Search
• Consideration of cardiac evaluation in an affected individual who has at least one pathogenic variant that is
• No special evaluations in an affected individual who is homozygous for the common Swedish pathogenic splice site variant
• Consultation with a clinical geneticist and/or genetic counselor
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with myopathy with deficiency of ISCU, the following evaluations are recommended:
Consideration of cardiac evaluation in an affected individual who has at least one pathogenic variant that is
No special evaluations in an affected individual who is homozygous for the common Swedish pathogenic splice site variant
Consultation with a clinical geneticist and/or genetic counselor
• Consideration of cardiac evaluation in an affected individual who has at least one pathogenic variant that is
• No special evaluations in an affected individual who is homozygous for the common Swedish pathogenic splice site variant
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
No specific therapy currently exists for this disorder.
## Prevention of Primary Manifestations
The major management goal is to prevent episodes of rhabdomyolysis and myoglobinuria. Anecdotal evidence suggests that this goal may be achieved by avoiding sustained fatiguing physical exertion.
## Prevention of Secondary Complications
The major secondary complications are those attributable to rhabdomyolysis and myoglobinuria, including renal failure and hyperkalemia. Management is similar to that for other causes of rhabdomyolysis including monitoring of renal and electrolyte status, maintenance of intravascular volume and urinary output, urine alkalinization, and institution of dialysis when needed [
## Agents/Circumstances to Avoid
Avoid sustained fatiguing physical exertion.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Antisense oligonucleotides that induce skipping of the aberrant splice site produced by the pathogenic variant have restored normal mRNA splicing in fibroblasts from affected individuals [
Search
## Genetic Counseling
Myopathy with deficiency of ISCU is inherited in an autosomal recessive manner.
The unaffected parents of an individual with myopathy with deficiency of ISCU are obligate heterozygotes (i.e., carriers of one mutated allele).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.
• The unaffected parents of an individual with myopathy with deficiency of ISCU are obligate heterozygotes (i.e., carriers of one mutated allele).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Myopathy with deficiency of ISCU is inherited in an autosomal recessive manner.
## Risk to Family Members
The unaffected parents of an individual with myopathy with deficiency of ISCU are obligate heterozygotes (i.e., carriers of one mutated allele).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The unaffected parents of an individual with myopathy with deficiency of ISCU are obligate heterozygotes (i.e., carriers of one mutated allele).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.
## Resources
Canada
United Kingdom
•
• Canada
•
•
•
•
• United Kingdom
•
## Molecular Genetics
Myopathy with Deficiency of ISCU: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Myopathy with Deficiency of ISCU (
The pathophysiology of exercise in affected individuals was described in the classic papers of
Selective skeletal muscle involvement in affected individuals with the common splice site variant relates to several factors. First, ISCU messenger RNA and protein are low in skeletal muscle compared to other tissues [
ISCU1 (
Variants listed in the table have been provided by the authors.
Also known as
In mammalian iron sulfur-cluster assembly, a cysteine desulfurase known as ISCS, encoded by
The missense pathogenic variant in exon 3 changes a glycine residue to a glutamate at amino acid position 50 [
## Molecular Pathogenesis
The pathophysiology of exercise in affected individuals was described in the classic papers of
Selective skeletal muscle involvement in affected individuals with the common splice site variant relates to several factors. First, ISCU messenger RNA and protein are low in skeletal muscle compared to other tissues [
ISCU1 (
Variants listed in the table have been provided by the authors.
Also known as
In mammalian iron sulfur-cluster assembly, a cysteine desulfurase known as ISCS, encoded by
The missense pathogenic variant in exon 3 changes a glycine residue to a glutamate at amino acid position 50 [
## References
## Literature Cited
## Chapter Notes
Supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases (RO1 AR050597)
10 February 2022 (ma) Chapter retired: extremely rare; qualified authors not available for update
3 March 2016 (ma) Comprehensive update posted live
1 September 2011 (me) Comprehensive update posted live
11 August 2009 (cd) Revision: sequence analysis and prenatal testing available clinically
31 March 2009 (me) Review posted live
18 December 2008 (fm) Original submission
• 10 February 2022 (ma) Chapter retired: extremely rare; qualified authors not available for update
• 3 March 2016 (ma) Comprehensive update posted live
• 1 September 2011 (me) Comprehensive update posted live
• 11 August 2009 (cd) Revision: sequence analysis and prenatal testing available clinically
• 31 March 2009 (me) Review posted live
• 18 December 2008 (fm) Original submission
## Acknowledgments
Supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases (RO1 AR050597)
## Revision History
10 February 2022 (ma) Chapter retired: extremely rare; qualified authors not available for update
3 March 2016 (ma) Comprehensive update posted live
1 September 2011 (me) Comprehensive update posted live
11 August 2009 (cd) Revision: sequence analysis and prenatal testing available clinically
31 March 2009 (me) Review posted live
18 December 2008 (fm) Original submission
• 10 February 2022 (ma) Chapter retired: extremely rare; qualified authors not available for update
• 3 March 2016 (ma) Comprehensive update posted live
• 1 September 2011 (me) Comprehensive update posted live
• 11 August 2009 (cd) Revision: sequence analysis and prenatal testing available clinically
• 31 March 2009 (me) Review posted live
• 18 December 2008 (fm) Original submission
|
[
"DR Crooks, MC Ghosh, RG Haller, WH Tong, TA Rouault. Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery.. Blood 2010;115:860-9",
"DR Crooks, SY Jeong, WH Tong, MC Ghosh, H Olivierre, RG Haller, TA Rouault. Tissue specificity of a human mitochondrial disease: differentiation-enhanced mis-splicing of the Fe-S scaffold gene ISCU renders patient cells more sensitive to oxidative stress in ISCU myopathy.. J Biol Chem 2012;287:40119-30",
"RE Hall, KG Henriksson, SF Lewis, RG Haller, NG Kennaway. Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins.. J Clin Invest 1993;92:2660-6",
"RG Haller, KG Henriksson, L Jorfeldt, E Hultman, R Wibom, K Sahlin, NH Areskog, M Gunder, K Ayyad, CG Blomqvist, RE Hall, P Thuillier, NG Kennaway, SF Lewis. Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.. J Clin Invest 1991;88:1197-206",
"K Heinicke, T Taivassalo, P Wyrick, H Wood, TG Babb, RG Haller. Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms.. Am J Physiol Regul Integr Comp Physiol 2011;301:R873-84",
"G Kollberg, E Holme. Antisense oligonucleotide therapeutics for iron-sulphur cluster deficiency myopathy.. Neuromuscul Disord 2009;19:833-6",
"G Kollberg, A Melberg, E Holme, A Oldfors. Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy.. Neuromuscul Disord 2011;21:115-20",
"G Kollberg, M Tulinius, A Melberg, N Darin, O Andersen, D Holmgren, A Oldfors, E Holme. Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy.. Brain 2009;132:2170-9",
"LE Larsson, H Linderholm, R Mueller, T Ringqvist, R Soernaes. Hereditary metabolic myopathy with paroxysmal myoglobinuria due to abnormal glycolysis.. J Neurol Neurosurg Psychiatry 1964;27:361-80",
"H Linderholm, B Essén-Gustavsson, LE Thornell. Low succinate dehydrogenase (SDH) activity in a patient with a hereditary myopathy with paroxysmal myoglobinuria.. J Intern Med 1990;228:43-52",
"H Linderholm, R Müller, T Ringqvist, R Sörnäs. Hereditary abnormal muscle metabolism with hyperkinetic circulation during exercise.. Acta Med Scand 1969;185:153-66",
"J Liu, N Oganesyan, DH Shin, J Jancarik, H Yokota, R Kim, SH Kim. Structural characterization of an iron-sulfur cluster assembly protein IscU in a zinc-bound form.. Proteins 2005;59:875-81",
"N Maio, TA Rouault. Iron-sulfur cluster biogenesis in mammalian cells: new insights into the molecular mechanisms of cluster delivery.. Biochim Biophys Acta 2015;1853:1493-512",
"DJ Malinoski, MS Slater, RJ Mullins. Crush injury and rhabdomyolysis.. Crit Care Clin 2004;20:171-92",
"F Mochel, MA Knight, WH Tong, D Hernandez, K Ayyad, T Taivassalo, PM Andersen, A Singleton, TA Rouault, KH Fischbeck, RG Haller. Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance.. Am J Hum Genet 2008;82:652-60",
"A Nordin, E Larsson, M Holmberg. The defective splicing caused by the ISCU intron mutation in patients with myopathy with lactic acidosis is repressed by PTBP1 but can be derepressed by IGF2BP1.. Hum Mutat 2012;33:467-70",
"A Nordin, E Larsson, L-E Thornell, M Holmberg. Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice.. Hum Genet 2011;129:371-8",
"A Olsson, L Lind, LE Thornell, M Holmberg. Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect.. Hum Mol Genet 2008;17:1666-72",
"TA Rouault, WH Tong. Iron-sulfur cluster biogenesis and human disease.. Trends Genet 2008;24:398-407",
"PS Sanaker, M Toompuu, VE Hogan, L He, C Tzoulis, ZM Chrzanowska-Lightowlers, RW Taylor, LA Bindoff. Differences in RNA processing underlie the tissue specific phenotype of ISCU myopathy.. Biochim Biophys Acta 2010;1802:539-44",
"Y Shan, E Napoli, G Cortopassi. Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones.. Hum Mol Genet 2007;16:929-41",
"A Suomalainen, JM Elo, KH Pietiläinen, AH Hakonen, K Sevastianova, M Korpela, P Isohanni, SK Marjavaara, T Tyni, S Kiuru-Enari, H Pihko, N Darin, K Õunap, LA Kluijtmans, A Paetau, J Buzkova, LA Bindoff, J Annunen-Rasila, J Uusimaa, A Rissanen, H Yki-Järvinen, M Hirano, M Tulinius, J Smeitink, H Tyynismaa. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study.. Lancet Neurol 2011;10:806-18",
"T Taivassalo, TD Jensen, N Kennaway, S DiMauro, J Vissing, RG Haller. The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients.. Brain 2003;126:413-23",
"WH Tong, GN Jameson, BH Huynh, TA Rouault. Subcellular compartmentalization of human Nfu, an iron-sulfur cluster scaffold protein, and its ability to assemble a [4Fe-4S] cluster.. Proc Natl Acad Sci U S A 2003;100:9762-7",
"WH Tong, TA Rouault. Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells.. EMBO J 2000;19:5692-700"
] |
31/3/2009
|
3/3/2016
|
11/8/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
myotonia-c
|
myotonia-c
|
[
"Chloride channel protein 1",
"CLCN1",
"Myotonia Congenita"
] |
Myotonia Congenita
|
Morten Dunø, John Vissing
|
Summary Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, facial muscles, and tongue may be involved. Stiffness is relieved by repeated contractions of the muscle (the "warm-up" phenomenon). Muscles are usually hypertrophic. Whereas autosomal recessive (AR) myotonia congenita is often associated with more severe manifestations (such as progressive minor distal weakness and attacks of transient weakness brought on by movement after rest), autosomal dominant (AD) myotonia congenita is not. The age of onset varies: in AD myotonia congenita onset is usually in infancy or early childhood; in AR myotonia congenita the average age of onset is slightly older. In both AR and AD myotonia congenita onset may be as late as the third or fourth decade of life. The molecular diagnosis of myotonia congenita is established in a proband with suggestive findings of myotonia and sometimes muscle hypertrophy, and either a heterozygous Myotonia congenita is inherited in either an autosomal recessive (Becker disease) or an autosomal dominant (Thomsen disease) manner; the same pathogenic variant may be associated with both autosomal dominant and autosomal recessive inheritance. Establishing the mode of inheritance in a simplex case (i.e., a single occurrence in a family) may not be possible unless molecular genetic testing reveals two Once the
|
## Diagnosis
No consensus clinical diagnostic criteria for myotonia congenita (sometimes referred to as "chloride channel myotonia") have been published.
Myotonia congenita
Episodes of muscle stiffness (myotonia) or cramps beginning in early childhood
Alleviation of stiffness by brief exercise (known as the "warm-up" effect)
Myotonic contraction elicited by percussion of muscles
The diagnosis of myotonia congenita
Note:
Identification of a heterozygous
Identification of biallelic
Distinguishing between AD and AR myotonia congenita depends mainly on the family history (i.e., the presence of an affected parent in autosomal dominant myotonia congenita), as some pathogenic variants can occur in both AR and AD myotonia congenita. (Note: The identification of two
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: To date, single-exon, multiexon, or whole-gene deletions/duplications have not been identified in individuals with AD myotonia congenita.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Myotonia Congenita
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic
The published variants are primarily large intragenic deletions. Only one large duplication has been reported.
• Episodes of muscle stiffness (myotonia) or cramps beginning in early childhood
• Alleviation of stiffness by brief exercise (known as the "warm-up" effect)
• Myotonic contraction elicited by percussion of muscles
• Identification of a heterozygous
• Identification of biallelic
• Distinguishing between AD and AR myotonia congenita depends mainly on the family history (i.e., the presence of an affected parent in autosomal dominant myotonia congenita), as some pathogenic variants can occur in both AR and AD myotonia congenita. (Note: The identification of two
## Suggestive Findings
Myotonia congenita
Episodes of muscle stiffness (myotonia) or cramps beginning in early childhood
Alleviation of stiffness by brief exercise (known as the "warm-up" effect)
Myotonic contraction elicited by percussion of muscles
• Episodes of muscle stiffness (myotonia) or cramps beginning in early childhood
• Alleviation of stiffness by brief exercise (known as the "warm-up" effect)
• Myotonic contraction elicited by percussion of muscles
## Establishing the Diagnosis
The diagnosis of myotonia congenita
Note:
Identification of a heterozygous
Identification of biallelic
Distinguishing between AD and AR myotonia congenita depends mainly on the family history (i.e., the presence of an affected parent in autosomal dominant myotonia congenita), as some pathogenic variants can occur in both AR and AD myotonia congenita. (Note: The identification of two
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: To date, single-exon, multiexon, or whole-gene deletions/duplications have not been identified in individuals with AD myotonia congenita.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Myotonia Congenita
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic
The published variants are primarily large intragenic deletions. Only one large duplication has been reported.
• Identification of a heterozygous
• Identification of biallelic
• Distinguishing between AD and AR myotonia congenita depends mainly on the family history (i.e., the presence of an affected parent in autosomal dominant myotonia congenita), as some pathogenic variants can occur in both AR and AD myotonia congenita. (Note: The identification of two
## Option 1
Note: To date, single-exon, multiexon, or whole-gene deletions/duplications have not been identified in individuals with AD myotonia congenita.
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Myotonia Congenita
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic
The published variants are primarily large intragenic deletions. Only one large duplication has been reported.
## Clinical Characteristics
Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, facial muscles, and tongue may be involved. Stiffness is relieved by repeated contractions of the muscle (the "warm-up" phenomenon). Muscles are usually hypertrophic. Whereas autosomal recessive (AR) myotonia congenita is often associated with more severe manifestations (such as progressive, minor distal weakness and attacks of transient weakness brought on by movement after rest), autosomal dominant (AD) myotonia congenita is not.
A study of more than 300 affected individuals from the UK revealed a ratio of 70% AR myotonia congenita to 30% AD myotonia congenita among families with a molecularly confirmed diagnosis [
Myotonia Congenita: Comparison of Select Features by Mode of Inheritance
AD = autosomal dominant; AR = autosomal recessive
The physician may note that the individual cannot extend the fingers after shaking hands, or a myotonic contraction may be elicited by percussion of muscles (e.g., the tongue, finger extensors, or thenar muscles).
The stiffness can be relieved by repeated contractions of the muscle, a feature known as the "warm-up" phenomenon.
Muscles are usually hypertrophic.
The AR form is often associated with more severe manifestations than the AD form.
While there are no clear-cut phenotype-genotype correlations, loss-of-function variants are expected to associate primarily with AR myotonia congenita.
The phenotypic manifestations of
Pathogenic variants identified in AD myotonia congenita can be associated with variable expression and reduced penetrance [
AD myotonia congenita is also known as Thomsen disease.
AR myotonia congenita is also known as Becker disease.
Myotonia congenita may also be referred to as chloride channel myotonia.
Myotonia levior is essentially the same as myotonia congenita.
Worldwide prevalence of myotonia congenita has been estimated at 1:100,000 [
• The physician may note that the individual cannot extend the fingers after shaking hands, or a myotonic contraction may be elicited by percussion of muscles (e.g., the tongue, finger extensors, or thenar muscles).
• The stiffness can be relieved by repeated contractions of the muscle, a feature known as the "warm-up" phenomenon.
• Muscles are usually hypertrophic.
• The AR form is often associated with more severe manifestations than the AD form.
## Clinical Description
Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, facial muscles, and tongue may be involved. Stiffness is relieved by repeated contractions of the muscle (the "warm-up" phenomenon). Muscles are usually hypertrophic. Whereas autosomal recessive (AR) myotonia congenita is often associated with more severe manifestations (such as progressive, minor distal weakness and attacks of transient weakness brought on by movement after rest), autosomal dominant (AD) myotonia congenita is not.
A study of more than 300 affected individuals from the UK revealed a ratio of 70% AR myotonia congenita to 30% AD myotonia congenita among families with a molecularly confirmed diagnosis [
Myotonia Congenita: Comparison of Select Features by Mode of Inheritance
AD = autosomal dominant; AR = autosomal recessive
The physician may note that the individual cannot extend the fingers after shaking hands, or a myotonic contraction may be elicited by percussion of muscles (e.g., the tongue, finger extensors, or thenar muscles).
The stiffness can be relieved by repeated contractions of the muscle, a feature known as the "warm-up" phenomenon.
Muscles are usually hypertrophic.
The AR form is often associated with more severe manifestations than the AD form.
• The physician may note that the individual cannot extend the fingers after shaking hands, or a myotonic contraction may be elicited by percussion of muscles (e.g., the tongue, finger extensors, or thenar muscles).
• The stiffness can be relieved by repeated contractions of the muscle, a feature known as the "warm-up" phenomenon.
• Muscles are usually hypertrophic.
• The AR form is often associated with more severe manifestations than the AD form.
## Genotype-Phenotype Correlations
While there are no clear-cut phenotype-genotype correlations, loss-of-function variants are expected to associate primarily with AR myotonia congenita.
The phenotypic manifestations of
## Penetrance
Pathogenic variants identified in AD myotonia congenita can be associated with variable expression and reduced penetrance [
## Nomenclature
AD myotonia congenita is also known as Thomsen disease.
AR myotonia congenita is also known as Becker disease.
Myotonia congenita may also be referred to as chloride channel myotonia.
Myotonia levior is essentially the same as myotonia congenita.
## Prevalence
Worldwide prevalence of myotonia congenita has been estimated at 1:100,000 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The differential diagnosis of myotonia congenita includes other disorders in which myotonia is a prominent finding. Myotonia congenita can usually be distinguished from these disorders based on the following:
Factors that provoke or alleviate myotonia
Presence or absence of extramuscular manifestations
Findings on electrodiagnostic and molecular genetic testing
Note: Pathogenic variants in
MC = myotonia congenita
Pathogenic variants in
• Factors that provoke or alleviate myotonia
• Presence or absence of extramuscular manifestations
• Findings on electrodiagnostic and molecular genetic testing
## Management
No specific clinical practice guidelines for myotonia congenita have been published. However, a general guideline on clinical presentation and management of nondystrophic myotonias is available [
To establish the extent of disease and needs in an individual diagnosed with myotonia congenita, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Consultation with a neurologist or other relevant specialist to evaluate the need for pharmacologic treatment. Severity of myotonia can be assessed by a myotonia questionnaire (e.g., the Myotonia Behavior Scale [
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of myotonia congenita in order to facilitate medical and personal decision making
Some individuals with minor complaints may only need to accommodate their activities and lifestyles to reduce symptoms [
Myotonic stiffness may respond to sodium channel blockers or other pharmacologic treatment options:
Lamotrigine, another sodium channel blocker, also significantly reduced myotonia in a randomized controlled trial in patients with both sodium and chloride channelopathies [
Other sodium channel blockers such as
Compounds with other presumed modes of action such as
See
In general, anesthesia should be used with caution [
Note: Non-depolarizing muscle relaxants appear to act normally in individuals with myotonia congenita but do not counteract a myotonic response caused by suxamethonium [
In rare cases, injections of
The beta-antagonist
Because individuals with myotonia congenita may be at increased risk for adverse anesthesia-related events, molecular genetic testing of at-risk family members (for the
See
A comprehensive birth plan is recommended for a pregnant woman with myotonia congenita to minimize the risks of muscular spasms due to factors such as medications, intramuscular injections, and cold [
Search
• Consultation with a neurologist or other relevant specialist to evaluate the need for pharmacologic treatment. Severity of myotonia can be assessed by a myotonia questionnaire (e.g., the Myotonia Behavior Scale [
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of myotonia congenita in order to facilitate medical and personal decision making
• Lamotrigine, another sodium channel blocker, also significantly reduced myotonia in a randomized controlled trial in patients with both sodium and chloride channelopathies [
• Other sodium channel blockers such as
• Compounds with other presumed modes of action such as
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with myotonia congenita, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Consultation with a neurologist or other relevant specialist to evaluate the need for pharmacologic treatment. Severity of myotonia can be assessed by a myotonia questionnaire (e.g., the Myotonia Behavior Scale [
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of myotonia congenita in order to facilitate medical and personal decision making
• Consultation with a neurologist or other relevant specialist to evaluate the need for pharmacologic treatment. Severity of myotonia can be assessed by a myotonia questionnaire (e.g., the Myotonia Behavior Scale [
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of myotonia congenita in order to facilitate medical and personal decision making
## Treatment of Manifestations
Some individuals with minor complaints may only need to accommodate their activities and lifestyles to reduce symptoms [
Myotonic stiffness may respond to sodium channel blockers or other pharmacologic treatment options:
Lamotrigine, another sodium channel blocker, also significantly reduced myotonia in a randomized controlled trial in patients with both sodium and chloride channelopathies [
Other sodium channel blockers such as
Compounds with other presumed modes of action such as
See
• Lamotrigine, another sodium channel blocker, also significantly reduced myotonia in a randomized controlled trial in patients with both sodium and chloride channelopathies [
• Other sodium channel blockers such as
• Compounds with other presumed modes of action such as
## Agents/Circumstances to Avoid
In general, anesthesia should be used with caution [
Note: Non-depolarizing muscle relaxants appear to act normally in individuals with myotonia congenita but do not counteract a myotonic response caused by suxamethonium [
In rare cases, injections of
The beta-antagonist
## Evaluation of Relatives at Risk
Because individuals with myotonia congenita may be at increased risk for adverse anesthesia-related events, molecular genetic testing of at-risk family members (for the
See
## Pregnancy Management
A comprehensive birth plan is recommended for a pregnant woman with myotonia congenita to minimize the risks of muscular spasms due to factors such as medications, intramuscular injections, and cold [
## Therapies Under Investigation
Search
## Genetic Counseling
Myotonia congenita can be inherited in either an autosomal recessive (Becker disease) or an autosomal dominant (Thomsen disease) manner.
Distinguishing between autosomal dominant and autosomal recessive myotonia congenita depends mainly on the family history (i.e., the presence of an affected parent in autosomal dominant myotonia congenita). However, a clear distinction can be difficult because the same
In a simplex case (i.e., the occurrence of a single individual with myotonia congenita in a family), establishing the mode of inheritance may not be possible unless molecular genetic testing reveals two
The parents of an individual with autosomal recessive myotonia congenita are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Occasionally, the heterozygous parent of a proband with autosomal recessive myotonia congenita (i.e., the proband has two
If both parents are known to be heterozygous for a
Intrafamilial clinical variability may be observed in sibs who inherit the same biallelic pathogenic variants [
Occasionally, the heterozygous sibs of a proband with autosomal recessive myotonia congenita (i.e., the proband has two
Carrier testing for at-risk relatives requires prior identification of the
The majority of individuals diagnosed with autosomal dominant myotonia congenita have an affected parent.
A proband with autosomal dominant myotonia congenita may potentially have the disorder as the result of a
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
The family history of some individuals diagnosed with autosomal dominant myotonia congenita may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or early death of the parent before the onset of symptoms. Therefore, an apparent negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial clinical variability may be observed in sibs who inherit the same pathogenic variant [
If the
If the parents have not been tested for the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an individual with autosomal recessive myotonia congenita are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Occasionally, the heterozygous parent of a proband with autosomal recessive myotonia congenita (i.e., the proband has two
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Intrafamilial clinical variability may be observed in sibs who inherit the same biallelic pathogenic variants [
• Occasionally, the heterozygous sibs of a proband with autosomal recessive myotonia congenita (i.e., the proband has two
• The majority of individuals diagnosed with autosomal dominant myotonia congenita have an affected parent.
• A proband with autosomal dominant myotonia congenita may potentially have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with autosomal dominant myotonia congenita may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or early death of the parent before the onset of symptoms. Therefore, an apparent negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial clinical variability may be observed in sibs who inherit the same pathogenic variant [
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Myotonia congenita can be inherited in either an autosomal recessive (Becker disease) or an autosomal dominant (Thomsen disease) manner.
Distinguishing between autosomal dominant and autosomal recessive myotonia congenita depends mainly on the family history (i.e., the presence of an affected parent in autosomal dominant myotonia congenita). However, a clear distinction can be difficult because the same
In a simplex case (i.e., the occurrence of a single individual with myotonia congenita in a family), establishing the mode of inheritance may not be possible unless molecular genetic testing reveals two
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an individual with autosomal recessive myotonia congenita are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Occasionally, the heterozygous parent of a proband with autosomal recessive myotonia congenita (i.e., the proband has two
If both parents are known to be heterozygous for a
Intrafamilial clinical variability may be observed in sibs who inherit the same biallelic pathogenic variants [
Occasionally, the heterozygous sibs of a proband with autosomal recessive myotonia congenita (i.e., the proband has two
Carrier testing for at-risk relatives requires prior identification of the
• The parents of an individual with autosomal recessive myotonia congenita are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Occasionally, the heterozygous parent of a proband with autosomal recessive myotonia congenita (i.e., the proband has two
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Intrafamilial clinical variability may be observed in sibs who inherit the same biallelic pathogenic variants [
• Occasionally, the heterozygous sibs of a proband with autosomal recessive myotonia congenita (i.e., the proband has two
## Heterozygote Detection
Carrier testing for at-risk relatives requires prior identification of the
## Autosomal Dominant Inheritance – Risk to Family Members
The majority of individuals diagnosed with autosomal dominant myotonia congenita have an affected parent.
A proband with autosomal dominant myotonia congenita may potentially have the disorder as the result of a
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
The family history of some individuals diagnosed with autosomal dominant myotonia congenita may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or early death of the parent before the onset of symptoms. Therefore, an apparent negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial clinical variability may be observed in sibs who inherit the same pathogenic variant [
If the
If the parents have not been tested for the
• The majority of individuals diagnosed with autosomal dominant myotonia congenita have an affected parent.
• A proband with autosomal dominant myotonia congenita may potentially have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with autosomal dominant myotonia congenita may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or early death of the parent before the onset of symptoms. Therefore, an apparent negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial clinical variability may be observed in sibs who inherit the same pathogenic variant [
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 5801
Bethesda MD 20824
United Kingdom
•
• PO Box 5801
• Bethesda MD 20824
•
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
Myotonia Congenita: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Myotonia Congenita (
Pathogenic variants associated with autosomal recessive (AR) inheritance are presumed to cause loss of function of the channel; pathogenic variants associated with autosomal dominant (AD) inheritance presumably act through a dominant-negative mechanism by primarily affecting dimerization [
Pathogenic variants causing AD myotonia congenita are often located in exon 8 [
Approximately 20 pathogenic variants have been solely associated with AD myotonia congenita, whereas approximately 12 pathogenic variants associate with both AR and AD myotonia congenita, making it difficult to predict mode of inheritance.
Unambiguous pedigrees with AR inheritance and AD inheritance have been described only for
Reduced penetrance of dominant-negative pathogenic variants
Incomplete dominance
Haplotype background
Incomplete pathogenic variant detection
Differences in variant expression
Notable CLCN1 Pathogenic Variants
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (
Most of the following reports regarding the p.Arg894Ter variant predate the gnomAD data set (see footnote 2):
See
• Reduced penetrance of dominant-negative pathogenic variants
• Incomplete dominance
• Haplotype background
• Incomplete pathogenic variant detection
• Differences in variant expression
## Molecular Pathogenesis
Pathogenic variants associated with autosomal recessive (AR) inheritance are presumed to cause loss of function of the channel; pathogenic variants associated with autosomal dominant (AD) inheritance presumably act through a dominant-negative mechanism by primarily affecting dimerization [
Pathogenic variants causing AD myotonia congenita are often located in exon 8 [
Approximately 20 pathogenic variants have been solely associated with AD myotonia congenita, whereas approximately 12 pathogenic variants associate with both AR and AD myotonia congenita, making it difficult to predict mode of inheritance.
Unambiguous pedigrees with AR inheritance and AD inheritance have been described only for
Reduced penetrance of dominant-negative pathogenic variants
Incomplete dominance
Haplotype background
Incomplete pathogenic variant detection
Differences in variant expression
Notable CLCN1 Pathogenic Variants
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (
Most of the following reports regarding the p.Arg894Ter variant predate the gnomAD data set (see footnote 2):
See
• Reduced penetrance of dominant-negative pathogenic variants
• Incomplete dominance
• Haplotype background
• Incomplete pathogenic variant detection
• Differences in variant expression
## Chapter Notes
Eskild Colding-Jørgensen, MD; University of Copenhagen (2005-2021)Morten Dunø, PhD (2005-present)John Vissing, MD, DMSci (2021-present)
25 February 2021 (bp) Comprehensive update posted live
6 August 2015 (me) Comprehensive update posted live
12 April 2011 (me) Comprehensive update posted live
8 July 2008 (me) Comprehensive update posted live
3 August 2005 (me) Review posted live
14 December 2004 (md) Original submission
• 25 February 2021 (bp) Comprehensive update posted live
• 6 August 2015 (me) Comprehensive update posted live
• 12 April 2011 (me) Comprehensive update posted live
• 8 July 2008 (me) Comprehensive update posted live
• 3 August 2005 (me) Review posted live
• 14 December 2004 (md) Original submission
## Author History
Eskild Colding-Jørgensen, MD; University of Copenhagen (2005-2021)Morten Dunø, PhD (2005-present)John Vissing, MD, DMSci (2021-present)
## Revision History
25 February 2021 (bp) Comprehensive update posted live
6 August 2015 (me) Comprehensive update posted live
12 April 2011 (me) Comprehensive update posted live
8 July 2008 (me) Comprehensive update posted live
3 August 2005 (me) Review posted live
14 December 2004 (md) Original submission
• 25 February 2021 (bp) Comprehensive update posted live
• 6 August 2015 (me) Comprehensive update posted live
• 12 April 2011 (me) Comprehensive update posted live
• 8 July 2008 (me) Comprehensive update posted live
• 3 August 2005 (me) Review posted live
• 14 December 2004 (md) Original submission
## References
Stunnenberg BC, LoRusso S, Arnold WD, Barohn RJ, Cannon SC, Fontaine B, Griggs RC, Hanna MG, Matthews E, Meola G, Sansone VA, Trivedi JR, van Engelen BGM, Vicart S, Statland JM. Guidelines on clinical presentation and management of nondystrophic myotonias. Muscle Nerve. 2020;62:430-44.
• Stunnenberg BC, LoRusso S, Arnold WD, Barohn RJ, Cannon SC, Fontaine B, Griggs RC, Hanna MG, Matthews E, Meola G, Sansone VA, Trivedi JR, van Engelen BGM, Vicart S, Statland JM. Guidelines on clinical presentation and management of nondystrophic myotonias. Muscle Nerve. 2020;62:430-44.
## Published Guidelines / Consensus Statements
Stunnenberg BC, LoRusso S, Arnold WD, Barohn RJ, Cannon SC, Fontaine B, Griggs RC, Hanna MG, Matthews E, Meola G, Sansone VA, Trivedi JR, van Engelen BGM, Vicart S, Statland JM. Guidelines on clinical presentation and management of nondystrophic myotonias. Muscle Nerve. 2020;62:430-44.
• Stunnenberg BC, LoRusso S, Arnold WD, Barohn RJ, Cannon SC, Fontaine B, Griggs RC, Hanna MG, Matthews E, Meola G, Sansone VA, Trivedi JR, van Engelen BGM, Vicart S, Statland JM. Guidelines on clinical presentation and management of nondystrophic myotonias. Muscle Nerve. 2020;62:430-44.
## Literature Cited
|
[] |
3/8/2005
|
25/2/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
myotonic-d
|
myotonic-d
|
[
"Steinert's Disease",
"Steinert's Disease",
"DM1",
"Myotonin-protein kinase",
"DMPK",
"Myotonic Dystrophy Type 1"
] |
Myotonic Dystrophy Type 1
|
Thomas D Bird
|
Summary Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system. The clinical findings, which span a continuum from mild to severe, have been categorized into three somewhat overlapping phenotypes: mild, classic, and congenital. Mild DM1 is characterized by cataract and mild myotonia (sustained muscle contraction); life span is normal. Classic DM1 is characterized by muscle weakness and wasting, myotonia, cataract, and often cardiac conduction abnormalities; adults may become physically disabled and may have a shortened life span. Congenital DM1 is characterized by hypotonia and severe generalized weakness at birth, often with respiratory insufficiency and early death; intellectual disability is common. DM1 is caused by expansion of a CTG trinucleotide repeat in the noncoding region of DM1 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the expanded allele. Pathogenic alleles may expand in length during gametogenesis, resulting in the transmission of longer trinucleotide repeat alleles that may be associated with earlier onset and more severe disease than that observed in the parent. Prenatal testing and preimplantation genetic testing are possible when the diagnosis of DM1 has been confirmed by molecular genetic testing in an affected family member.
|
## Diagnosis
Myotonic dystrophy type 1 (DM1)
Muscle weakness, especially of the distal leg, hand, neck, and face
Myotonia (sustained muscle contraction), which often manifests as the inability to quickly release a hand grip (grip myotonia) and which can be demonstrated by tapping a muscle (e.g., the thenar muscles) with a reflex hammer (percussion myotonia)
Posterior subcapsular cataracts detectable as red and green iridescent opacities on slit lamp examination
DM1
Hypotonia
Facial muscle weakness
Generalized weakness
Positional malformations including clubfoot
Respiratory insufficiency
The diagnosis of DM1
See
Testing approaches include the following:
For an introduction to multigene panels click
Molecular Genetic Testing Used in Myotonic Dystrophy Type 1
See
See
Testing to quantitate the number of
Note: Non-molecular testing that has been used in the past to establish the diagnosis of DM1 currently has little role in diagnosis and is primarily used if molecular testing of
• Muscle weakness, especially of the distal leg, hand, neck, and face
• Myotonia (sustained muscle contraction), which often manifests as the inability to quickly release a hand grip (grip myotonia) and which can be demonstrated by tapping a muscle (e.g., the thenar muscles) with a reflex hammer (percussion myotonia)
• Posterior subcapsular cataracts detectable as red and green iridescent opacities on slit lamp examination
• Hypotonia
• Facial muscle weakness
• Generalized weakness
• Positional malformations including clubfoot
• Respiratory insufficiency
• For an introduction to multigene panels click
## Suggestive Findings
Myotonic dystrophy type 1 (DM1)
Muscle weakness, especially of the distal leg, hand, neck, and face
Myotonia (sustained muscle contraction), which often manifests as the inability to quickly release a hand grip (grip myotonia) and which can be demonstrated by tapping a muscle (e.g., the thenar muscles) with a reflex hammer (percussion myotonia)
Posterior subcapsular cataracts detectable as red and green iridescent opacities on slit lamp examination
DM1
Hypotonia
Facial muscle weakness
Generalized weakness
Positional malformations including clubfoot
Respiratory insufficiency
• Muscle weakness, especially of the distal leg, hand, neck, and face
• Myotonia (sustained muscle contraction), which often manifests as the inability to quickly release a hand grip (grip myotonia) and which can be demonstrated by tapping a muscle (e.g., the thenar muscles) with a reflex hammer (percussion myotonia)
• Posterior subcapsular cataracts detectable as red and green iridescent opacities on slit lamp examination
• Hypotonia
• Facial muscle weakness
• Generalized weakness
• Positional malformations including clubfoot
• Respiratory insufficiency
## Establishing the Diagnosis
The diagnosis of DM1
See
Testing approaches include the following:
For an introduction to multigene panels click
Molecular Genetic Testing Used in Myotonic Dystrophy Type 1
See
See
Testing to quantitate the number of
Note: Non-molecular testing that has been used in the past to establish the diagnosis of DM1 currently has little role in diagnosis and is primarily used if molecular testing of
• For an introduction to multigene panels click
## Molecular Genetic Testing
Testing approaches include the following:
For an introduction to multigene panels click
Molecular Genetic Testing Used in Myotonic Dystrophy Type 1
See
See
Testing to quantitate the number of
• For an introduction to multigene panels click
## Other Testing
Note: Non-molecular testing that has been used in the past to establish the diagnosis of DM1 currently has little role in diagnosis and is primarily used if molecular testing of
## Clinical Characteristics
DM1 is a systemic disease potentially affecting nearly every organ system. Clinical findings in myotonic dystrophy type 1 (DM1) span a continuum from mild to severe.
Correlation of Phenotype and CTG Repeat Length in Myotonic Dystrophy Type 1
Cataracts
Mild myotonia
Weakness
Myotonia
Cataracts
Balding
Cardiac arrhythmia
Infantile hypotonia
Respiratory deficits
Intellectual disability
Classic signs in adults
From
NA = not applicable
CTG repeat sizes are known to overlap between phenotypes.
Normal CTG repeat size is 5-34.
Does not include neonatal deaths
Individuals with mild DM1 may have only cataract, mild myotonia, or diabetes mellitus. They may have fully active lives and a normal or minimally shortened life span [
Within this range of CTG repeat size, only a rough correlation with severity of symptoms exists. Individuals with CTG repeat sizes in the 100-to-1,000 range usually develop classic DM1 with muscle weakness and wasting, myotonia, cataracts, and often cardiac conduction abnormalities.
While the age of onset for classic DM1 is typically in the 20s and 30s (and less commonly after age 40 years), classic DM1 may be evident in childhood, when subtle signs such as myotonia and typical facial features including ptosis, weak eyelid closure, weak smile, and thin face are observed.
Fatigue is a common finding [
Musculoskeletal pain is fairly common, especially in the lower limbs.
Gallstones occur as a result of increased tone of the gallbladder sphincter [
Liver function tests (e.g., transaminases) are often elevated for unclear reasons [
Frontal-parietal lobe deficits have been documented on formal testing [
Avoidant, obsessive-compulsive, and passive-aggressive personality features have been reported [
In one study of 200 individuals with DM1, personality traits and psychological symptoms were usually in the normal range, but 27% were at high risk of developing a psychiatric disorder [
Anxiety and depression are often seen and general quality of life can be seriously impaired [
Hypersomnia and sleep apnea are other well-recognized manifestations that appear later [
Brain MRI may demonstrate mild cortical atrophy and white matter abnormalities. The white matter changes can be diffuse and extensive [
At autopsy, brain neurons may contain tau-associated neurofibrillary tangles [
Some affected individuals have ophthalmoplegia.
Several studies have evaluated life span and mortality in DM1 (
A transmission ratio distortion at conception favors transmission of larger CTG repeats than those present in the parent [
In general, longer CTG repeat expansions correlate with an earlier age of onset and more severe disease [
The
A person who was a compound heterozygote for expanded alleles with 1,260 and 60 CTG repeats was reported to have cerebral abnormalities [
Penetrance is high (nearly 100% by age 50 years) when all manifestations of the disease, even those that are subtle, are sought. However, mild cases (e.g., persons with only cataracts) may be missed [
Because
Most often a child with early-onset, severe DM1 (i.e., congenital DM1) has inherited the expanded
In a study of children of parents with small expansions (50-100 CTG repeats), those with expanded alleles transmitted paternally had a larger increase in CTG repeats (median: 425 repeats; range: 70-2,000) than did those with maternally transmitted expanded alleles (median: 200 repeats; range: 57-1,400) [
Estimates of the prevalence of DM1 range from 1:100,000 in some areas of Japan to 1:10,000 in Iceland, with an overall estimated worldwide prevalence of 1:20,000 [
A report in 2021 found a prevalence of 4.76:10,000 for DMPK CTG expansions of ≥50 CTG repeats in a newborn blood spot screening program in New York State [
Founder effects may increase the prevalence in specific regions, such as Quebec [
• Cataracts
• Mild myotonia
• Weakness
• Myotonia
• Cataracts
• Balding
• Cardiac arrhythmia
• Infantile hypotonia
• Respiratory deficits
• Intellectual disability
• Classic signs in adults
## Clinical Description
DM1 is a systemic disease potentially affecting nearly every organ system. Clinical findings in myotonic dystrophy type 1 (DM1) span a continuum from mild to severe.
Correlation of Phenotype and CTG Repeat Length in Myotonic Dystrophy Type 1
Cataracts
Mild myotonia
Weakness
Myotonia
Cataracts
Balding
Cardiac arrhythmia
Infantile hypotonia
Respiratory deficits
Intellectual disability
Classic signs in adults
From
NA = not applicable
CTG repeat sizes are known to overlap between phenotypes.
Normal CTG repeat size is 5-34.
Does not include neonatal deaths
Individuals with mild DM1 may have only cataract, mild myotonia, or diabetes mellitus. They may have fully active lives and a normal or minimally shortened life span [
Within this range of CTG repeat size, only a rough correlation with severity of symptoms exists. Individuals with CTG repeat sizes in the 100-to-1,000 range usually develop classic DM1 with muscle weakness and wasting, myotonia, cataracts, and often cardiac conduction abnormalities.
While the age of onset for classic DM1 is typically in the 20s and 30s (and less commonly after age 40 years), classic DM1 may be evident in childhood, when subtle signs such as myotonia and typical facial features including ptosis, weak eyelid closure, weak smile, and thin face are observed.
Fatigue is a common finding [
Musculoskeletal pain is fairly common, especially in the lower limbs.
Gallstones occur as a result of increased tone of the gallbladder sphincter [
Liver function tests (e.g., transaminases) are often elevated for unclear reasons [
Frontal-parietal lobe deficits have been documented on formal testing [
Avoidant, obsessive-compulsive, and passive-aggressive personality features have been reported [
In one study of 200 individuals with DM1, personality traits and psychological symptoms were usually in the normal range, but 27% were at high risk of developing a psychiatric disorder [
Anxiety and depression are often seen and general quality of life can be seriously impaired [
Hypersomnia and sleep apnea are other well-recognized manifestations that appear later [
Brain MRI may demonstrate mild cortical atrophy and white matter abnormalities. The white matter changes can be diffuse and extensive [
At autopsy, brain neurons may contain tau-associated neurofibrillary tangles [
Some affected individuals have ophthalmoplegia.
Several studies have evaluated life span and mortality in DM1 (
A transmission ratio distortion at conception favors transmission of larger CTG repeats than those present in the parent [
• Cataracts
• Mild myotonia
• Weakness
• Myotonia
• Cataracts
• Balding
• Cardiac arrhythmia
• Infantile hypotonia
• Respiratory deficits
• Intellectual disability
• Classic signs in adults
## Mild DM1
Individuals with mild DM1 may have only cataract, mild myotonia, or diabetes mellitus. They may have fully active lives and a normal or minimally shortened life span [
## Classic DM1
Within this range of CTG repeat size, only a rough correlation with severity of symptoms exists. Individuals with CTG repeat sizes in the 100-to-1,000 range usually develop classic DM1 with muscle weakness and wasting, myotonia, cataracts, and often cardiac conduction abnormalities.
While the age of onset for classic DM1 is typically in the 20s and 30s (and less commonly after age 40 years), classic DM1 may be evident in childhood, when subtle signs such as myotonia and typical facial features including ptosis, weak eyelid closure, weak smile, and thin face are observed.
Fatigue is a common finding [
Musculoskeletal pain is fairly common, especially in the lower limbs.
Gallstones occur as a result of increased tone of the gallbladder sphincter [
Liver function tests (e.g., transaminases) are often elevated for unclear reasons [
Frontal-parietal lobe deficits have been documented on formal testing [
Avoidant, obsessive-compulsive, and passive-aggressive personality features have been reported [
In one study of 200 individuals with DM1, personality traits and psychological symptoms were usually in the normal range, but 27% were at high risk of developing a psychiatric disorder [
Anxiety and depression are often seen and general quality of life can be seriously impaired [
Hypersomnia and sleep apnea are other well-recognized manifestations that appear later [
Brain MRI may demonstrate mild cortical atrophy and white matter abnormalities. The white matter changes can be diffuse and extensive [
At autopsy, brain neurons may contain tau-associated neurofibrillary tangles [
Some affected individuals have ophthalmoplegia.
Several studies have evaluated life span and mortality in DM1 (
## Congenital DM1
A transmission ratio distortion at conception favors transmission of larger CTG repeats than those present in the parent [
## Genotype-Phenotype Correlations
In general, longer CTG repeat expansions correlate with an earlier age of onset and more severe disease [
The
A person who was a compound heterozygote for expanded alleles with 1,260 and 60 CTG repeats was reported to have cerebral abnormalities [
## Penetrance
Penetrance is high (nearly 100% by age 50 years) when all manifestations of the disease, even those that are subtle, are sought. However, mild cases (e.g., persons with only cataracts) may be missed [
## Anticipation
Because
Most often a child with early-onset, severe DM1 (i.e., congenital DM1) has inherited the expanded
In a study of children of parents with small expansions (50-100 CTG repeats), those with expanded alleles transmitted paternally had a larger increase in CTG repeats (median: 425 repeats; range: 70-2,000) than did those with maternally transmitted expanded alleles (median: 200 repeats; range: 57-1,400) [
## Prevalence
Estimates of the prevalence of DM1 range from 1:100,000 in some areas of Japan to 1:10,000 in Iceland, with an overall estimated worldwide prevalence of 1:20,000 [
A report in 2021 found a prevalence of 4.76:10,000 for DMPK CTG expansions of ≥50 CTG repeats in a newborn blood spot screening program in New York State [
Founder effects may increase the prevalence in specific regions, such as Quebec [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Hypotonia in infancy is seen in many disorders, including
DM2 is the only other known genetic form of multisystem myotonic dystrophy identified to date (although others likely exist). The distinction between DM1, DM2, and other inherited myopathies is made by determining the number of CTG repeats in
Occasionally, DM1 has been misdiagnosed as motor neuron disease (see
## Management
To establish the extent of disease and needs
Recommended Evaluations Following Initial Diagnosis in Adults with Myotonic Dystrophy Type 1
Pneumonia & flu vaccinations
Referral to pulmonologist if symptomatic
Liver enzyme elevation is common.
Consider internal medicine &/or gastroenterology consultation.
Miscarriage & preterm delivery is common in affected women; see
To establish the extent of disease and needs
Recommended Evaluations Following Initial Diagnosis in Children with Myotonic Dystrophy Type 1
Management guidelines have been developed [
No specific treatment exists for the progressive weakness in individuals with DM1.
A physiatrist, occupational therapist, or physical therapist can help evaluate affected individuals regarding the need for ankle-foot orthoses, wheelchairs, or other assistive devices as the disease progresses. Orthopedic surgery may benefit children with musculoskeletal deformities [
Special education support is indicated for children with DM1.
Increased weakness in DM1 has been associated with both hypothyroidism and certain cholesterol-lowering medications (i.e., statins); thus, some strength may return if these causative factors are eliminated.
Myotonia in DM1 is typically mild to moderate and rarely requires treatment [
Pain management can be an important part of DM1 treatment. Different medications and combinations of medications work for some individuals, although none has been routinely effective; medications that have been used include mexiletine, gabapentin, nonsteroidal anti-inflammatory drugs, low-dose thyroid replacement, low-dose steroids, and tricyclic antidepressants. When used as part of a comprehensive pain management program, low-dose analgesics may provide relief.
Consultation with a cardiologist is appropriate for individuals with cardiac symptoms or EKG evidence of arrhythmia because fatal arrhythmias can occur prior to other symptoms in individuals with DM1. More advanced, invasive electrophysiologic testing of the heart may be required [
Cataracts can be removed if they impair vision. Recurrence after surgery has been reported [
Males with low serum concentration of testosterone require hormone replacement therapy if they are symptomatic.
In most cases, surgical excision of pilomatrixoma including clear margins and its overlying skin is the preferred treatment [
An extensive review found no evidence for successful treatment of hypersomnia with routine psychostimulants [
Cardiac pacemakers or implantable cardioverter-defibrillators may prevent life-threatening arrhythmias [
Mechanical ventilation for pulmonary insufficiency may be needed [
Gallbladder removal is sometimes required [
Careful attention to anesthetic management during surgery is required [
The following are appropriate:
Annual EKG to detect asymptomatic cardiac conduction defects. Some centers perform annual 24-hour Holter monitoring of individuals with DM1 who do not have cardiac symptoms [
Annual measurement of fasting serum glucose concentration and glycosylated hemoglobin concentration, with treatment for diabetes mellitus if indicated [
Ophthalmologic examination every two years to evaluate for cataract formation
Attention to nutritional status including mastication and trouble eating [
Polysomnographic follow up of sleep complaints [
Statins used to lower cholesterol may sometimes cause muscle pain and weakness.
Malignant hyperthermia during anesthesia including the use of vecuronium [
Aggressive doxorubicin-based chemotherapy for lymphoma in a person with DM1 produced sudden atrial fibrillations [
It is appropriate to clarify the genetic status of apparently asymptomatic at-risk adult relatives of an affected individual to allow for early diagnosis and treatment of cardiac manifestations, diabetes mellitus, and cataracts.
See
Women with DM1 are at risk for complications during pregnancy including increased spontaneous abortion rate, premature labor, prolonged labor, retained placenta, placenta previa, and postpartum hemorrhage [
Complications related to the presence of congenital DM1 in the fetus include reduced fetal movement and polyhydramnios.
See
Search
Moderate-intensity strength training does no harm, but it is unclear whether it offers measurable benefits [
• Annual EKG to detect asymptomatic cardiac conduction defects. Some centers perform annual 24-hour Holter monitoring of individuals with DM1 who do not have cardiac symptoms [
• Annual measurement of fasting serum glucose concentration and glycosylated hemoglobin concentration, with treatment for diabetes mellitus if indicated [
• Ophthalmologic examination every two years to evaluate for cataract formation
• Attention to nutritional status including mastication and trouble eating [
• Polysomnographic follow up of sleep complaints [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs
Recommended Evaluations Following Initial Diagnosis in Adults with Myotonic Dystrophy Type 1
Pneumonia & flu vaccinations
Referral to pulmonologist if symptomatic
Liver enzyme elevation is common.
Consider internal medicine &/or gastroenterology consultation.
Miscarriage & preterm delivery is common in affected women; see
To establish the extent of disease and needs
Recommended Evaluations Following Initial Diagnosis in Children with Myotonic Dystrophy Type 1
## Treatment of Manifestations
Management guidelines have been developed [
No specific treatment exists for the progressive weakness in individuals with DM1.
A physiatrist, occupational therapist, or physical therapist can help evaluate affected individuals regarding the need for ankle-foot orthoses, wheelchairs, or other assistive devices as the disease progresses. Orthopedic surgery may benefit children with musculoskeletal deformities [
Special education support is indicated for children with DM1.
Increased weakness in DM1 has been associated with both hypothyroidism and certain cholesterol-lowering medications (i.e., statins); thus, some strength may return if these causative factors are eliminated.
Myotonia in DM1 is typically mild to moderate and rarely requires treatment [
Pain management can be an important part of DM1 treatment. Different medications and combinations of medications work for some individuals, although none has been routinely effective; medications that have been used include mexiletine, gabapentin, nonsteroidal anti-inflammatory drugs, low-dose thyroid replacement, low-dose steroids, and tricyclic antidepressants. When used as part of a comprehensive pain management program, low-dose analgesics may provide relief.
Consultation with a cardiologist is appropriate for individuals with cardiac symptoms or EKG evidence of arrhythmia because fatal arrhythmias can occur prior to other symptoms in individuals with DM1. More advanced, invasive electrophysiologic testing of the heart may be required [
Cataracts can be removed if they impair vision. Recurrence after surgery has been reported [
Males with low serum concentration of testosterone require hormone replacement therapy if they are symptomatic.
In most cases, surgical excision of pilomatrixoma including clear margins and its overlying skin is the preferred treatment [
An extensive review found no evidence for successful treatment of hypersomnia with routine psychostimulants [
## Prevention of Secondary Complications
Cardiac pacemakers or implantable cardioverter-defibrillators may prevent life-threatening arrhythmias [
Mechanical ventilation for pulmonary insufficiency may be needed [
Gallbladder removal is sometimes required [
Careful attention to anesthetic management during surgery is required [
## Surveillance
The following are appropriate:
Annual EKG to detect asymptomatic cardiac conduction defects. Some centers perform annual 24-hour Holter monitoring of individuals with DM1 who do not have cardiac symptoms [
Annual measurement of fasting serum glucose concentration and glycosylated hemoglobin concentration, with treatment for diabetes mellitus if indicated [
Ophthalmologic examination every two years to evaluate for cataract formation
Attention to nutritional status including mastication and trouble eating [
Polysomnographic follow up of sleep complaints [
• Annual EKG to detect asymptomatic cardiac conduction defects. Some centers perform annual 24-hour Holter monitoring of individuals with DM1 who do not have cardiac symptoms [
• Annual measurement of fasting serum glucose concentration and glycosylated hemoglobin concentration, with treatment for diabetes mellitus if indicated [
• Ophthalmologic examination every two years to evaluate for cataract formation
• Attention to nutritional status including mastication and trouble eating [
• Polysomnographic follow up of sleep complaints [
## Agents/Circumstances to Avoid
Statins used to lower cholesterol may sometimes cause muscle pain and weakness.
Malignant hyperthermia during anesthesia including the use of vecuronium [
Aggressive doxorubicin-based chemotherapy for lymphoma in a person with DM1 produced sudden atrial fibrillations [
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic at-risk adult relatives of an affected individual to allow for early diagnosis and treatment of cardiac manifestations, diabetes mellitus, and cataracts.
See
## Pregnancy Management
Women with DM1 are at risk for complications during pregnancy including increased spontaneous abortion rate, premature labor, prolonged labor, retained placenta, placenta previa, and postpartum hemorrhage [
Complications related to the presence of congenital DM1 in the fetus include reduced fetal movement and polyhydramnios.
See
## Therapies Under Investigation
Search
## Other
Moderate-intensity strength training does no harm, but it is unclear whether it offers measurable benefits [
## Genetic Counseling
Myotonic dystrophy type 1 (DM1) is inherited in an autosomal dominant manner.
Virtually all individuals with DM1 inherited their expanded CTG allele from a parent who also has an allele in the abnormal range (>34 CTG repeats); however, the parent with the expanded allele may or may not appear to be affected. The parent may appear to be unaffected because of failure to recognize symptoms of mild DM1 or the parent may have no symptoms and have an abnormal, but small, CTG repeat expansion.
New expansions of a normal allele (≤34 CTG repeats) into the abnormal range are rare.
If both parents of a proband are asymptomatic, it is appropriate to offer
If a CTG expansion in the abnormal range (>34 repeats) cannot be detected in the leukocyte DNA of either parent, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could be explored.
If one parent has an expanded
An expanded
Each child of an individual with an expanded
An expanded
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
For more information, see the National Society of Genetic Counselors
Testing is appropriate to consider in symptomatic individuals in a family with an established diagnosis of DM1 regardless of age.
Note: (1) Abnormal test results do not predict the age of onset or severity of the disease because of the overlap of CTG repeat length associated with the three phenotypes and the possibility of somatic mosaicism for the size of the CTG expansion. However, CTG repeat lengths of 730-1,000 or greater are more likely to be associated with congenital DM1 [
• Virtually all individuals with DM1 inherited their expanded CTG allele from a parent who also has an allele in the abnormal range (>34 CTG repeats); however, the parent with the expanded allele may or may not appear to be affected. The parent may appear to be unaffected because of failure to recognize symptoms of mild DM1 or the parent may have no symptoms and have an abnormal, but small, CTG repeat expansion.
• New expansions of a normal allele (≤34 CTG repeats) into the abnormal range are rare.
• If both parents of a proband are asymptomatic, it is appropriate to offer
• If a CTG expansion in the abnormal range (>34 repeats) cannot be detected in the leukocyte DNA of either parent, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could be explored.
• If one parent has an expanded
• An expanded
• Each child of an individual with an expanded
• An expanded
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Myotonic dystrophy type 1 (DM1) is inherited in an autosomal dominant manner.
## Risk to Family Members
Virtually all individuals with DM1 inherited their expanded CTG allele from a parent who also has an allele in the abnormal range (>34 CTG repeats); however, the parent with the expanded allele may or may not appear to be affected. The parent may appear to be unaffected because of failure to recognize symptoms of mild DM1 or the parent may have no symptoms and have an abnormal, but small, CTG repeat expansion.
New expansions of a normal allele (≤34 CTG repeats) into the abnormal range are rare.
If both parents of a proband are asymptomatic, it is appropriate to offer
If a CTG expansion in the abnormal range (>34 repeats) cannot be detected in the leukocyte DNA of either parent, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could be explored.
If one parent has an expanded
An expanded
Each child of an individual with an expanded
An expanded
• Virtually all individuals with DM1 inherited their expanded CTG allele from a parent who also has an allele in the abnormal range (>34 CTG repeats); however, the parent with the expanded allele may or may not appear to be affected. The parent may appear to be unaffected because of failure to recognize symptoms of mild DM1 or the parent may have no symptoms and have an abnormal, but small, CTG repeat expansion.
• New expansions of a normal allele (≤34 CTG repeats) into the abnormal range are rare.
• If both parents of a proband are asymptomatic, it is appropriate to offer
• If a CTG expansion in the abnormal range (>34 repeats) cannot be detected in the leukocyte DNA of either parent, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could be explored.
• If one parent has an expanded
• An expanded
• Each child of an individual with an expanded
• An expanded
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
For more information, see the National Society of Genetic Counselors
Testing is appropriate to consider in symptomatic individuals in a family with an established diagnosis of DM1 regardless of age.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Note: (1) Abnormal test results do not predict the age of onset or severity of the disease because of the overlap of CTG repeat length associated with the three phenotypes and the possibility of somatic mosaicism for the size of the CTG expansion. However, CTG repeat lengths of 730-1,000 or greater are more likely to be associated with congenital DM1 [
## Resources
University of Washington Medical Center, Medical Genetics and Neurology
Seattle WA
Neuromuscular Network
United Kingdom
•
•
•
•
•
•
•
•
•
•
•
• University of Washington Medical Center, Medical Genetics and Neurology
• Seattle WA
•
•
•
•
• Neuromuscular Network
•
•
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
Myotonic Dystrophy Type 1: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Myotonic Dystrophy Type 1 (
Variants listed in the table have been provided by the author.
NA = not applicable
The CTG variant is in the 3' untranslated region of the gene (indicated by *), with the first nucleotide after the stop codon numbered as *1. Parentheses indicate the range of numbers of the CTG repeats, here indicating that normal alleles range from 5 to 34 repeats. A specific single allele with five repeats would be designated c.*224_226CTG[5].
## Chapter Notes
NIH CAP Award (3 MO1 RR00425-2856)
Cameron Adams, MD; Cedars-Sinai Medical Center (1999-2004)Thomas D Bird, MD (2004-present)
14 November 2024 (tb) Revision: reference added:
21 March 2024 (tb) Revision: references added:
25 March 2021 (tb) Revision: addition to
29 October 2020 (tb) Revision: addition to
3 October 2019 (tb) Revision: additions to
6 December 2018 (ma) Revision: updated practice guidelines
12 July 2018 (sw) Comprehensive update posted live
10 September 2015 (me) Comprehensive update posted live
16 May 2013 (me) Comprehensive update posted live
8 February 2011 (me) Comprehensive update posted live
15 November 2007 (me) Comprehensive update posted live
17 September 1999 (me) Review posted live
31 December 1998 (ca) Original submission
• 14 November 2024 (tb) Revision: reference added:
• 21 March 2024 (tb) Revision: references added:
• 25 March 2021 (tb) Revision: addition to
• 29 October 2020 (tb) Revision: addition to
• 3 October 2019 (tb) Revision: additions to
• 6 December 2018 (ma) Revision: updated practice guidelines
• 12 July 2018 (sw) Comprehensive update posted live
• 10 September 2015 (me) Comprehensive update posted live
• 16 May 2013 (me) Comprehensive update posted live
• 8 February 2011 (me) Comprehensive update posted live
• 15 November 2007 (me) Comprehensive update posted live
• 17 September 1999 (me) Review posted live
• 31 December 1998 (ca) Original submission
## Acknowledgments
NIH CAP Award (3 MO1 RR00425-2856)
## Author History
Cameron Adams, MD; Cedars-Sinai Medical Center (1999-2004)Thomas D Bird, MD (2004-present)
## Revision History
14 November 2024 (tb) Revision: reference added:
21 March 2024 (tb) Revision: references added:
25 March 2021 (tb) Revision: addition to
29 October 2020 (tb) Revision: addition to
3 October 2019 (tb) Revision: additions to
6 December 2018 (ma) Revision: updated practice guidelines
12 July 2018 (sw) Comprehensive update posted live
10 September 2015 (me) Comprehensive update posted live
16 May 2013 (me) Comprehensive update posted live
8 February 2011 (me) Comprehensive update posted live
15 November 2007 (me) Comprehensive update posted live
17 September 1999 (me) Review posted live
31 December 1998 (ca) Original submission
• 14 November 2024 (tb) Revision: reference added:
• 21 March 2024 (tb) Revision: references added:
• 25 March 2021 (tb) Revision: addition to
• 29 October 2020 (tb) Revision: addition to
• 3 October 2019 (tb) Revision: additions to
• 6 December 2018 (ma) Revision: updated practice guidelines
• 12 July 2018 (sw) Comprehensive update posted live
• 10 September 2015 (me) Comprehensive update posted live
• 16 May 2013 (me) Comprehensive update posted live
• 8 February 2011 (me) Comprehensive update posted live
• 15 November 2007 (me) Comprehensive update posted live
• 17 September 1999 (me) Review posted live
• 31 December 1998 (ca) Original submission
## References
Ashizawa T, Gagnon C, Groh WJ, Gutmann L, Johnson NE, Meola G, Moxley R 3rd, Pandya S, Rogers MT, Simpson E, Angeard N, Bassez G, Berggren KN, Bhakta D, Bozzali M, Broderick A, Byrne JLB, Campbell C, Cup E, Day JW, De Mattia E, Duboc D, Duong T, Eichinger K, Ekstrom AB, van Engelen B, Esparis B, Eymard B, Ferschl M, Gadalla SM, Gallais B, Goodglick T, Heatwole C, Hilbert J, Holland V, Kierkegaard M, Koopman WJ, Lane K, Maas D, Mankodi A, Mathews KD, Monckton DG, Moser D, Nazarian S, Nguyen L, Nopoulos P, Petty R, Phetteplace J, Puymirat J, Raman S, Richer L, Roma E, Sampson J, Sansone V, Schoser B, Sterling L, Statland J, Subramony SH, Tian C, Trujillo C, Tomaselli G, Turner C, Venance S, Verma A, White M, Winblad S. Consensus-based care recommendations for adults with myotonic dystrophy type 1. Neurol Clin Pract. 2018;8:507-20. [
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
Kamsteeg EJ, Kress W, Catalli C, Hertz JM, Witsch-Baumgartner M, Buckley MF, van Engelen BG, Schwartz M, Scheffer H. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2. Eur J Hum Genet. 2012;20:1203-8. [
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
Prior TW. American College of Medical Genetics (ACMG) Laboratory Quality Assurance Committee technical standards and guidelines for myotonic dystrophy type 1 testing. Available
• Ashizawa T, Gagnon C, Groh WJ, Gutmann L, Johnson NE, Meola G, Moxley R 3rd, Pandya S, Rogers MT, Simpson E, Angeard N, Bassez G, Berggren KN, Bhakta D, Bozzali M, Broderick A, Byrne JLB, Campbell C, Cup E, Day JW, De Mattia E, Duboc D, Duong T, Eichinger K, Ekstrom AB, van Engelen B, Esparis B, Eymard B, Ferschl M, Gadalla SM, Gallais B, Goodglick T, Heatwole C, Hilbert J, Holland V, Kierkegaard M, Koopman WJ, Lane K, Maas D, Mankodi A, Mathews KD, Monckton DG, Moser D, Nazarian S, Nguyen L, Nopoulos P, Petty R, Phetteplace J, Puymirat J, Raman S, Richer L, Roma E, Sampson J, Sansone V, Schoser B, Sterling L, Statland J, Subramony SH, Tian C, Trujillo C, Tomaselli G, Turner C, Venance S, Verma A, White M, Winblad S. Consensus-based care recommendations for adults with myotonic dystrophy type 1. Neurol Clin Pract. 2018;8:507-20. [
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• Kamsteeg EJ, Kress W, Catalli C, Hertz JM, Witsch-Baumgartner M, Buckley MF, van Engelen BG, Schwartz M, Scheffer H. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2. Eur J Hum Genet. 2012;20:1203-8. [
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Prior TW. American College of Medical Genetics (ACMG) Laboratory Quality Assurance Committee technical standards and guidelines for myotonic dystrophy type 1 testing. Available
## Published Guidelines / Consensus Statements
Ashizawa T, Gagnon C, Groh WJ, Gutmann L, Johnson NE, Meola G, Moxley R 3rd, Pandya S, Rogers MT, Simpson E, Angeard N, Bassez G, Berggren KN, Bhakta D, Bozzali M, Broderick A, Byrne JLB, Campbell C, Cup E, Day JW, De Mattia E, Duboc D, Duong T, Eichinger K, Ekstrom AB, van Engelen B, Esparis B, Eymard B, Ferschl M, Gadalla SM, Gallais B, Goodglick T, Heatwole C, Hilbert J, Holland V, Kierkegaard M, Koopman WJ, Lane K, Maas D, Mankodi A, Mathews KD, Monckton DG, Moser D, Nazarian S, Nguyen L, Nopoulos P, Petty R, Phetteplace J, Puymirat J, Raman S, Richer L, Roma E, Sampson J, Sansone V, Schoser B, Sterling L, Statland J, Subramony SH, Tian C, Trujillo C, Tomaselli G, Turner C, Venance S, Verma A, White M, Winblad S. Consensus-based care recommendations for adults with myotonic dystrophy type 1. Neurol Clin Pract. 2018;8:507-20. [
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
Kamsteeg EJ, Kress W, Catalli C, Hertz JM, Witsch-Baumgartner M, Buckley MF, van Engelen BG, Schwartz M, Scheffer H. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2. Eur J Hum Genet. 2012;20:1203-8. [
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
Prior TW. American College of Medical Genetics (ACMG) Laboratory Quality Assurance Committee technical standards and guidelines for myotonic dystrophy type 1 testing. Available
• Ashizawa T, Gagnon C, Groh WJ, Gutmann L, Johnson NE, Meola G, Moxley R 3rd, Pandya S, Rogers MT, Simpson E, Angeard N, Bassez G, Berggren KN, Bhakta D, Bozzali M, Broderick A, Byrne JLB, Campbell C, Cup E, Day JW, De Mattia E, Duboc D, Duong T, Eichinger K, Ekstrom AB, van Engelen B, Esparis B, Eymard B, Ferschl M, Gadalla SM, Gallais B, Goodglick T, Heatwole C, Hilbert J, Holland V, Kierkegaard M, Koopman WJ, Lane K, Maas D, Mankodi A, Mathews KD, Monckton DG, Moser D, Nazarian S, Nguyen L, Nopoulos P, Petty R, Phetteplace J, Puymirat J, Raman S, Richer L, Roma E, Sampson J, Sansone V, Schoser B, Sterling L, Statland J, Subramony SH, Tian C, Trujillo C, Tomaselli G, Turner C, Venance S, Verma A, White M, Winblad S. Consensus-based care recommendations for adults with myotonic dystrophy type 1. Neurol Clin Pract. 2018;8:507-20. [
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• Kamsteeg EJ, Kress W, Catalli C, Hertz JM, Witsch-Baumgartner M, Buckley MF, van Engelen BG, Schwartz M, Scheffer H. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2. Eur J Hum Genet. 2012;20:1203-8. [
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Prior TW. American College of Medical Genetics (ACMG) Laboratory Quality Assurance Committee technical standards and guidelines for myotonic dystrophy type 1 testing. Available
## Literature Cited
|
[] |
17/9/1999
|
12/7/2018
|
14/11/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
myotonic-d2
|
myotonic-d2
|
[
"Proximal Myotonic Myopathy (PROMM)",
"Proximal Myotonic Myopathy (PROMM)",
"CCHC-type zinc finger nucleic acid binding protein",
"CNBP",
"Myotonic Dystrophy Type 2"
] |
Myotonic Dystrophy Type 2
|
Benedikt Schoser
|
Summary Myotonic dystrophy type 2 (DM2) is characterized by myotonia and muscle dysfunction (proximal and axial weakness, myalgia, and stiffness), and less commonly by posterior subcapsular cataracts, cardiac conduction defects, insulin-insensitive type 2 diabetes mellitus, and other endocrine abnormalities. While myotonia (involuntary muscle contraction with delayed relaxation) has been reported during the first decade, onset is typically in the third to fourth decade, most commonly with fluctuating or episodic muscle pain that can be debilitating and proximal and axial weakness of the neck flexors and the hip flexors. Subsequently, weakness occurs in the elbow extensors and finger flexors. Facial weakness and weakness of the ankle dorsiflexors are less common. Myotonia rarely causes severe symptoms. In a subset of individuals, calf hypertrophy in combination with brisk reflexes is notable. The diagnosis of DM2 is established in a proband by identification of a heterozygous pathogenic expansion of a CCTG repeat within a complex repeat motif, (TG) DM2 is inherited in an autosomal dominant manner. To date, all individuals whose biological parents have been evaluated with molecular genetic testing have had one parent with a CCTG repeat expansion;
|
## Diagnosis
In 2019, consensus-based care recommendations and recommendations on the molecular diagnosis of myotonic dystrophy type 2 (DM2) were published [
DM2
The diagnosis of DM2
≤30 uninterrupted CCTG repeats
11-26 CCTG repeats
Testing approaches can include
Molecular Genetic Testing Used in Myotonic Dystrophy Type 2
See
See
Testing to quantitate the number of
Detection frequency varies by method used. When routine PCR analysis, Southern blot analysis, and PCR repeat-primed assay are all used, the variant detection frequency is greater than 99%.
Type 1 fiber atrophy is a common feature in individuals with congenital DM1, distinguishing it from DM2.
Preferential type 2 fiber atrophy has been observed in individuals with DM2 [
•
• ≤30 uninterrupted CCTG repeats
• 11-26 CCTG repeats
• ≤30 uninterrupted CCTG repeats
• 11-26 CCTG repeats
• ≤30 uninterrupted CCTG repeats
• 11-26 CCTG repeats
• Type 1 fiber atrophy is a common feature in individuals with congenital DM1, distinguishing it from DM2.
• Preferential type 2 fiber atrophy has been observed in individuals with DM2 [
## Suggestive Findings
DM2
## Establishing the Diagnosis
The diagnosis of DM2
≤30 uninterrupted CCTG repeats
11-26 CCTG repeats
Testing approaches can include
Molecular Genetic Testing Used in Myotonic Dystrophy Type 2
See
See
Testing to quantitate the number of
Detection frequency varies by method used. When routine PCR analysis, Southern blot analysis, and PCR repeat-primed assay are all used, the variant detection frequency is greater than 99%.
Type 1 fiber atrophy is a common feature in individuals with congenital DM1, distinguishing it from DM2.
Preferential type 2 fiber atrophy has been observed in individuals with DM2 [
•
• ≤30 uninterrupted CCTG repeats
• 11-26 CCTG repeats
• ≤30 uninterrupted CCTG repeats
• 11-26 CCTG repeats
• ≤30 uninterrupted CCTG repeats
• 11-26 CCTG repeats
• Type 1 fiber atrophy is a common feature in individuals with congenital DM1, distinguishing it from DM2.
• Preferential type 2 fiber atrophy has been observed in individuals with DM2 [
## Molecular Genetic Testing
Testing approaches can include
Molecular Genetic Testing Used in Myotonic Dystrophy Type 2
See
See
Testing to quantitate the number of
Detection frequency varies by method used. When routine PCR analysis, Southern blot analysis, and PCR repeat-primed assay are all used, the variant detection frequency is greater than 99%.
## Other Testing
Type 1 fiber atrophy is a common feature in individuals with congenital DM1, distinguishing it from DM2.
Preferential type 2 fiber atrophy has been observed in individuals with DM2 [
• Type 1 fiber atrophy is a common feature in individuals with congenital DM1, distinguishing it from DM2.
• Preferential type 2 fiber atrophy has been observed in individuals with DM2 [
## Clinical Characteristics
Core phenotype characteristics of myotonic dystrophy type 2 (DM2) are myotonia, proximal and axial muscle weakness, and late muscle atrophy in combination with myalgia. DM2 is a multisystem disease and additional features include cardiac conduction defects, posterior subcapsular cataracts, insulin-insensitive type 2 diabetes mellitus, and other endocrine dysfunctions.
To date, more than 1500 individuals in more than 700 families have been identified with a pathogenic variant in
Select Features of Myotonic Dystrophy Type 2
Myotonia (i.e., involuntary muscle contraction and delayed relaxation caused by muscle hyperexcitability) is present in almost all individuals with DM2 but only rarely causes severe symptoms. Proximal leg myotonia is a prominent finding.
Fluctuating or episodic muscle pain is reported by a majority of affected individuals and can be debilitating [
In women with DM2, symptoms may worsen during pregnancy [
No significant correlation exists between CCTG repeat size and age of onset of weakness or other measures of disease severity (e.g., age of cataract extraction). The observation that phenotypic features in individuals with CCTG repeat expansions in both
A correlation does exist between the repeat size and the age of the individual with DM2 at the time that the repeat size is measured, indicating that the repeat length increases with age [
Penetrance is age dependent and approaches 100%.
Anticipation is not observed in DM2. There is no correlation between disease severity and CCTG repeat length; therefore, intergenerational changes in repeat length would not be expected to worsen disease severity.
The International Myotonic Dystrophy Consortium (IDMC) and Online Mendelian Inheritance in Man (OMIM) both recognize that DM2 and the historical term proximal myotonic myopathy (PROMM) refer to the same condition. PROMM is still sometimes used to refer to the clinical phenotype if the causative variant is unknown; however, when the diagnosis is established through molecular genetic testing of
No other genetic causes of multisystem myotonic dystrophies have been confirmed, although their existence has been suggested. The International Myotonic Dystrophy Consortium has agreed that any newly identified multisystem myotonic dystrophies will be sequentially named as forms of myotonic dystrophy.
One family posited to have a myotonic dystrophy type 3 (DM3) [
Prevalence appears to differ in various populations; however, few definitive demographic studies have been performed. A higher prevalence of DM2 is observed in Germany, Czech Republic, Serbia, and Poland and in individuals of German or Polish descent [
## Clinical Description
Core phenotype characteristics of myotonic dystrophy type 2 (DM2) are myotonia, proximal and axial muscle weakness, and late muscle atrophy in combination with myalgia. DM2 is a multisystem disease and additional features include cardiac conduction defects, posterior subcapsular cataracts, insulin-insensitive type 2 diabetes mellitus, and other endocrine dysfunctions.
To date, more than 1500 individuals in more than 700 families have been identified with a pathogenic variant in
Select Features of Myotonic Dystrophy Type 2
Myotonia (i.e., involuntary muscle contraction and delayed relaxation caused by muscle hyperexcitability) is present in almost all individuals with DM2 but only rarely causes severe symptoms. Proximal leg myotonia is a prominent finding.
Fluctuating or episodic muscle pain is reported by a majority of affected individuals and can be debilitating [
In women with DM2, symptoms may worsen during pregnancy [
## Genotype-Phenotype Correlations
No significant correlation exists between CCTG repeat size and age of onset of weakness or other measures of disease severity (e.g., age of cataract extraction). The observation that phenotypic features in individuals with CCTG repeat expansions in both
A correlation does exist between the repeat size and the age of the individual with DM2 at the time that the repeat size is measured, indicating that the repeat length increases with age [
## Penetrance
Penetrance is age dependent and approaches 100%.
## Anticipation
Anticipation is not observed in DM2. There is no correlation between disease severity and CCTG repeat length; therefore, intergenerational changes in repeat length would not be expected to worsen disease severity.
## Nomenclature
The International Myotonic Dystrophy Consortium (IDMC) and Online Mendelian Inheritance in Man (OMIM) both recognize that DM2 and the historical term proximal myotonic myopathy (PROMM) refer to the same condition. PROMM is still sometimes used to refer to the clinical phenotype if the causative variant is unknown; however, when the diagnosis is established through molecular genetic testing of
No other genetic causes of multisystem myotonic dystrophies have been confirmed, although their existence has been suggested. The International Myotonic Dystrophy Consortium has agreed that any newly identified multisystem myotonic dystrophies will be sequentially named as forms of myotonic dystrophy.
One family posited to have a myotonic dystrophy type 3 (DM3) [
## Prevalence
Prevalence appears to differ in various populations; however, few definitive demographic studies have been performed. A higher prevalence of DM2 is observed in Germany, Czech Republic, Serbia, and Poland and in individuals of German or Polish descent [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Routine clinical evaluation can reliably identify myotonic dystrophy. Molecular genetic testing is required for definitive diagnosis of
The most robust clinical difference between DM1 and DM2 is that clubfeet, neonatal weakness and early respiratory insufficiency, developmental delay / intellectual disability, craniofacial abnormalities, and childhood hypotonia and weakness have been reported in individuals with DM1 only. DM2 has not been associated with developmental abnormalities and thus does not cause severe childhood manifestations [
Adults with DM1 often have more weakness and myotonia than adults with DM2.
Individuals with DM1 tend to have more pronounced facial, bulbar, and distal weakness; as well as muscle atrophy, cardiac involvement, and central nervous system abnormalities including central hypersomnia [
Note: The cataracts in individuals with DM1 and DM2 are indistinguishable.
The other major group in the differential diagnosis of DM2 is distal myopathy (see
Myopathies of Interest in the Differential Diagnosis of Myotonic Dystrophy Type 2
Weakness of ankle dorsiflexion usually at age 20-60 yrs, then slow progression to proximal leg & arm muscles
± dilated cardiomyopathy & conduction defects
Foot drop & a steppage gait
Progression to loss of ambulation after 12-15 yrs
Weakness of ankle dorsiflexion usually starting in late 40s, then slow progression to finger & wrist extensor muscles & intrinsic hand muscles
Eventually proximal leg muscles become involved.
± dilated cardiomyopathy & conduction defects
Weakness of ankle extension usually starting in late 40s, then slow progression to proximal leg muscles
± neuropathy & contractures
Distal paresis & difficulties climbing stairs
Progresses to proximal & axial muscles
Later: Paget disease of bone & rapidly progressive frontotemporal dementia
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Electrical myotonia occurs in several conditions (e.g., hypothyreosis) but the presence of myotonia in multiple family members restricts diagnostic possibilities to either DM1 or DM2, or to the nondystrophic myotonias, which are caused by mutation of chloride, sodium, or calcium channel genes, resulting in
Occasionally, individuals with DM2 have been misdiagnosed as having atypical motor neuron disease [
• The most robust clinical difference between DM1 and DM2 is that clubfeet, neonatal weakness and early respiratory insufficiency, developmental delay / intellectual disability, craniofacial abnormalities, and childhood hypotonia and weakness have been reported in individuals with DM1 only. DM2 has not been associated with developmental abnormalities and thus does not cause severe childhood manifestations [
• Adults with DM1 often have more weakness and myotonia than adults with DM2.
• Individuals with DM1 tend to have more pronounced facial, bulbar, and distal weakness; as well as muscle atrophy, cardiac involvement, and central nervous system abnormalities including central hypersomnia [
• Weakness of ankle dorsiflexion usually at age 20-60 yrs, then slow progression to proximal leg & arm muscles
• ± dilated cardiomyopathy & conduction defects
• Foot drop & a steppage gait
• Progression to loss of ambulation after 12-15 yrs
• Weakness of ankle dorsiflexion usually starting in late 40s, then slow progression to finger & wrist extensor muscles & intrinsic hand muscles
• Eventually proximal leg muscles become involved.
• ± dilated cardiomyopathy & conduction defects
• Weakness of ankle extension usually starting in late 40s, then slow progression to proximal leg muscles
• ± neuropathy & contractures
• Distal paresis & difficulties climbing stairs
• Progresses to proximal & axial muscles
• Later: Paget disease of bone & rapidly progressive frontotemporal dementia
## Multisystem Myotonic Myopathies
Routine clinical evaluation can reliably identify myotonic dystrophy. Molecular genetic testing is required for definitive diagnosis of
The most robust clinical difference between DM1 and DM2 is that clubfeet, neonatal weakness and early respiratory insufficiency, developmental delay / intellectual disability, craniofacial abnormalities, and childhood hypotonia and weakness have been reported in individuals with DM1 only. DM2 has not been associated with developmental abnormalities and thus does not cause severe childhood manifestations [
Adults with DM1 often have more weakness and myotonia than adults with DM2.
Individuals with DM1 tend to have more pronounced facial, bulbar, and distal weakness; as well as muscle atrophy, cardiac involvement, and central nervous system abnormalities including central hypersomnia [
Note: The cataracts in individuals with DM1 and DM2 are indistinguishable.
• The most robust clinical difference between DM1 and DM2 is that clubfeet, neonatal weakness and early respiratory insufficiency, developmental delay / intellectual disability, craniofacial abnormalities, and childhood hypotonia and weakness have been reported in individuals with DM1 only. DM2 has not been associated with developmental abnormalities and thus does not cause severe childhood manifestations [
• Adults with DM1 often have more weakness and myotonia than adults with DM2.
• Individuals with DM1 tend to have more pronounced facial, bulbar, and distal weakness; as well as muscle atrophy, cardiac involvement, and central nervous system abnormalities including central hypersomnia [
## Other Myopathies to Consider
The other major group in the differential diagnosis of DM2 is distal myopathy (see
Myopathies of Interest in the Differential Diagnosis of Myotonic Dystrophy Type 2
Weakness of ankle dorsiflexion usually at age 20-60 yrs, then slow progression to proximal leg & arm muscles
± dilated cardiomyopathy & conduction defects
Foot drop & a steppage gait
Progression to loss of ambulation after 12-15 yrs
Weakness of ankle dorsiflexion usually starting in late 40s, then slow progression to finger & wrist extensor muscles & intrinsic hand muscles
Eventually proximal leg muscles become involved.
± dilated cardiomyopathy & conduction defects
Weakness of ankle extension usually starting in late 40s, then slow progression to proximal leg muscles
± neuropathy & contractures
Distal paresis & difficulties climbing stairs
Progresses to proximal & axial muscles
Later: Paget disease of bone & rapidly progressive frontotemporal dementia
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
• Weakness of ankle dorsiflexion usually at age 20-60 yrs, then slow progression to proximal leg & arm muscles
• ± dilated cardiomyopathy & conduction defects
• Foot drop & a steppage gait
• Progression to loss of ambulation after 12-15 yrs
• Weakness of ankle dorsiflexion usually starting in late 40s, then slow progression to finger & wrist extensor muscles & intrinsic hand muscles
• Eventually proximal leg muscles become involved.
• ± dilated cardiomyopathy & conduction defects
• Weakness of ankle extension usually starting in late 40s, then slow progression to proximal leg muscles
• ± neuropathy & contractures
• Distal paresis & difficulties climbing stairs
• Progresses to proximal & axial muscles
• Later: Paget disease of bone & rapidly progressive frontotemporal dementia
## Nondystrophic Myotonias
Electrical myotonia occurs in several conditions (e.g., hypothyreosis) but the presence of myotonia in multiple family members restricts diagnostic possibilities to either DM1 or DM2, or to the nondystrophic myotonias, which are caused by mutation of chloride, sodium, or calcium channel genes, resulting in
## Other
Occasionally, individuals with DM2 have been misdiagnosed as having atypical motor neuron disease [
## Management
To establish the extent of disease and needs in an individual diagnosed with myotonic dystrophy type 2 (DM2), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Myotonic Dystrophy Type 2
Consider echocardiogram &/or cardiac MRI to evaluate for cardiomyopathy.
Holter monitoring or invasive electrophysiologic testing if symptomatic or significant rhythm or conduction abnormalities on routine EKG
Detailed guidelines for treatment are provided in the new international care recommendations for DM2 [
Treatment of Manifestations in Individuals with Myotonic Dystrophy Type 2
Fatal arrhythmias can occur before onset of other symptoms.
Defibrillators are beneficial for those w/arrhythmias; the role of pacemaker/ defibrillators in asymptomatic persons is unknown.
NSAIDS = nonsteroidal anti-inflammatory drugs; OT = occupational therapist; PT = physical therapist
Anesthetic risk may be increased in those with DM2; therefore, careful assessment of cardiac and respiratory function before and after surgery is recommended [
Increased weakness in individuals with DM2 has been associated with hypothyroidism and vitamin D deficiency; thus, some strength may return if hypothyroidism or vitamin D deficiency is treated.
Detailed guidelines for surveillance are provided in recently published international care recommendations for DM2 [
Recommended Surveillance for Individuals with Myotonic Dystrophy Type 2
EKG
Echocardiogram
24-hr Holter monitoring
Fasting serum glucose concentration
Glycosylated hemoglobin level
Thyroid hormone levels
Serum vitamin D
OT = occupational therapist; PT = physical therapist
Increased weakness has been associated with the use of certain cholesterol-lowering medications. In these cases, some strength can return if statin-type cholesterol-lowering medications are eliminated.
Note: Not all individuals with DM2 have an adverse response to statin medications, and thus diagnosis of DM2 is not an absolute contraindication to use of these drugs.
See
The effects of DM2 on both smooth and striated muscle can complicate pregnancy, labor, and delivery and increase myotonia. Careful gynecologic monitoring is advised.
See
Search
• Consider echocardiogram &/or cardiac MRI to evaluate for cardiomyopathy.
• Holter monitoring or invasive electrophysiologic testing if symptomatic or significant rhythm or conduction abnormalities on routine EKG
• Fatal arrhythmias can occur before onset of other symptoms.
• Defibrillators are beneficial for those w/arrhythmias; the role of pacemaker/ defibrillators in asymptomatic persons is unknown.
• EKG
• Echocardiogram
• 24-hr Holter monitoring
• Fasting serum glucose concentration
• Glycosylated hemoglobin level
• Thyroid hormone levels
• Serum vitamin D
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with myotonic dystrophy type 2 (DM2), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Myotonic Dystrophy Type 2
Consider echocardiogram &/or cardiac MRI to evaluate for cardiomyopathy.
Holter monitoring or invasive electrophysiologic testing if symptomatic or significant rhythm or conduction abnormalities on routine EKG
• Consider echocardiogram &/or cardiac MRI to evaluate for cardiomyopathy.
• Holter monitoring or invasive electrophysiologic testing if symptomatic or significant rhythm or conduction abnormalities on routine EKG
## Treatment of Manifestations
Detailed guidelines for treatment are provided in the new international care recommendations for DM2 [
Treatment of Manifestations in Individuals with Myotonic Dystrophy Type 2
Fatal arrhythmias can occur before onset of other symptoms.
Defibrillators are beneficial for those w/arrhythmias; the role of pacemaker/ defibrillators in asymptomatic persons is unknown.
NSAIDS = nonsteroidal anti-inflammatory drugs; OT = occupational therapist; PT = physical therapist
• Fatal arrhythmias can occur before onset of other symptoms.
• Defibrillators are beneficial for those w/arrhythmias; the role of pacemaker/ defibrillators in asymptomatic persons is unknown.
## Prevention of Secondary Complications
Anesthetic risk may be increased in those with DM2; therefore, careful assessment of cardiac and respiratory function before and after surgery is recommended [
Increased weakness in individuals with DM2 has been associated with hypothyroidism and vitamin D deficiency; thus, some strength may return if hypothyroidism or vitamin D deficiency is treated.
## Surveillance
Detailed guidelines for surveillance are provided in recently published international care recommendations for DM2 [
Recommended Surveillance for Individuals with Myotonic Dystrophy Type 2
EKG
Echocardiogram
24-hr Holter monitoring
Fasting serum glucose concentration
Glycosylated hemoglobin level
Thyroid hormone levels
Serum vitamin D
OT = occupational therapist; PT = physical therapist
• EKG
• Echocardiogram
• 24-hr Holter monitoring
• Fasting serum glucose concentration
• Glycosylated hemoglobin level
• Thyroid hormone levels
• Serum vitamin D
## Agents/Circumstances to Avoid
Increased weakness has been associated with the use of certain cholesterol-lowering medications. In these cases, some strength can return if statin-type cholesterol-lowering medications are eliminated.
Note: Not all individuals with DM2 have an adverse response to statin medications, and thus diagnosis of DM2 is not an absolute contraindication to use of these drugs.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
The effects of DM2 on both smooth and striated muscle can complicate pregnancy, labor, and delivery and increase myotonia. Careful gynecologic monitoring is advised.
See
## Therapies Under Investigation
Search
## Genetic Counseling
Myotonic dystrophy type 2 (DM2) is inherited in an autosomal dominant manner.
To date, all probands whose biological parents have been evaluated with molecular genetic testing have had one parent with a
Probands with
If a positive family history for DM2 has not already been established, molecular genetic testing is recommended for the parents (and adult children) of a proband.
The family history of some individuals diagnosed with DM2 may appear to be negative because of failure to recognize the disorder in family members (see
If a parent of the proband is affected and/or is known to have a CCTG repeat expansion, the risk to the sibs is 50%.
The CCTG repeat expansion shows size differences between generations in the same family. In general, the repeat size appears to contract when passed on to the subsequent generation and then to increase in size as the affected individual ages (see
Each child of an individual with a CCTG repeat expansion has a 50% chance of inheriting the expansion.
The CCTG repeat tract tends to contract when passed from one generation to the next and then to increase in size as the affected individual ages. Anticipation is not observed in DM2.
Predictive testing for at-risk relatives is possible once a CCTG repeat expansion has been identified in an affected family member.
Predictive testing can determine whether an individual has a CCTG repeat expansion, and thus whether that individual is at risk of developing the disease. However, there is no correlation between repeat size and age of onset or clinical manifestations.
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of DM2, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the CCTG repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Note: Age of onset and clinical manifestations cannot be predicted by the CCTG repeat length.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• To date, all probands whose biological parents have been evaluated with molecular genetic testing have had one parent with a
• Probands with
• If a positive family history for DM2 has not already been established, molecular genetic testing is recommended for the parents (and adult children) of a proband.
• The family history of some individuals diagnosed with DM2 may appear to be negative because of failure to recognize the disorder in family members (see
• If a parent of the proband is affected and/or is known to have a CCTG repeat expansion, the risk to the sibs is 50%.
• The CCTG repeat expansion shows size differences between generations in the same family. In general, the repeat size appears to contract when passed on to the subsequent generation and then to increase in size as the affected individual ages (see
• Each child of an individual with a CCTG repeat expansion has a 50% chance of inheriting the expansion.
• The CCTG repeat tract tends to contract when passed from one generation to the next and then to increase in size as the affected individual ages. Anticipation is not observed in DM2.
• Predictive testing for at-risk relatives is possible once a CCTG repeat expansion has been identified in an affected family member.
• Predictive testing can determine whether an individual has a CCTG repeat expansion, and thus whether that individual is at risk of developing the disease. However, there is no correlation between repeat size and age of onset or clinical manifestations.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Myotonic dystrophy type 2 (DM2) is inherited in an autosomal dominant manner.
## Risk to Family Members
To date, all probands whose biological parents have been evaluated with molecular genetic testing have had one parent with a
Probands with
If a positive family history for DM2 has not already been established, molecular genetic testing is recommended for the parents (and adult children) of a proband.
The family history of some individuals diagnosed with DM2 may appear to be negative because of failure to recognize the disorder in family members (see
If a parent of the proband is affected and/or is known to have a CCTG repeat expansion, the risk to the sibs is 50%.
The CCTG repeat expansion shows size differences between generations in the same family. In general, the repeat size appears to contract when passed on to the subsequent generation and then to increase in size as the affected individual ages (see
Each child of an individual with a CCTG repeat expansion has a 50% chance of inheriting the expansion.
The CCTG repeat tract tends to contract when passed from one generation to the next and then to increase in size as the affected individual ages. Anticipation is not observed in DM2.
• To date, all probands whose biological parents have been evaluated with molecular genetic testing have had one parent with a
• Probands with
• If a positive family history for DM2 has not already been established, molecular genetic testing is recommended for the parents (and adult children) of a proband.
• The family history of some individuals diagnosed with DM2 may appear to be negative because of failure to recognize the disorder in family members (see
• If a parent of the proband is affected and/or is known to have a CCTG repeat expansion, the risk to the sibs is 50%.
• The CCTG repeat expansion shows size differences between generations in the same family. In general, the repeat size appears to contract when passed on to the subsequent generation and then to increase in size as the affected individual ages (see
• Each child of an individual with a CCTG repeat expansion has a 50% chance of inheriting the expansion.
• The CCTG repeat tract tends to contract when passed from one generation to the next and then to increase in size as the affected individual ages. Anticipation is not observed in DM2.
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once a CCTG repeat expansion has been identified in an affected family member.
Predictive testing can determine whether an individual has a CCTG repeat expansion, and thus whether that individual is at risk of developing the disease. However, there is no correlation between repeat size and age of onset or clinical manifestations.
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of DM2, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Predictive testing for at-risk relatives is possible once a CCTG repeat expansion has been identified in an affected family member.
• Predictive testing can determine whether an individual has a CCTG repeat expansion, and thus whether that individual is at risk of developing the disease. However, there is no correlation between repeat size and age of onset or clinical manifestations.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the CCTG repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Note: Age of onset and clinical manifestations cannot be predicted by the CCTG repeat length.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Neuromuscular Network
United Kingdom
•
•
•
•
•
•
•
•
• Neuromuscular Network
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
Myotonic Dystrophy Type 2: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Myotonic Dystrophy Type 2 (
The presence of an expanded (TG)
Gain-of-function RNA mechanism in which the CUG and CCUG repeats (respectively) alter cellular function, including alternative splicing of various genes [
RNA foci containing RNA of the abnormally expanded allele that colocalize with several forms of the RNA-binding protein muscleblind [
Sequestration of splicing factors of the muscleblind-like (MBNL) family, a key mechanisms for RNA toxicity in DM, may also contribute to DM2 since MBNL proteins have a high affinity for CUG or CCUG repeats. Reduced MBNL proteins affect alternative splicing, polyadenylation, or expression level for hundreds of genes.
Expanded RNA repeats can result in repeat-associated non-ATG (RNA) translation, leading to production of neurotoxic peptides [
CELF1, an RNA-binding protein involved in RNA metabolism, is upregulated in DM2 muscle tissue [
This toxic gain-of-function RNA process results in missplicing of the chloride channel, cardiac troponin T, and the insulin receptor contributing to the myotonia, cardiac involvement, and insulin insensitivity [
All 3 repeat tracts (TG, TCTG, & CCTG) are present in all normal & pathogenic alleles.
TG & TCTG repeat tracts are highly polymorphic; for methods other than sequencing,
The CCTG repeat tract in normal alleles typically contains ≥1 tetranucleotide interruptions (TCTG or GCTG) [
CCTG sequence interruptions are routinely found on normal alleles, but not pathogenic CCTG expansions, suggesting that loss of these interruptions from normal alleles may ↑ instability & predispose to germline expansion.
Abnormal CCTG repeat size ↑ w/age.
>25% of affected individuals have ≥2 CCTG expansion sizes detectable in peripheral blood.
Somatic heterogeneity of CCTG repeat size makes it difficult to establish a pathogenic threshold [
During germline transmission (TG)
No significant difference by sex of transmitting parent [
Due to variability in the TG and TCTG portions of the repeat tract, a total repeat size in base pairs is frequently reported [
Expanded (TG)
• Gain-of-function RNA mechanism in which the CUG and CCUG repeats (respectively) alter cellular function, including alternative splicing of various genes [
• RNA foci containing RNA of the abnormally expanded allele that colocalize with several forms of the RNA-binding protein muscleblind [
• Sequestration of splicing factors of the muscleblind-like (MBNL) family, a key mechanisms for RNA toxicity in DM, may also contribute to DM2 since MBNL proteins have a high affinity for CUG or CCUG repeats. Reduced MBNL proteins affect alternative splicing, polyadenylation, or expression level for hundreds of genes.
• Expanded RNA repeats can result in repeat-associated non-ATG (RNA) translation, leading to production of neurotoxic peptides [
• CELF1, an RNA-binding protein involved in RNA metabolism, is upregulated in DM2 muscle tissue [
• All 3 repeat tracts (TG, TCTG, & CCTG) are present in all normal & pathogenic alleles.
• TG & TCTG repeat tracts are highly polymorphic; for methods other than sequencing,
• The CCTG repeat tract in normal alleles typically contains ≥1 tetranucleotide interruptions (TCTG or GCTG) [
• CCTG sequence interruptions are routinely found on normal alleles, but not pathogenic CCTG expansions, suggesting that loss of these interruptions from normal alleles may ↑ instability & predispose to germline expansion.
• Abnormal CCTG repeat size ↑ w/age.
• >25% of affected individuals have ≥2 CCTG expansion sizes detectable in peripheral blood.
• Somatic heterogeneity of CCTG repeat size makes it difficult to establish a pathogenic threshold [
• During germline transmission (TG)
• No significant difference by sex of transmitting parent [
## Molecular Pathogenesis
The presence of an expanded (TG)
Gain-of-function RNA mechanism in which the CUG and CCUG repeats (respectively) alter cellular function, including alternative splicing of various genes [
RNA foci containing RNA of the abnormally expanded allele that colocalize with several forms of the RNA-binding protein muscleblind [
Sequestration of splicing factors of the muscleblind-like (MBNL) family, a key mechanisms for RNA toxicity in DM, may also contribute to DM2 since MBNL proteins have a high affinity for CUG or CCUG repeats. Reduced MBNL proteins affect alternative splicing, polyadenylation, or expression level for hundreds of genes.
Expanded RNA repeats can result in repeat-associated non-ATG (RNA) translation, leading to production of neurotoxic peptides [
CELF1, an RNA-binding protein involved in RNA metabolism, is upregulated in DM2 muscle tissue [
This toxic gain-of-function RNA process results in missplicing of the chloride channel, cardiac troponin T, and the insulin receptor contributing to the myotonia, cardiac involvement, and insulin insensitivity [
All 3 repeat tracts (TG, TCTG, & CCTG) are present in all normal & pathogenic alleles.
TG & TCTG repeat tracts are highly polymorphic; for methods other than sequencing,
The CCTG repeat tract in normal alleles typically contains ≥1 tetranucleotide interruptions (TCTG or GCTG) [
CCTG sequence interruptions are routinely found on normal alleles, but not pathogenic CCTG expansions, suggesting that loss of these interruptions from normal alleles may ↑ instability & predispose to germline expansion.
Abnormal CCTG repeat size ↑ w/age.
>25% of affected individuals have ≥2 CCTG expansion sizes detectable in peripheral blood.
Somatic heterogeneity of CCTG repeat size makes it difficult to establish a pathogenic threshold [
During germline transmission (TG)
No significant difference by sex of transmitting parent [
Due to variability in the TG and TCTG portions of the repeat tract, a total repeat size in base pairs is frequently reported [
Expanded (TG)
• Gain-of-function RNA mechanism in which the CUG and CCUG repeats (respectively) alter cellular function, including alternative splicing of various genes [
• RNA foci containing RNA of the abnormally expanded allele that colocalize with several forms of the RNA-binding protein muscleblind [
• Sequestration of splicing factors of the muscleblind-like (MBNL) family, a key mechanisms for RNA toxicity in DM, may also contribute to DM2 since MBNL proteins have a high affinity for CUG or CCUG repeats. Reduced MBNL proteins affect alternative splicing, polyadenylation, or expression level for hundreds of genes.
• Expanded RNA repeats can result in repeat-associated non-ATG (RNA) translation, leading to production of neurotoxic peptides [
• CELF1, an RNA-binding protein involved in RNA metabolism, is upregulated in DM2 muscle tissue [
• All 3 repeat tracts (TG, TCTG, & CCTG) are present in all normal & pathogenic alleles.
• TG & TCTG repeat tracts are highly polymorphic; for methods other than sequencing,
• The CCTG repeat tract in normal alleles typically contains ≥1 tetranucleotide interruptions (TCTG or GCTG) [
• CCTG sequence interruptions are routinely found on normal alleles, but not pathogenic CCTG expansions, suggesting that loss of these interruptions from normal alleles may ↑ instability & predispose to germline expansion.
• Abnormal CCTG repeat size ↑ w/age.
• >25% of affected individuals have ≥2 CCTG expansion sizes detectable in peripheral blood.
• Somatic heterogeneity of CCTG repeat size makes it difficult to establish a pathogenic threshold [
• During germline transmission (TG)
• No significant difference by sex of transmitting parent [
## References
## Published Guidelines / Consensus Statements
## Literature Cited
## Chapter Notes
Joline C Dalton, MS; University of Minnesota (2006-2020)John W Day, PhD; Stanford University (2006-2020)Laura PW Ranum, PhD; University of Florida (2006-2020)Benedikt Schoser, MD (2020-present)
19 March 2020 (sw) Comprehensive update posted live
3 July 2013 (me) Comprehensive update posted live
23 April 2007 (jwd) Revision: Allele sizes; to provide information to aid clinicians in interpreting test reports
21 September 2006 (me) Review posted live
14 June 2004 (jwd) Original submission
• 19 March 2020 (sw) Comprehensive update posted live
• 3 July 2013 (me) Comprehensive update posted live
• 23 April 2007 (jwd) Revision: Allele sizes; to provide information to aid clinicians in interpreting test reports
• 21 September 2006 (me) Review posted live
• 14 June 2004 (jwd) Original submission
## Author History
Joline C Dalton, MS; University of Minnesota (2006-2020)John W Day, PhD; Stanford University (2006-2020)Laura PW Ranum, PhD; University of Florida (2006-2020)Benedikt Schoser, MD (2020-present)
## Revision History
19 March 2020 (sw) Comprehensive update posted live
3 July 2013 (me) Comprehensive update posted live
23 April 2007 (jwd) Revision: Allele sizes; to provide information to aid clinicians in interpreting test reports
21 September 2006 (me) Review posted live
14 June 2004 (jwd) Original submission
• 19 March 2020 (sw) Comprehensive update posted live
• 3 July 2013 (me) Comprehensive update posted live
• 23 April 2007 (jwd) Revision: Allele sizes; to provide information to aid clinicians in interpreting test reports
• 21 September 2006 (me) Review posted live
• 14 June 2004 (jwd) Original submission
Complex repeat at the
On normal alleles, the overall length of the CCTG portion ranges from 11 to 26 tetranucleotide repeats and typically includes single interruptions (represented by the two vertical lines) that are variable in number (0-2), in location within the CCTG tract, and in repeat motif, but that commonly include individual GCTC and TCTG interruptions separately located within the CCTG tract.
On pathogenic alleles, only the CCTG repeat tract expands, without interruptions, resulting in overall repeat lengths of 75 to more than 11,000 pure CCTG tetranucleotide repeats.
|
[
"B Udd, G Meola, R Krahe, DG Wansink, G Bassez, W Kress, B Schoser, R Moxley. Myotonic dystrophy type 2 (DM2) and related disorders report of the 180th ENMC workshop including guidelines on diagnostics and management 3–5 December 2010, Naarden, The Netherlands.. Neuromuscul Disord. 2011;21:443-50"
] |
21/9/2006
|
19/3/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
myrf-cugs
|
myrf-cugs
|
[
"MYRF-Related Cardiac-Urogenital Syndrome",
"MYRF-CUGS",
"Myelin regulatory factor",
"MYRF",
"MYRF-Related Cardiac Urogenital Syndrome"
] |
Julie D Kaplan, Blythe Stewart, Lev Prasov, Tucker Louise C Pyle
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Ambiguous genitalia, micropenis, hypospadias, and/or cryptorchidism in 46,XY individuals or müllerian anomalies in 46,XX individuals
Eye anomalies including high hyperopia and nanophthalmos
Congenital heart defects including hypoplastic left heart or scimitar syndrome (partial or total anomalous pulmonary venous return of the right lung to the inferior vena cava with dextroposition of the heart, right lung and pulmonary artery hypoplasia, and anomalous systemic blood supply to the lung)
Congenital diaphragmatic hernia
Pulmonary hypoplasia, even in the absence of a diaphragmatic abnormality
Hypoplasia or aplasia of ovaries and/or müllerian structures in 46,XX individuals
Presence of müllerian structures in 46,XY individuals
Intestinal malrotation
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Ambiguous genitalia, micropenis, hypospadias, and/or cryptorchidism in 46,XY individuals or müllerian anomalies in 46,XX individuals
• Eye anomalies including high hyperopia and nanophthalmos
• Congenital heart defects including hypoplastic left heart or scimitar syndrome (partial or total anomalous pulmonary venous return of the right lung to the inferior vena cava with dextroposition of the heart, right lung and pulmonary artery hypoplasia, and anomalous systemic blood supply to the lung)
• Congenital diaphragmatic hernia
• Pulmonary hypoplasia, even in the absence of a diaphragmatic abnormality
• Hypoplasia or aplasia of ovaries and/or müllerian structures in 46,XX individuals
• Presence of müllerian structures in 46,XY individuals
• Intestinal malrotation
• For an introduction to multigene panels click
## Suggestive Findings
Ambiguous genitalia, micropenis, hypospadias, and/or cryptorchidism in 46,XY individuals or müllerian anomalies in 46,XX individuals
Eye anomalies including high hyperopia and nanophthalmos
Congenital heart defects including hypoplastic left heart or scimitar syndrome (partial or total anomalous pulmonary venous return of the right lung to the inferior vena cava with dextroposition of the heart, right lung and pulmonary artery hypoplasia, and anomalous systemic blood supply to the lung)
Congenital diaphragmatic hernia
Pulmonary hypoplasia, even in the absence of a diaphragmatic abnormality
Hypoplasia or aplasia of ovaries and/or müllerian structures in 46,XX individuals
Presence of müllerian structures in 46,XY individuals
Intestinal malrotation
• Ambiguous genitalia, micropenis, hypospadias, and/or cryptorchidism in 46,XY individuals or müllerian anomalies in 46,XX individuals
• Eye anomalies including high hyperopia and nanophthalmos
• Congenital heart defects including hypoplastic left heart or scimitar syndrome (partial or total anomalous pulmonary venous return of the right lung to the inferior vena cava with dextroposition of the heart, right lung and pulmonary artery hypoplasia, and anomalous systemic blood supply to the lung)
• Congenital diaphragmatic hernia
• Pulmonary hypoplasia, even in the absence of a diaphragmatic abnormality
• Hypoplasia or aplasia of ovaries and/or müllerian structures in 46,XX individuals
• Presence of müllerian structures in 46,XY individuals
• Intestinal malrotation
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
To date, more than 60 individuals with
CDH = congenital diaphragmatic hernia; ID = intellectual disability; IQ = intelligence quotient
The frequency of features is dependent upon whether the affected individual was ascertained prenatally or postnatally. Those individuals ascertained postnatally (particularly at older ages) are much less likely to have severe malformations such as congenital diaphragmatic hernia [
Normal IQ level is considered greater than or equal to 70.
Primary gastrointestinal issues are rare, although secondary gastrointestinal issues (including poor feeding or G-tube dependence) are more common, often due to cardiopulmonary disease.
Nanophthalmos is associated with secondary complications including amblyopia, esotropia, angle closure glaucoma, and spontaneous and postsurgical choroidal effusions [
Other reported ophthalmic abnormalities include amblyopia, strabismus, and foveal hypoplasia [
Three had speech delay;
Eight had global delays or severe delays (7 of the 8 had cardiopulmonary issues that required extensive hospitalizations and surgeries);
Of individuals without cardiopulmonary malformations, only one was reported with a developmental disorder, in this case autism spectrum disorder.
Atrial septal defect
Ventriculoseptal defect
Aortic arch hypoplasia
Coarctation of the aorta
Bicuspid aortic valve
Aortic atresia
Mitral valve atresia
Tetralogy of Fallot
There are further reports of affected individuals having gastroesophageal reflux disease, poor feeding, and gastrostomy tube dependence, although some of these issues may be secondary to cardiopulmonary disease.
Two individuals had liver lobation abnormalities and three had hepatomegaly.
There has also been one report of a 46,XY individual with hepatotesticular fusion and splenotesticular fusion [
One individual is reported to have short stature [
Microcephaly has been observed in three affected individuals [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
Poor feeding, which may be secondary to neurologic issues and the effects of severe cardiopulmonary disease, has also been reported.
Hypotonia has been reported in four affected individuals.
One individual with an autism spectrum disorder diagnosis has been reported; this individual had no major cardiopulmonary disease.
One individual who underwent brain MRI had a posterior fossa cyst [
Two affected individuals had delayed myelination patterns noted on brain MRI.
One affected individual had thymic fibrosis and involution [
One individual had hypothyroidism [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
One individual had a growth hormone-secreting pituitary tumor [
Individuals with truncating/altering C-terminal pathogenic variants (splicing or single-base deletion) that are predicted to alter or truncate the C terminus of the myelin regulatory factor (MYRF) protein tend to have high hyperopia and nanophthalmos as the predominant feature [
In one large kindred in which nanophthalmos segregated with a pathogenic
In another family of five affected individuals, the proband had nanophthalmos only and the father had nanophthalmos and unilateral cryptorchidism; the other three individuals had more classic
Currently it is felt that these individuals can have other features of
Because nanopthalmos / high hyperopia appears to be one of the most common features in
The prevalence of
• Three had speech delay;
• Eight had global delays or severe delays (7 of the 8 had cardiopulmonary issues that required extensive hospitalizations and surgeries);
• Of individuals without cardiopulmonary malformations, only one was reported with a developmental disorder, in this case autism spectrum disorder.
• Atrial septal defect
• Ventriculoseptal defect
• Aortic arch hypoplasia
• Coarctation of the aorta
• Bicuspid aortic valve
• Aortic atresia
• Mitral valve atresia
• Tetralogy of Fallot
• There are further reports of affected individuals having gastroesophageal reflux disease, poor feeding, and gastrostomy tube dependence, although some of these issues may be secondary to cardiopulmonary disease.
• Two individuals had liver lobation abnormalities and three had hepatomegaly.
• There has also been one report of a 46,XY individual with hepatotesticular fusion and splenotesticular fusion [
• One individual is reported to have short stature [
• Microcephaly has been observed in three affected individuals [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
• Poor feeding, which may be secondary to neurologic issues and the effects of severe cardiopulmonary disease, has also been reported.
•
• Hypotonia has been reported in four affected individuals.
• One individual with an autism spectrum disorder diagnosis has been reported; this individual had no major cardiopulmonary disease.
• One individual who underwent brain MRI had a posterior fossa cyst [
• Two affected individuals had delayed myelination patterns noted on brain MRI.
• Hypotonia has been reported in four affected individuals.
• One individual with an autism spectrum disorder diagnosis has been reported; this individual had no major cardiopulmonary disease.
• One individual who underwent brain MRI had a posterior fossa cyst [
• Two affected individuals had delayed myelination patterns noted on brain MRI.
•
• One affected individual had thymic fibrosis and involution [
• One individual had hypothyroidism [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
• One individual had a growth hormone-secreting pituitary tumor [
• One affected individual had thymic fibrosis and involution [
• One individual had hypothyroidism [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
• One individual had a growth hormone-secreting pituitary tumor [
• Hypotonia has been reported in four affected individuals.
• One individual with an autism spectrum disorder diagnosis has been reported; this individual had no major cardiopulmonary disease.
• One individual who underwent brain MRI had a posterior fossa cyst [
• Two affected individuals had delayed myelination patterns noted on brain MRI.
• One affected individual had thymic fibrosis and involution [
• One individual had hypothyroidism [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
• One individual had a growth hormone-secreting pituitary tumor [
• In one large kindred in which nanophthalmos segregated with a pathogenic
• In another family of five affected individuals, the proband had nanophthalmos only and the father had nanophthalmos and unilateral cryptorchidism; the other three individuals had more classic
## Clinical Description
To date, more than 60 individuals with
CDH = congenital diaphragmatic hernia; ID = intellectual disability; IQ = intelligence quotient
The frequency of features is dependent upon whether the affected individual was ascertained prenatally or postnatally. Those individuals ascertained postnatally (particularly at older ages) are much less likely to have severe malformations such as congenital diaphragmatic hernia [
Normal IQ level is considered greater than or equal to 70.
Primary gastrointestinal issues are rare, although secondary gastrointestinal issues (including poor feeding or G-tube dependence) are more common, often due to cardiopulmonary disease.
Nanophthalmos is associated with secondary complications including amblyopia, esotropia, angle closure glaucoma, and spontaneous and postsurgical choroidal effusions [
Other reported ophthalmic abnormalities include amblyopia, strabismus, and foveal hypoplasia [
Three had speech delay;
Eight had global delays or severe delays (7 of the 8 had cardiopulmonary issues that required extensive hospitalizations and surgeries);
Of individuals without cardiopulmonary malformations, only one was reported with a developmental disorder, in this case autism spectrum disorder.
Atrial septal defect
Ventriculoseptal defect
Aortic arch hypoplasia
Coarctation of the aorta
Bicuspid aortic valve
Aortic atresia
Mitral valve atresia
Tetralogy of Fallot
There are further reports of affected individuals having gastroesophageal reflux disease, poor feeding, and gastrostomy tube dependence, although some of these issues may be secondary to cardiopulmonary disease.
Two individuals had liver lobation abnormalities and three had hepatomegaly.
There has also been one report of a 46,XY individual with hepatotesticular fusion and splenotesticular fusion [
One individual is reported to have short stature [
Microcephaly has been observed in three affected individuals [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
Poor feeding, which may be secondary to neurologic issues and the effects of severe cardiopulmonary disease, has also been reported.
Hypotonia has been reported in four affected individuals.
One individual with an autism spectrum disorder diagnosis has been reported; this individual had no major cardiopulmonary disease.
One individual who underwent brain MRI had a posterior fossa cyst [
Two affected individuals had delayed myelination patterns noted on brain MRI.
One affected individual had thymic fibrosis and involution [
One individual had hypothyroidism [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
One individual had a growth hormone-secreting pituitary tumor [
• Three had speech delay;
• Eight had global delays or severe delays (7 of the 8 had cardiopulmonary issues that required extensive hospitalizations and surgeries);
• Of individuals without cardiopulmonary malformations, only one was reported with a developmental disorder, in this case autism spectrum disorder.
• Atrial septal defect
• Ventriculoseptal defect
• Aortic arch hypoplasia
• Coarctation of the aorta
• Bicuspid aortic valve
• Aortic atresia
• Mitral valve atresia
• Tetralogy of Fallot
• There are further reports of affected individuals having gastroesophageal reflux disease, poor feeding, and gastrostomy tube dependence, although some of these issues may be secondary to cardiopulmonary disease.
• Two individuals had liver lobation abnormalities and three had hepatomegaly.
• There has also been one report of a 46,XY individual with hepatotesticular fusion and splenotesticular fusion [
• One individual is reported to have short stature [
• Microcephaly has been observed in three affected individuals [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
• Poor feeding, which may be secondary to neurologic issues and the effects of severe cardiopulmonary disease, has also been reported.
•
• Hypotonia has been reported in four affected individuals.
• One individual with an autism spectrum disorder diagnosis has been reported; this individual had no major cardiopulmonary disease.
• One individual who underwent brain MRI had a posterior fossa cyst [
• Two affected individuals had delayed myelination patterns noted on brain MRI.
• Hypotonia has been reported in four affected individuals.
• One individual with an autism spectrum disorder diagnosis has been reported; this individual had no major cardiopulmonary disease.
• One individual who underwent brain MRI had a posterior fossa cyst [
• Two affected individuals had delayed myelination patterns noted on brain MRI.
•
• One affected individual had thymic fibrosis and involution [
• One individual had hypothyroidism [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
• One individual had a growth hormone-secreting pituitary tumor [
• One affected individual had thymic fibrosis and involution [
• One individual had hypothyroidism [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
• One individual had a growth hormone-secreting pituitary tumor [
• Hypotonia has been reported in four affected individuals.
• One individual with an autism spectrum disorder diagnosis has been reported; this individual had no major cardiopulmonary disease.
• One individual who underwent brain MRI had a posterior fossa cyst [
• Two affected individuals had delayed myelination patterns noted on brain MRI.
• One affected individual had thymic fibrosis and involution [
• One individual had hypothyroidism [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
• One individual had a growth hormone-secreting pituitary tumor [
## Genotype-Phenotype Correlations
Individuals with truncating/altering C-terminal pathogenic variants (splicing or single-base deletion) that are predicted to alter or truncate the C terminus of the myelin regulatory factor (MYRF) protein tend to have high hyperopia and nanophthalmos as the predominant feature [
In one large kindred in which nanophthalmos segregated with a pathogenic
In another family of five affected individuals, the proband had nanophthalmos only and the father had nanophthalmos and unilateral cryptorchidism; the other three individuals had more classic
Currently it is felt that these individuals can have other features of
• In one large kindred in which nanophthalmos segregated with a pathogenic
• In another family of five affected individuals, the proband had nanophthalmos only and the father had nanophthalmos and unilateral cryptorchidism; the other three individuals had more classic
## Nomenclature
Because nanopthalmos / high hyperopia appears to be one of the most common features in
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; ASD = atrial septal defect; CDH = congenital diaphragmatic hernia; CHD = congenital heart defects; GU = genitourinary; HLHS = hypoplastic left heart syndrome;
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
If gonads are not palpable, pelvic & abdominal ultrasound may be considered.
In 46,XY persons w/dysgenetic gonads, there may be ↑ risk of premalignant germ cell neoplasia or gonadoblastoma.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval of aspiration risk & nutritional status, esp in those w/cardiac &/or pulmonary malformations, delayed milestones, or neurologic deficits
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To evaluate for malrotation
This is esp important when PEG or gastrostomy tube is being considered.
Community or
Social work involvement for parental support
Home nursing referral
DD = developmental delay; DSD = differences of sex development; PEG = percutaneous gastrostomy; MOI = mode of inheritance;
Müllerian structures may be difficult to visualize on imaging in individuals who are not exposed to estrogen. Therefore, inability to visualize internal müllerian structures on imaging does not rule out their presence. Examination under anesthesia and/or laparoscopy may be required to detect the presence of müllerian structures and to define any müllerian anomalies.
Growth and feeding issues are often secondary complications in affected individuals with cardiopulmonary issues.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in cardiology, endocrinology, genetics, gastroenterology, gynecology, ophthalmology, pulmonology, psychology, and urology (see
Which may incl hormonal therapy, psychosocial support, gender identity assessment, & surgical intervention (e.g., orchidopexy &/or hypospadias repair)
In those being raised male or who have some gonadal function, surveillance for gonadoblastoma may be indicated (see
After age 14 yrs, low-dose testosterone replacement therapy can be initiated:
In adulthood, treatment should plateau, at best possible dosage, typically between 50 & 400 mg every 2-4 wks.
If person has short stature & is eligible for GH therapy, either delay testosterone therapy or give at lower doses initially to maximize growth potential.
Side effects incl pain assoc w/injection & large variations of serum testosterone concentration between injections, resulting in ↑ risk of mood swings.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
DSD = differences of sex development; GH = growth hormone; HRT = hormone replacement therapy; IM = intramuscularly
The DSD team should include geneticist, endocrinologist, psychologist, urologist, and possibly gynecologist. If a multidisciplinary team is unavailable, these specialties can be consulted individually.
Prior to initiating treatment with supplemental testosterone in adults, perform a digital rectal examination and measurement of prostate-specific antigen, abnormalities of which would be a contraindication to the treatment.
Physicians should check for the most current preparations and dosage recommendations before initiating testosterone replacement therapy.
Initial high doses of testosterone should be avoided to prevent priapism.
Injection of testosterone enanthate is the preferred method of replacement therapy because of low cost and easy, at-home regulation of dosage.
Alternative delivery systems that result in a more stable dosing include transdermal patches (scrotal and nonscrotal) and transdermal gels. Testosterone-containing gels, however, are associated with the risk of interpersonal transfer, which can be reduced by the use of newer hydroalcoholic gels.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Recommended Surveillance for Individuals with
DXA = dual-energy x-ray absorptiometry; DSD = differences of sex development; PSA = prostate-specific antigen
Concentrations lower than 200 ng/dL or higher than 500 ng/dL may require adjustment of total dose or frequency.
To evaluate for the presence of an overt prostate cancer, which would be a contraindication to supplemental testosterone treatment
Increased hematocrit may lead to a subsequent risk of hypoxia and sleep apnea.
Contraindications to hormone replacement therapy include hormone-responsive cancers.
Oral androgens such as methyltestosterone and fluoxymesterone should not be given in hormone replacement therapy (especially for long-term therapy) because of liver toxicity.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of screening and treatment measures. Intrafamilial variability of affected individuals is high, and features may be previously underappreciated in a family.
See
Search
• If gonads are not palpable, pelvic & abdominal ultrasound may be considered.
• In 46,XY persons w/dysgenetic gonads, there may be ↑ risk of premalignant germ cell neoplasia or gonadoblastoma.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval of aspiration risk & nutritional status, esp in those w/cardiac &/or pulmonary malformations, delayed milestones, or neurologic deficits
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• To evaluate for malrotation
• This is esp important when PEG or gastrostomy tube is being considered.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Which may incl hormonal therapy, psychosocial support, gender identity assessment, & surgical intervention (e.g., orchidopexy &/or hypospadias repair)
• In those being raised male or who have some gonadal function, surveillance for gonadoblastoma may be indicated (see
• After age 14 yrs, low-dose testosterone replacement therapy can be initiated:
• In adulthood, treatment should plateau, at best possible dosage, typically between 50 & 400 mg every 2-4 wks.
• If person has short stature & is eligible for GH therapy, either delay testosterone therapy or give at lower doses initially to maximize growth potential.
• Side effects incl pain assoc w/injection & large variations of serum testosterone concentration between injections, resulting in ↑ risk of mood swings.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
If gonads are not palpable, pelvic & abdominal ultrasound may be considered.
In 46,XY persons w/dysgenetic gonads, there may be ↑ risk of premalignant germ cell neoplasia or gonadoblastoma.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval of aspiration risk & nutritional status, esp in those w/cardiac &/or pulmonary malformations, delayed milestones, or neurologic deficits
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To evaluate for malrotation
This is esp important when PEG or gastrostomy tube is being considered.
Community or
Social work involvement for parental support
Home nursing referral
DD = developmental delay; DSD = differences of sex development; PEG = percutaneous gastrostomy; MOI = mode of inheritance;
Müllerian structures may be difficult to visualize on imaging in individuals who are not exposed to estrogen. Therefore, inability to visualize internal müllerian structures on imaging does not rule out their presence. Examination under anesthesia and/or laparoscopy may be required to detect the presence of müllerian structures and to define any müllerian anomalies.
Growth and feeding issues are often secondary complications in affected individuals with cardiopulmonary issues.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• If gonads are not palpable, pelvic & abdominal ultrasound may be considered.
• In 46,XY persons w/dysgenetic gonads, there may be ↑ risk of premalignant germ cell neoplasia or gonadoblastoma.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval of aspiration risk & nutritional status, esp in those w/cardiac &/or pulmonary malformations, delayed milestones, or neurologic deficits
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• To evaluate for malrotation
• This is esp important when PEG or gastrostomy tube is being considered.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in cardiology, endocrinology, genetics, gastroenterology, gynecology, ophthalmology, pulmonology, psychology, and urology (see
Which may incl hormonal therapy, psychosocial support, gender identity assessment, & surgical intervention (e.g., orchidopexy &/or hypospadias repair)
In those being raised male or who have some gonadal function, surveillance for gonadoblastoma may be indicated (see
After age 14 yrs, low-dose testosterone replacement therapy can be initiated:
In adulthood, treatment should plateau, at best possible dosage, typically between 50 & 400 mg every 2-4 wks.
If person has short stature & is eligible for GH therapy, either delay testosterone therapy or give at lower doses initially to maximize growth potential.
Side effects incl pain assoc w/injection & large variations of serum testosterone concentration between injections, resulting in ↑ risk of mood swings.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
DSD = differences of sex development; GH = growth hormone; HRT = hormone replacement therapy; IM = intramuscularly
The DSD team should include geneticist, endocrinologist, psychologist, urologist, and possibly gynecologist. If a multidisciplinary team is unavailable, these specialties can be consulted individually.
Prior to initiating treatment with supplemental testosterone in adults, perform a digital rectal examination and measurement of prostate-specific antigen, abnormalities of which would be a contraindication to the treatment.
Physicians should check for the most current preparations and dosage recommendations before initiating testosterone replacement therapy.
Initial high doses of testosterone should be avoided to prevent priapism.
Injection of testosterone enanthate is the preferred method of replacement therapy because of low cost and easy, at-home regulation of dosage.
Alternative delivery systems that result in a more stable dosing include transdermal patches (scrotal and nonscrotal) and transdermal gels. Testosterone-containing gels, however, are associated with the risk of interpersonal transfer, which can be reduced by the use of newer hydroalcoholic gels.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Which may incl hormonal therapy, psychosocial support, gender identity assessment, & surgical intervention (e.g., orchidopexy &/or hypospadias repair)
• In those being raised male or who have some gonadal function, surveillance for gonadoblastoma may be indicated (see
• After age 14 yrs, low-dose testosterone replacement therapy can be initiated:
• In adulthood, treatment should plateau, at best possible dosage, typically between 50 & 400 mg every 2-4 wks.
• If person has short stature & is eligible for GH therapy, either delay testosterone therapy or give at lower doses initially to maximize growth potential.
• Side effects incl pain assoc w/injection & large variations of serum testosterone concentration between injections, resulting in ↑ risk of mood swings.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Surveillance
Recommended Surveillance for Individuals with
DXA = dual-energy x-ray absorptiometry; DSD = differences of sex development; PSA = prostate-specific antigen
Concentrations lower than 200 ng/dL or higher than 500 ng/dL may require adjustment of total dose or frequency.
To evaluate for the presence of an overt prostate cancer, which would be a contraindication to supplemental testosterone treatment
Increased hematocrit may lead to a subsequent risk of hypoxia and sleep apnea.
## Agents/Circumstances to Avoid
Contraindications to hormone replacement therapy include hormone-responsive cancers.
Oral androgens such as methyltestosterone and fluoxymesterone should not be given in hormone replacement therapy (especially for long-term therapy) because of liver toxicity.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of screening and treatment measures. Intrafamilial variability of affected individuals is high, and features may be previously underappreciated in a family.
See
## Therapies Under Investigation
Search
## Genetic Counseling
Many individuals with
In some families, individuals with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, determine their need for screening and treatment (see
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and gonadal mosaicism for a
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
The manifestations of
If the
If the parents have not been tested for the
Each child of an individual with
Manifestations within a family are highly variable and offspring may have significantly more or fewer manifestations than the proband.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Many individuals with
• In some families, individuals with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, determine their need for screening and treatment (see
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The manifestations of
• If the
• If the parents have not been tested for the
• Each child of an individual with
• Manifestations within a family are highly variable and offspring may have significantly more or fewer manifestations than the proband.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
## Risk to Family Members
Many individuals with
In some families, individuals with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, determine their need for screening and treatment (see
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and gonadal mosaicism for a
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
The manifestations of
If the
If the parents have not been tested for the
Each child of an individual with
Manifestations within a family are highly variable and offspring may have significantly more or fewer manifestations than the proband.
• Many individuals with
• In some families, individuals with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, determine their need for screening and treatment (see
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The manifestations of
• If the
• If the parents have not been tested for the
• Each child of an individual with
• Manifestations within a family are highly variable and offspring may have significantly more or fewer manifestations than the proband.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
•
•
• United Kingdom
•
•
•
•
•
•
•
## Molecular Genetics
MYRF-Related Cardiac Urogenital Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MYRF-Related Cardiac Urogenital Syndrome (
## Molecular Pathogenesis
## Chapter Notes
We thank all of the patients and their families for their participation in our studies.
Dr Pyle's work has been supported by T32GM008638 and K08CA248704. Dr Prasov's work has been supported in part by K08EY032098 and the E Matilda Ziegler Foundation for the Blind, and the Research to Prevent Blindness Career Development Award, the Bright Focus Foundation, and the Glaucoma Research Foundation.
31 July 2025 (ma) Comprehensive update posted live
10 November 2022 (ma) Review posted live
22 June 2022 (jk) Original submission
• 31 July 2025 (ma) Comprehensive update posted live
• 10 November 2022 (ma) Review posted live
• 22 June 2022 (jk) Original submission
## Author Notes
## Acknowledgments
We thank all of the patients and their families for their participation in our studies.
Dr Pyle's work has been supported by T32GM008638 and K08CA248704. Dr Prasov's work has been supported in part by K08EY032098 and the E Matilda Ziegler Foundation for the Blind, and the Research to Prevent Blindness Career Development Award, the Bright Focus Foundation, and the Glaucoma Research Foundation.
## Revision History
31 July 2025 (ma) Comprehensive update posted live
10 November 2022 (ma) Review posted live
22 June 2022 (jk) Original submission
• 31 July 2025 (ma) Comprehensive update posted live
• 10 November 2022 (ma) Review posted live
• 22 June 2022 (jk) Original submission
## References
## Literature Cited
|
[] |
10/11/2022
|
31/7/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
nad-def
|
nad-def
|
[
"Vertebral, Cardiac, Renal, and Limb Defects (VCRL)",
"Vertebral, Cardiac, Renal, and Limb Defects (VCRL)",
"3-hydroxyanthranilate 3,4-dioxygenase",
"Glutamine-dependent NAD(+) synthetase",
"Kynureninase",
"HAAO",
"KYNU",
"NADSYN1",
"Congenital NAD Deficiency Disorder"
] |
Congenital NAD Deficiency Disorder
|
Paul Mark, Sally Dunwoodie
|
Summary Congenital NAD deficiency disorder (CNDD) is a multisystem condition in which cardiac, renal, vertebral, and limb anomalies are common, mimicking the clinical features described in VACTERL association. Congenital heart defects can include left-sided heart lesions, right-sided heart lesions, or both. Almost all surviving individuals have short stature, many with disproportionately shortened limbs. Vertebral anomalies, including hemivertebrae and vertebral fusion, occur frequently, often with rib anomalies. Renal anomalies may be severe, including dysplasia/hypoplasia and renal agenesis. Developmental delay / intellectual disability has been reported in more than half of affected individuals, although some affected individuals have had normal development, and some individuals succumbed to their congenital anomalies before developmental assessment could be performed. Other less common features may include cleft palate, eye anomalies, sensorineural hearing loss, tracheoesophageal fistula, polysplenia, anteriorly displaced anus, tethered spinal cord, cystic hygroma, epilepsy, hypothyroidism, and hypoparathyroidism. The diagnosis of CNDD is established in a proband with suggestive findings and biallelic pathogenic variants in CNDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CNDD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the CNDD-related pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
|
## Diagnosis
No consensus clinical diagnostic criteria for congenital NAD deficiency disorder (CNDD) have been published. However, the spectrum of congenital anomalies may overlap with the clinically described VACTERL association (
CNDD
Congenital heart defects affecting:
Both the left- and right-sided structures (tetralogy of Fallot) OR
The left-sided structures (hypoplastic left heart, mitral valve defects, coarctation of the aorta, bicuspid aortic valve) OR
The right-sided structures (absent pulmonary trunk, double-outlet right ventricle)
Renal anomalies, including renal aplasia, hypoplasia, and dysplasia
Vertebral anomalies, including butterfly vertebra, hemivertebra, wedge-shaped vertebra, and fused vertebra, on spinal radiographs
Shortened long bones, including rhizomelia and brachymelia, usually affecting both the arms and legs
Short metacarpals with accessory ossicles on hand radiographs
Short stature, frequently but not always with shortened long bones
Microcephaly
Nonspecific dysmorphic features, including cupped and/or low-set ears (See
Sensorineural hearing loss
Nuchal redundancy or cystic hygroma
Cutaneous syndactyly of fingers and/or toes
Other hand anomalies, including hyperphalangism, short phalanges, and/or short metacarpals
Developmental delay / intellectual disability, ranging from mild to severe, although some affected individuals have no developmental issues
Sacral dimple or other sacral stigmata, such as a sacral hair tuft
Clubfeet
The diagnosis of CNDD
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of CNDD, the molecular genetic testing approach is use of a
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by multiple congenital anomalies, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital NAD Deficiency Disorder
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
One affected individual with a homozygous deletion of exon 5 of
• Congenital heart defects affecting:
• Both the left- and right-sided structures (tetralogy of Fallot) OR
• The left-sided structures (hypoplastic left heart, mitral valve defects, coarctation of the aorta, bicuspid aortic valve) OR
• The right-sided structures (absent pulmonary trunk, double-outlet right ventricle)
• Both the left- and right-sided structures (tetralogy of Fallot) OR
• The left-sided structures (hypoplastic left heart, mitral valve defects, coarctation of the aorta, bicuspid aortic valve) OR
• The right-sided structures (absent pulmonary trunk, double-outlet right ventricle)
• Renal anomalies, including renal aplasia, hypoplasia, and dysplasia
• Vertebral anomalies, including butterfly vertebra, hemivertebra, wedge-shaped vertebra, and fused vertebra, on spinal radiographs
• Shortened long bones, including rhizomelia and brachymelia, usually affecting both the arms and legs
• Short metacarpals with accessory ossicles on hand radiographs
• Both the left- and right-sided structures (tetralogy of Fallot) OR
• The left-sided structures (hypoplastic left heart, mitral valve defects, coarctation of the aorta, bicuspid aortic valve) OR
• The right-sided structures (absent pulmonary trunk, double-outlet right ventricle)
• Short stature, frequently but not always with shortened long bones
• Microcephaly
• Nonspecific dysmorphic features, including cupped and/or low-set ears (See
• Sensorineural hearing loss
• Nuchal redundancy or cystic hygroma
• Cutaneous syndactyly of fingers and/or toes
• Other hand anomalies, including hyperphalangism, short phalanges, and/or short metacarpals
• Developmental delay / intellectual disability, ranging from mild to severe, although some affected individuals have no developmental issues
• Sacral dimple or other sacral stigmata, such as a sacral hair tuft
• Clubfeet
## Suggestive Findings
CNDD
Congenital heart defects affecting:
Both the left- and right-sided structures (tetralogy of Fallot) OR
The left-sided structures (hypoplastic left heart, mitral valve defects, coarctation of the aorta, bicuspid aortic valve) OR
The right-sided structures (absent pulmonary trunk, double-outlet right ventricle)
Renal anomalies, including renal aplasia, hypoplasia, and dysplasia
Vertebral anomalies, including butterfly vertebra, hemivertebra, wedge-shaped vertebra, and fused vertebra, on spinal radiographs
Shortened long bones, including rhizomelia and brachymelia, usually affecting both the arms and legs
Short metacarpals with accessory ossicles on hand radiographs
Short stature, frequently but not always with shortened long bones
Microcephaly
Nonspecific dysmorphic features, including cupped and/or low-set ears (See
Sensorineural hearing loss
Nuchal redundancy or cystic hygroma
Cutaneous syndactyly of fingers and/or toes
Other hand anomalies, including hyperphalangism, short phalanges, and/or short metacarpals
Developmental delay / intellectual disability, ranging from mild to severe, although some affected individuals have no developmental issues
Sacral dimple or other sacral stigmata, such as a sacral hair tuft
Clubfeet
• Congenital heart defects affecting:
• Both the left- and right-sided structures (tetralogy of Fallot) OR
• The left-sided structures (hypoplastic left heart, mitral valve defects, coarctation of the aorta, bicuspid aortic valve) OR
• The right-sided structures (absent pulmonary trunk, double-outlet right ventricle)
• Both the left- and right-sided structures (tetralogy of Fallot) OR
• The left-sided structures (hypoplastic left heart, mitral valve defects, coarctation of the aorta, bicuspid aortic valve) OR
• The right-sided structures (absent pulmonary trunk, double-outlet right ventricle)
• Renal anomalies, including renal aplasia, hypoplasia, and dysplasia
• Vertebral anomalies, including butterfly vertebra, hemivertebra, wedge-shaped vertebra, and fused vertebra, on spinal radiographs
• Shortened long bones, including rhizomelia and brachymelia, usually affecting both the arms and legs
• Short metacarpals with accessory ossicles on hand radiographs
• Both the left- and right-sided structures (tetralogy of Fallot) OR
• The left-sided structures (hypoplastic left heart, mitral valve defects, coarctation of the aorta, bicuspid aortic valve) OR
• The right-sided structures (absent pulmonary trunk, double-outlet right ventricle)
• Short stature, frequently but not always with shortened long bones
• Microcephaly
• Nonspecific dysmorphic features, including cupped and/or low-set ears (See
• Sensorineural hearing loss
• Nuchal redundancy or cystic hygroma
• Cutaneous syndactyly of fingers and/or toes
• Other hand anomalies, including hyperphalangism, short phalanges, and/or short metacarpals
• Developmental delay / intellectual disability, ranging from mild to severe, although some affected individuals have no developmental issues
• Sacral dimple or other sacral stigmata, such as a sacral hair tuft
• Clubfeet
## Establishing the Diagnosis
The diagnosis of CNDD
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of CNDD, the molecular genetic testing approach is use of a
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by multiple congenital anomalies, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital NAD Deficiency Disorder
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
One affected individual with a homozygous deletion of exon 5 of
## Option 1
When the phenotypic findings suggest the diagnosis of CNDD, the molecular genetic testing approach is use of a
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by multiple congenital anomalies, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital NAD Deficiency Disorder
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
One affected individual with a homozygous deletion of exon 5 of
## Clinical Characteristics
Congenital NAD deficiency disorder (CNDD) is a multisystem condition in which cardiac, renal, vertebral, and limb anomalies are common. Short stature with shortened long bones, developmental delay / intellectual disability, and other organ system involvement may also be present [
Congenital NAD Deficiency Disorder: Frequency of Select Features
Not every individual was assessed for every feature.
Almost all surviving individuals have short stature, many with disproportionately shortened limbs, which is likely due to NAD deficiency. Height z scores range from +0.25 to −6.1.
A minority of individuals have microcephaly, with z scores ranging from −2.3 to −6.4.
Upper limb anomalies may include single palmar crease, hyperphalangism, short phalanges, and short metacarpals with accessory ossicles. A transverse terminal hand reduction with rudimentary fifth digit has also been observed.
Lower limb anomalies may include shortened metatarsals, limb asymmetry, and absent toes.
Syndactyly has been reported in both fingers and toes.
Neuromuscular limb anomalies may include talipes, arthrogryposis, and pterygia.
One individual with seizures (Lenox-Gastaut syndrome) has been reported.
Small brain on autopsy was recorded in two individuals. Five other individuals had documented microcephaly (see
Other findings on brain imaging include hydrocephalus and hypoplastic cerebellum.
The phenotype does not differ by the associated gene.
No genotype-phenotype correlations for
To date, there are 27 reported individuals from 25 families with CNDD, of whom 16 are still living.
• Almost all surviving individuals have short stature, many with disproportionately shortened limbs, which is likely due to NAD deficiency. Height z scores range from +0.25 to −6.1.
• A minority of individuals have microcephaly, with z scores ranging from −2.3 to −6.4.
• Upper limb anomalies may include single palmar crease, hyperphalangism, short phalanges, and short metacarpals with accessory ossicles. A transverse terminal hand reduction with rudimentary fifth digit has also been observed.
• Lower limb anomalies may include shortened metatarsals, limb asymmetry, and absent toes.
• Syndactyly has been reported in both fingers and toes.
• Neuromuscular limb anomalies may include talipes, arthrogryposis, and pterygia.
• One individual with seizures (Lenox-Gastaut syndrome) has been reported.
• Small brain on autopsy was recorded in two individuals. Five other individuals had documented microcephaly (see
• Other findings on brain imaging include hydrocephalus and hypoplastic cerebellum.
## Clinical Description
Congenital NAD deficiency disorder (CNDD) is a multisystem condition in which cardiac, renal, vertebral, and limb anomalies are common. Short stature with shortened long bones, developmental delay / intellectual disability, and other organ system involvement may also be present [
Congenital NAD Deficiency Disorder: Frequency of Select Features
Not every individual was assessed for every feature.
Almost all surviving individuals have short stature, many with disproportionately shortened limbs, which is likely due to NAD deficiency. Height z scores range from +0.25 to −6.1.
A minority of individuals have microcephaly, with z scores ranging from −2.3 to −6.4.
Upper limb anomalies may include single palmar crease, hyperphalangism, short phalanges, and short metacarpals with accessory ossicles. A transverse terminal hand reduction with rudimentary fifth digit has also been observed.
Lower limb anomalies may include shortened metatarsals, limb asymmetry, and absent toes.
Syndactyly has been reported in both fingers and toes.
Neuromuscular limb anomalies may include talipes, arthrogryposis, and pterygia.
One individual with seizures (Lenox-Gastaut syndrome) has been reported.
Small brain on autopsy was recorded in two individuals. Five other individuals had documented microcephaly (see
Other findings on brain imaging include hydrocephalus and hypoplastic cerebellum.
• Almost all surviving individuals have short stature, many with disproportionately shortened limbs, which is likely due to NAD deficiency. Height z scores range from +0.25 to −6.1.
• A minority of individuals have microcephaly, with z scores ranging from −2.3 to −6.4.
• Upper limb anomalies may include single palmar crease, hyperphalangism, short phalanges, and short metacarpals with accessory ossicles. A transverse terminal hand reduction with rudimentary fifth digit has also been observed.
• Lower limb anomalies may include shortened metatarsals, limb asymmetry, and absent toes.
• Syndactyly has been reported in both fingers and toes.
• Neuromuscular limb anomalies may include talipes, arthrogryposis, and pterygia.
• One individual with seizures (Lenox-Gastaut syndrome) has been reported.
• Small brain on autopsy was recorded in two individuals. Five other individuals had documented microcephaly (see
• Other findings on brain imaging include hydrocephalus and hypoplastic cerebellum.
## Phenotype Correlations by Gene
The phenotype does not differ by the associated gene.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for
## Prevalence
To date, there are 27 reported individuals from 25 families with CNDD, of whom 16 are still living.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Many of the congenital anomalies seen in congenital NAD deficiency disorder (CNDD) can be seen as isolated anomalies in an otherwise unaffected individual.
Genetic Disorders in the Differential Diagnosis of Congenital NAD Deficiency Disorder
Pierre Robin sequence is more common in Catel-Manzke syndrome than in CNDD.
Cardiac, vertebral, & renal anomalies & multiple other features occur much more frequently in CNDD than in Catel-Manzke syndrome.
Only ~75% of persons w/FA have physical abnormalities &, of these persons, renal (20%), cardiac (6%), & spine anomalies (2%) are far less common than in CNDD.
Bone marrow failure & cancer susceptibility have not been reported in CNDD.
AD = autosomal dominant; AR = autosomal recessive; CNDD = congenital NAD deficiency disorder; MOI = mode of inheritance
Biallelic pathogenic variants in
Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner (
• Pierre Robin sequence is more common in Catel-Manzke syndrome than in CNDD.
• Cardiac, vertebral, & renal anomalies & multiple other features occur much more frequently in CNDD than in Catel-Manzke syndrome.
• Only ~75% of persons w/FA have physical abnormalities &, of these persons, renal (20%), cardiac (6%), & spine anomalies (2%) are far less common than in CNDD.
• Bone marrow failure & cancer susceptibility have not been reported in CNDD.
## Management
No clinical practice guidelines for congenital NAD deficiency disorder (CNDD) have been published.
To establish the extent of disease and needs in an individual diagnosed with CNDD, the evaluations summarized in
Congenital NAD Deficiency Disorder: Recommended Evaluations Following Initial Diagnosis
To assess for vertebral & rib anomalies
Consider CT of spine, particularly if cervical spine anomalies are suspected.
To assess for renal &/or bladder anomalies
Consider referral to urologist &/or nephrologist as appropriate
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl brain MRI if seizures, microcephaly, or neuromuscular findings are present
Consider EEG if seizures are a concern.
Community or
Social work involvement for parental support;
Home nursing referral.
CNDD = congenital NAD deficiency disorder; MOI = mode of inheritance; PTH = parathyroid hormone; T
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for congenital NAD deficiency disorder.
Congenital NAD Deficiency Disorder: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Congenital NAD Deficiency Disorder: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
BUN = blood urea nitrogen; OT = occupational therapy; PT = physical therapy
Which may include obtaining thyroid-stimulating hormone and free thyroxine levels.
Avoidance of medications that impair kidney function, in those with renal aplasia (solitary kidney) and/or known impaired kidney function.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from more in-depth evaluation for occult congenital malformations.
See
Search
• To assess for vertebral & rib anomalies
• Consider CT of spine, particularly if cervical spine anomalies are suspected.
• To assess for renal &/or bladder anomalies
• Consider referral to urologist &/or nephrologist as appropriate
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl brain MRI if seizures, microcephaly, or neuromuscular findings are present
• Consider EEG if seizures are a concern.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CNDD, the evaluations summarized in
Congenital NAD Deficiency Disorder: Recommended Evaluations Following Initial Diagnosis
To assess for vertebral & rib anomalies
Consider CT of spine, particularly if cervical spine anomalies are suspected.
To assess for renal &/or bladder anomalies
Consider referral to urologist &/or nephrologist as appropriate
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl brain MRI if seizures, microcephaly, or neuromuscular findings are present
Consider EEG if seizures are a concern.
Community or
Social work involvement for parental support;
Home nursing referral.
CNDD = congenital NAD deficiency disorder; MOI = mode of inheritance; PTH = parathyroid hormone; T
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To assess for vertebral & rib anomalies
• Consider CT of spine, particularly if cervical spine anomalies are suspected.
• To assess for renal &/or bladder anomalies
• Consider referral to urologist &/or nephrologist as appropriate
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl brain MRI if seizures, microcephaly, or neuromuscular findings are present
• Consider EEG if seizures are a concern.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There is no cure for congenital NAD deficiency disorder.
Congenital NAD Deficiency Disorder: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Congenital NAD Deficiency Disorder: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
BUN = blood urea nitrogen; OT = occupational therapy; PT = physical therapy
Which may include obtaining thyroid-stimulating hormone and free thyroxine levels.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Agents/Circumstances to Avoid
Avoidance of medications that impair kidney function, in those with renal aplasia (solitary kidney) and/or known impaired kidney function.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from more in-depth evaluation for occult congenital malformations.
See
## Therapies Under Investigation
Search
## Genetic Counseling
Congenital NAD deficiency disorder (CNDD) is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a causative pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Maternal isodisomy of chromosome 2 has been reported in a proband with
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a CNDD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the CNDD-related pathogenic variants in the family.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
It is appropriate to offer carrier testing for reproductive partners of known carriers, particularly if consanguinity is likely.
Once the CNDD-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a causative pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Maternal isodisomy of chromosome 2 has been reported in a proband with
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Maternal isodisomy of chromosome 2 has been reported in a proband with
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Maternal isodisomy of chromosome 2 has been reported in a proband with
• If both parents are known to be heterozygous for a CNDD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• It is appropriate to offer carrier testing for reproductive partners of known carriers, particularly if consanguinity is likely.
## Mode of Inheritance
Congenital NAD deficiency disorder (CNDD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a causative pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Maternal isodisomy of chromosome 2 has been reported in a proband with
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a CNDD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a causative pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Maternal isodisomy of chromosome 2 has been reported in a proband with
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Maternal isodisomy of chromosome 2 has been reported in a proband with
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Maternal isodisomy of chromosome 2 has been reported in a proband with
• If both parents are known to be heterozygous for a CNDD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the CNDD-related pathogenic variants in the family.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
It is appropriate to offer carrier testing for reproductive partners of known carriers, particularly if consanguinity is likely.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• It is appropriate to offer carrier testing for reproductive partners of known carriers, particularly if consanguinity is likely.
## Prenatal Testing and Preimplantation Genetic Testing
Once the CNDD-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
## Molecular Genetics
Congenital NAD Deficiency Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Congenital NAD Deficiency Disorder (
Nicotinamide adenine dinucleotide in the oxidized form (known as NAD
## Molecular Pathogenesis
Nicotinamide adenine dinucleotide in the oxidized form (known as NAD
## Chapter Notes
The authors would like to thank all individuals with Congenital NAD deficiency disorder and their families for sharing their medical and personal stories.
We acknowledge funds awarded to SLD to conduct this research by the National Health and Medical Research Council (NHMRC) Principal Research Fellowship (ID1135886), Leadership Level 3 Fellowship (ID2007896), and Project Grant (ID1162878); a NSW Health Cardiovascular Research Capacity Program Senior Researcher Grant; and philanthropic support from the Key Foundation.
27 July 2023 (ma) Review posted live
15 December 2022 (pm) Original submission
• 27 July 2023 (ma) Review posted live
• 15 December 2022 (pm) Original submission
## Acknowledgments
The authors would like to thank all individuals with Congenital NAD deficiency disorder and their families for sharing their medical and personal stories.
We acknowledge funds awarded to SLD to conduct this research by the National Health and Medical Research Council (NHMRC) Principal Research Fellowship (ID1135886), Leadership Level 3 Fellowship (ID2007896), and Project Grant (ID1162878); a NSW Health Cardiovascular Research Capacity Program Senior Researcher Grant; and philanthropic support from the Key Foundation.
## Revision History
27 July 2023 (ma) Review posted live
15 December 2022 (pm) Original submission
• 27 July 2023 (ma) Review posted live
• 15 December 2022 (pm) Original submission
## References
## Literature Cited
|
[] |
27/7/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.