Congenital Muscular Dystrophies
Background
Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
For More Information
Background
Congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessively inherited diseases, which include Walker-Warburg syndrome (WWS), Muscle-Eye-Brain Disease (MEB), Fukuyama Congenital Muscular Dystrophy (FCMD)and Congenital Muscular Dystrophy Type 1C (MDC1C).They usually present at birth or within the first 6 months of life. Initial signs include hypotonia, muscle weakness and the variable appearance of contractures characterized by dystrophic changes on skeletal-muscle biopsy. The heterogeneous nature of CMD is reflected by differing degrees of motor developmental delay, physical disability, muscle pathology, elevation of serum creatine kinase (CK) and a variable presence of mental retardation and structural brain defects. WWS, MEB, FCMD and MDC1C are caused by mutations affecting glycosylation enzymes - proteins that add sugars to other proteins. In these diseases, defects in the sugar-adding mechanism disrupt the properties of a-dystroglycan, a protein critical for normal muscle function. Disruption of á-dystroglycan by various mechanisms causes the phenotypes associated with WWS, MEB, FCMD and MDC1C. Congenital muscular dystrophies are among the most frequent autosomal recessively inherited neuromuscular disorders.
Walker-Warburg Syndrome (WWS): WWS is the most severe form of the congenital muscular dystrophies, and often presents in the prenatal period. The life expectancy of individuals with WWS is less than three years. WWS is genetically heterogeneous, mutations in the POMT1, POMT2, POMGnT1 and FKRP genes have been found in about 25% of WWS patients.
Muscle-Eye-Brain (MEB) disease: MEB disease progress is pathologically and clinically slower than the other types of CMDs. Neonatal hypotonia, developmental delay and ocular abnormalities are characteristic of MEB disease. Approximately 80% of MEB patients were found to have mutations in the POMGnT1 gene and 10% in the FKRP gene. Although MEB has been reported in individuals of various ethnic backgrounds, it is more common in Finland. Several mutations have been described in non-Finish patients whereas a single mutation accounts for 99% of the mutant chromosomes in the Finnish population.
Fukuyama Congenital Muscular Dystrophy (FCMD): FCMD presents during the neonatal period with hypotonia, weakness and poor suck reflex. Although FCMD has been reported in individuals of various ethnic backgrounds, it is most common in Japan. The majority of cases (~95%) are due to mutations in FCMD, with mutations in the FKRP gene accounting for about 5%.
Congenital Muscular Dystrophy Type 1C (MDC1C): MDC1C is a severe form of congenital muscular dystrophy with onset at birth, significant facial weakness and hypertrophy of the leg muscles. The majority of cases (~90%) have mutations the FKRP gene.
WWS, MEB, FCMD and CMD1C are autosomal recessive disorders. An individual is said to be affected if s/he receives two copies of a defective gene, one from each parent. Any person with one copy of the defective gene is a carrier. Carriers are not affected themselves by the condition and will never develop the disease. However, if their partner is also a carrier, there is a one in four chance (25%) that their child will be born with the condition. There is a three in four chance (75%) that their child will not have the condition.
Who should be tested
- individuals clinically suspected of being affected with WWS, MEB, FCMD or MDC1C
- individuals with a family history of WWS, MEB, FCMD or MDC1C, to determine the carrier status of unaffected individuals
- pregnancies at increased risk of being affected with WWS, MEB, FCMD or MDC1C
Testing Methodology
Direct Mutation Analysis: Direct sequencing to identify point mutations in the POMT1, POMT2, POMGnT1, FCMD, and FKRP genes
Potential Outcomes & Interpretation of Test Results
Reason for referral | Gene Mutations | Explanation |
|---|---|---|
carrier testing | none detected / none detected |
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carrier testing | mutation detected / none detected |
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diagnosis | none detected / none detected |
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diagnosis | mutation detected / none detected |
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diagnosis | mutation detected / none detected |
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Cautions
- Current molecular testing will not detect all possible mutations in this gene. A negative result does not rule out the possibility that the individual carries a rare POMT1, POMT2, POMGnT1, FCMD, or FKRP gene mutation not detected by this assay.
- We strongly recommend additional testing including muscle biopsy and serum creatine kinase analysis be done on these patients, as it can be a useful complement to molecular testing.
- The clinical course or severity of symptoms cannot be predicted by molecular analysis.
- Test results should be interpreted in the context of clinical findings, family history, ethnic background and other laboratory data.
- This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.
For More Information
- Online Mendelian Inheritance in Man
- Item #253280 – Muscle Eye Brain Disease
- Item #236670 – Walker Warburg Syndrome
- Item #253800 – Fukuyama Congenital Muscular Dystrophy
- Item #606612 – Congenital Muscular Dystrophy type 1C
- GeneReviews online clinical information resource
- Funded by the U.S. National Institutes of Health, Developed at the University of Washington, Seattle.
- Diesen C. et al. (2004) POMGnT1 mutation and phenotypic spectrum in muscle-eye-brain disease. Journal of Medical Genetics 41:e115.
- Van Reeuwijk J. et al. (2004) Glyc-O-genetics of Walker-Warburg syndrome. Clinical Genetics 67: 281-289.