Brain, Vol. 117, No. 1, 1-14, 1994
© 1994 Oxford University Press
research-article |
Clinical variability in Becker muscular dystrophy Genetic, biochemical and immunohistochemical correlates
1Institute of Clinical Neurology, Dino Ferrari Centre, University of Milano Milano 2Istituti Clinici di Perfezionamento Milano 3Second Neurological Division, Ospedale S. Donato Milanese Milano 4Institute of Neurological and Neurosurgical Sciences, University of Messina Medea, Bosisio Parini, Como 5IRCCS E. Medea Bosisio Parini, Como 6Ospedale Valduce Como 7Institute of Clinical Neurology, University of Verona Italy 8The Red Cross Hospital Athens, Greece
Correspondence to:
Correspondence to: Dr Giacomo P. Comi, Istituto di Clinica Neurologica, Universitá di Milano, Via F. Sforza 35, 20122 Milano, Italy.
We have investigated 59 Becker muscular dystrophy patients, representing 56 independent mutations, to test the hypothesis of predictability of muscle dystrophin expression and clinical phenotype based on location of dystrophin gene mutations. Partial intragenic deletions and duplications account for 82% of the independent mutations, of which 76.7% were deletions and 5.3% duplications. Mutations in which boundaries could 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 through exon 9) and 9% at proximal and central parts of domain II. Domain I deleted patients tended to have a worse clinical phenotype, with earlier presentation, faster progression rate and lower dystrophin expression, while distal rod domain deleted patients showed a more classic Becker muscular dystrophy phenotype. Between these two groups, only the differences in the immunohistochemical patterns of dystrophin expression and disease progression rate were statistically significant. Partial clinical and biochemical heterogeneity was observed in the distal domain II patient group, due to the presence of few patients covering the extremities of clinical severity. Two asymptomatic patients had deletions located in the central (exons 41–44) and distal parts (exons 50–53) of the rod domain. Severe myalgia and cramps were often reported as early onset symptoms (18 out of 59): no correlation was found between this symptomatology and the location of the mutation. Relative levels of muscle dystrophin correlated with immunohistochemical patterns of subsarcolemma staining. Dystrophin levels (as estimated by 30 kDa antibody immuno-reactivity) correlated with age of reaching a moderate degree of muscle involvement as well as with delay in reaching that stage, a parameter of disease progression rate. Our data confirm that different Becker muscular dystrophy gene in-frame mutations have different effects on dystrophin expression and clinical severity, indicating several functional roles of the dystrophin domains.
Becker muscular dystrophy; dystrophin; dystrophin gene mutation
Received March 8, 1993. Revised June 1, 1993. Accepted June 25, 1993.