CLINICAL VARIABILITY IN BECKER MUSCULAR-DYSTROPHY - GENETIC, BIOCHEMICAL AND IMMUNOHISTOCHEMICAL CORRELATES

We have investigated 59 Becker muscular dystrophy patients, representi ng 56 independent mutations, to test the hypothesis of predictability of muscle dystrophin expression and clinical phenotype based on locati on of dystrophin gene mutations. Partial intragenic deletions and dupl ications account for 82% of the independent mutations, of which 76.7% were deletions and 5.3% duplications. Mutations in which boundaries co uld be defined, were of in-frame type (35 out of 37, 94.6%), with two exceptions. Eighty-two percent of mutations were located at the distal part of the rod domain (exons 45-60), 9% at domain I (promoter throug h exon 9) and 9% at proximal and central parts of domain II. Domain I deleted patients tended to have a worse clinical phenotype, with earli er presentation, faster progression rate and lower dystrophin expressi on, while distal rod domain deleted patients showed a more classic Pec ker muscular dystrophy phenotype. Between these two groups, only the d ifferences in; the immunohistochemical patterns of dystrophin expressi on and disease progression rate were statistically significant. Partia l clinical and biochemical heterogeneity was observed in the distal do main II patient group, due to the presence of few patients covering th e extremities of clinical severity. Two asymptomatic patients had dele tions located in the central (exons 41-44) and distal parts (exons 50- 53) of the rod domain. Severe myalgia and cramps were often reported a s early onset symptoms (18 out of 59): no correlation was found betwee n this symptomatology and the location of the mutation. Relative level s of muscle dystrophin correlated with immunohistochemical patterns of subsarcolemma staining. Dystrophin levels (as estimated by 30 kDa ant ibody immuno-reactivity) correlated with age of reaching a moderate de gree of muscle involvement as well as with delay in reaching that stag e, a parameter of disease progression rate. Our data confirm that diff erent Becker muscular dystrophy gene in-frame mutations have different effects on dystrophin ,expression and clinical severity, indicating s everal functional roles of the dystrophin domains.