Duchenne/Becker Muscular Dystrophy
Background
Who should be tested?
Testing Methodology
Potential Outcomes Interpretation of Test Results
Cautions
For More Information
Background
Duchenne muscular dystrophy (DMD) is one of the most common inherited diseases, occurring once in every 3,500 males. It is typically characterized by progressive muscle weakness, inability to walk after age 12, serious respiratory infections by age 14 to 18, and respiratory failure in the 20s to 30s. Becker muscular dystrophy (BMD) has a similar disease course to DMD, but with slower onset and progression. BMD is also less common, occurring once in 35000 males.
Both BMD and DMD are caused by a mutation within the dystrophin gene on the X chromosome. Males normally have one X chromosome in each cell. If that X chromosome carries the mutation in the dystrophin gene, the boy will have muscular dystrophy. As a result, males are most often affected. Females normally have two X chromosomes in each cell. If one X chromosome carries the mutation in the dystrophin gene and the other one does not, the girl will be a carrier of muscular dystrophy. In some cases, a female carrier will show some symptoms of the disease (a manifesting carrier), although most carriers do not have and will not develop muscular dystrophy. Carrier females may, however, pass the mutation on to their children. If a female is a carrier, her sons have a 50 per cent chance of inheriting the mutation and being affected with D/BMD. Her daughters are unlikely to be affected by D/BMD but have a 50 per cent chance of inheriting the mutation and being carriers themselves.
Approximately 65 per cent of affected males have a deletion in the dystrophin gene; 5 per cent have a duplication. The remaining 30 per cent of males have smaller point mutations in the dystrophin gene. If no mutation is found, but D/BMD is strongly indicated, further investigation using linkage analysis may be required.
Who should be tested?
- individuals clinically suspected of being affected with D/BMD
- women with a family history of D/BMD, to determine the carrier status of unaffected individuals
- pregnancies at risk due to a family history of D/BMD
Testing Methodology
D/BMD testing is done in two stages. All samples are tested for a deletion or duplication, but not all samples are tested for point mutations.
Direct Deletion/Duplication Analysis: All samples are analyzed for the presence of a deletion or duplication in the dystrophin gene by quantitative multiplex PCR analysis of all 79 exons of the gene.
Direct Sequence Analysis: In cases where there is no detectable deletion or duplication in the dystrophin gene, but strong clinical evidence suggesting D/BMD in the family, direct sequencing of the DNA sample may be used to detect other mutations in the dystrophin gene. Clinical information regarding the diagnosis of D/BMD may be requested prior to sequence analysis.
Linkage Analysis: In cases where there is no detectable deletion or duplication in the dystrophin gene, but there is clinical evidence for D/BMD in the family, linkage analysis may be used for carrier testing and prenatal diagnosis. DNA markers associated with the dystrophin gene in the affected male are compared to the pattern of markers in relatives to determine if the mutated gene is found in other members of the family. This information plus the family history is used to calculate the likelihood that a person is a carrier of D/BMD.
Test Sensitivity: Deletions or duplications in the dystrophin gene are found in 70 per cent of individuals affected with Duchenne/Becker muscular dystrophy. These cases will be detected by diagnostic procedures in place in the Molecular Genetics Laboratory.
- Approximately 30 per cent of D/BMD cases are caused by other types of mutations in the dystrophin gene. Most of these will be detected by sequence analysis.
Potential Outcomes & Interpretation of Test Results
Sex of | Dystrophin Gene Mutation | Explanation |
|---|---|---|
Male | none detected |
|
Male | mutation detected |
|
Female | none detected |
|
Female | mutation detected |
|
Cautions
- Current molecular testing may not detect all possible mutations in this gene. A negative test, therefore, does not rule out the diagnosis of muscular dystrophy, or eliminate the possibility the individual is a carrier.
- Linkage analysis may be used to assess carrier risk when deletions or duplications are not detected in families with a clear clinical history of D/BMD. Linked markers provided an assessment of risk, but are not an absolute diagnosis, due to the possibility of recombination between the marker loci and the disease locus.
- It is helpful to first identify the mutations(s) in an affected family member or in the parent of the affected family member. If the familial mutation can be identified in this way, the molecular test is conducted only for the familial mutation.
- 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, 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:
- GeneReviews online clinical information resource
- Online Mendelian Inheritance in Man - Item #310200
- Understanding Gene Testing
- To locate a genetics center near you, please visit the Canadian Association of genetic Counsellors website.