Confirmatory testing in a dystrophin-associated muscular dystrophy
Analysis of a potential carrier status in women out of affected families
Prenatal diagnostics in subsequent pregnancies
Muscular Dystrophy Duchenne and Becker-Kiener - DMD
Clinical Features
Duchenne muscular dystrophy is the most common genetic muscular disease in males. Between the end of the first and the fourth year of life, the affected boys show retardation in walking, insecure gait, stumbling, frequent falling and problems in running and climbing stairs. Muscular wasting is first evident at the lower extremities and is combined with pseudohypertrophy of the calves. Creatine kinase levels are regularly and extremely elevated from birth on. Myocardial involvement develops in an age-dependent manner and nearly all patients are affected at later disease stages. Around one third of the patients show psychomotor or mental retardation.
Becker-Kiener muscular dystrophy follows a similar, but considerably milder disease course with no mental retardation. Myocardial involvement in young age is observed only rarely, cardiomyopathy and heart failure are common in late stages.
Rarely, dilatative cardiomyopathy can represent the prevailing or only symptom caused by abnormalities in the dystrophin gene.
Genetic Information
The muscular dystrophies are X-linked recessive conditions and therefore affect predominantly males. The underlying molecular defect is an abnormality in the dystrophin gene, with deletions in approx. 60% of cases and duplications in approx. 6%. Around 34% of cases are caused by point mutations. Around one third of the boys is affected by de novo mutations, in the remaining cases the mother has a carrier status without symptoms. Due to the possibility of an unbalanced X-inactivation female carriers may show mild symptoms in around 8%.
The genetic abnormalities may have arisen in the mother�s germinal cells (gonadal mosaicism). This may account for the fact that the mutation cannot be confirmed from the mother�s peripheral blood cells; however, there is a risk for repeated conduction in about 20% of sporadic cases.
Clinic
| male, affected | clinical manifestation |
Serume CK concentration |
| DMD | 100% |
> 10 fold elevated |
| BMD | 100% |
> 5 fold elevated |
| DMD-dependend dilatative Cardiomyopathy |
mostly | elevated |
| female carrier |
||
| DMD | app. 60% |
2 - 10 fold elevated |
| BMD |
app. 30% |
2 - 10 fold elevated |
Distribution of mutation frequencies
| Mutation | DMD |
BMD |
| Deletion |
app. 65% |
app. 85% |
| Duplication |
app. 6 - 10% |
app. 6 - 10% |
| Point mutation | app. 25 - 30% |
app. 5 - 10% |
Prevalence
DMD: in males 1: 3 500
BMD: in males 1: 20 000
Diagnostic
Indication
Method
Direct diagnostics:
Screening for deletions and duplication of all 79 exons Point mutation screening by MLPA and if necessary, subsequent sequencing (if possible analysis should be performed in an affected male family member, first)
Indirect diagnostics:
Linkage analyses for detection of carriers in affected families
Sample Requirement
2 - 4 ml of EDTA blood
Duration
approx. 2 weeks