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Five-hundred fifty-six patients with histologic evidence of myopathy on muscle biopsy and normal dystrophin levels on immunofluorescence or immunoblot analysis were studied for mutations of the alpha, beta, and gamma sarcoglycan gene to determine the mutation frequency and its relation to a clinical phenotype.
Sarcoglycan deficiency was evident in the biopsies of 54 patients (10%), all falling into one of three clinical categories: a) congenital muscular dystrophy (weakness or hypotonia at birth, contractures before 6 months of age, dystrophic muscle biopsy); b) Duchenne-like muscular dystrophy (proximal weakness with onset after 6 months of age, elevated creatine kinase, dystrophic muscle biopsy); or c) limb-girdle muscular dystrophy (similar to Becker’s muscular dystrophy with presentation after 10 years of age). Other neuromuscular disorders including inflammatory myopathy, metabolic myopathy, distal myopathy, myoglobinuria, congenital myopathy or hypotonia, isolated high creatine kinase with or without myopathy or muscle cramps, and other muscular dystrophies did not demonstrate sarcoglycan deficiency.
Two of 69 congenital muscular dystrophy patients demonstrated sarcoglycan deficiency; one was tested and did not have a mutation. Of 83 Duchenne-like muscular dystrophy patients, 29 (35%) were sarcoglycan deficient, 18 (22%) demonstrating a mutation (8 alpha, 8 beta, 2 gamma), 11 (13%) showing no mutation. Twenty-three of 180 (13%) limb-girdle muscular dystrophy patients demonstrated sarcoglycan deficiency; 11 (6%) demonstrated a mutation (9 alpha, 0 beta, 2 gamma), nine (5%) showed no mutation, and three were not tested. Of 50 patients tested overall, 29 (58%) had a mutation, involving alpha sarcoglycan in 17 (34%), beta sarcoglycan in eight (16%), and gamma sarcoglycan in four (8%). Beta sarcoglycan gene mutations tended toward more severe dystrophy compared to alpha or gamma gene mutations and, interestingly, despite the presence of sarcoglycan in cardiac muscle, none of the seven patients tested had electrocardiographic or echocardiographic abnormalities.
Patients with normal dystrophin levels and either Duchenne-like muscular dystrophy or limb-girdle muscular dystrophy, but not congenital muscular dystrophy, have an 11% incidence of a sarcoglycan gene mutation. Complete sarcoglycan deficiency has a 79% incidence of mutation, most often of the alpha sarcoglycan gene (58%), while most patients (61%) with partial sarcoglycan deficiency have no mutation whatsoever.
Dystrophin in skeletal muscle is a subsarcolemmal, cytoskeletal protein, normally associated with several glycoproteins that link intracellular dystrophin to extracellular matrix proteins, known as laminins, the overall function of which appears to be maintenance of muscle membrane structural integrity (Ibraghimov-Beskrovnaya O, et al. Nature 1992;355;696-702).
Initially characterized by molecular weight, three dystrophin-associated glycoproteins are now referred to as alpha sarcoglycan (the 50 kd glycoprotein), beta sarcoglycan (the 43 kd glycoprotein), and gamma sarcoglycan (the 35 kd glycoprotein), although the 50 kd glycoprotein also goes by the name adhalin (Matsumura K, et al. Nature 1992;359:320-322). Delta sarcoglycan is a separate 35 kd glycoprotein, deficiency of which has been reported in two Brazilian families with autosomal recessive limb-girdle muscular dystrophy mapped to chromosome 5 (Nigro V, et al. Nat Genet 1996;14:195-198). Dystroglycans and syntrophins are extracellular and intracellular proteins, respectively, which participate in the large dystrophin-glycoprotein complex but for which no primary defects have been identified to date.
Nomenclature for the diverse forms of limb-girdle muscular dystrophy has recently been resolved by a consensus conference (Bushby KMD, Beckmann JS. Neuromusc Disord 1995;5:337-343). Autosomal dominant limb-girdle muscular dystrophy will be LGMD1 and the recessive forms LGMD2, starting with LGMD2A and so on down the alphabet as responsible genes are chronologically described.
Genetic classification of the limb girdle muscular dystrophies thus awaits recognition of gene mutations. Several have already been pigeonholed (see Table).
Type Deficiency MutatioOld Name
LGMD1 Chromosome 5
LGMD2A calpain III Chromosome 15
LGMD2C gamma sarcoglycaChromosome 13 secondary adhalin deficiency
LGMD2D alpha sarcoglycaChromosome 17 primary adhalin deficiency
LGMD2E beta sarcoglycaChromsome 4q
Due to the complex interaction of the various proteins of the dystrophin-glycoprotein complex, it is not surprising that a primary defect of dystrophin results in secondary deficiency of sarcoglycan. Similarly, mutation of one sarcoglycan gene results in deficiency of that sarcoglycan as well as deficiency of alpha sarcoglycan, even in the presence of normal dystrophin, facilitating patient screening for sarcoglycan defects.
Genetic classification permits greater accuracy of clinical phenotype description, significantly improving the prognostic information we offer our patients. Ultimately, one hopes that determining the genetic underpinnings of disease will allow for early and effective treatment to prevent the onset or change the course of inherited disease. mr