Gp. Comi et al., CLINICAL VARIABILITY IN BECKER MUSCULAR-DYSTROPHY - GENETIC, BIOCHEMICAL AND IMMUNOHISTOCHEMICAL CORRELATES, Brain, 117, 1994, pp. 1-14
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.