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Source: Fanin M, et al. Calpain-3 and dysferlin protein screening in patients with limb-girdle dystrophy and myopathy. Neurology. 2001;56:660-665.
Among a database of approximately 5000 muscle biopsies performed for childhood or adult onset, proximal or distal, limb-girdle muscular weakness with elevated serum creatine kinase, 407 revealed a nonspecific myopathic or dystrophic process. All demonstrated normal dystrophin and sarcoglycan by Western blot or gene analysis, and normal telethonin and merosin by immunoflourescence. Using Western blot and immunohistochemistry, these 407 biopsies were tested for calpain-3 and dysferlin deficiency. Fifty-eight biopsies from clearly defined neuromuscular diseases, including Duchenne, Becker, and facioscapulohumeral muscular dystrophy, inflammatory myopathy, metabolic, and congenital myopathy, served as controls.
Strikingly, calpain-3 deficiency was found in 16% (n = 66), with total absence in 47% (n = 31) and severe deficiency (3-50% of control) in the remainder. Dysferlin deficiency was seen in 6.5% (n = 26), being absent in 35% (n = 9), and severely deficient (20% or less of control) in 65% (n = 17). Among patients with a limb-girdle muscular dystrophy (LGMD) phenotype, 28% (53/191) had calpain-3 deficiency, and among those with distal myopathy, 60% (21/35) were dysferlin deficient. Immunoblot analysis is useful in the diagnosis of unclassified myopathy or dystrophy, where approximately 25% will be calpain-3 or dysferlin deficient.
LGMDs have long resisted orderly classification. Recently, positional cloning techniques have demonstrated 11 types of genetically defined LGMDs.1 Three autosomal dominant LGMDs are designated 1A, 1B, and 1C—the last being the caveolin 3 gene (see Table). Autosomal recessive forms include deficiency of calpain, dysferlin, or sarcoglycan. Sarcoglycanopathies are divided into 4 types based on alpha, beta, gamma, or delta sarcoglycan deficiency (see Table).
|Table: LGMD’s Specific Chromosomal Identities|
Epsilon sarcoglycan has also been identified, localizing to chromosome 7q21, but is not yet known to be involved in muscle disease. Calpain-3 and dysferlin deficiency (see Table) appear to be the most common forms of LGMD. Two other mutations, at chromosomes 17q11-12 and 9q31-33, also result in autosomal recessive LGMD, but their gene products remain undefined.
Calpain-3 (also called p94) is a skeletal-muscle-specific, calcium-dependent, cysteine protease that interacts with titin (connectin) and exists in the cytosol and nucleus. Its function is unclear, perhaps regulating muscle cell differentiation, but its pathogenic role in LGMD remains puzzling. Dysferlin localizes to the muscle membrane and has been implicated both in LGMD2B and Miyoshi myopathy, a distal form of muscular dystrophy, but again its role is undefined. Further clinical heterogeneity of dysferlin deficiency has recently been reported in a family with anterior compartment distal leg weakness rapidly progressing to severe proximal weakness. Muscle biopsy demonstrated absent dysferlin immunostaining, and nucleotide sequence analysis revealed a single base pair deletion creating a frameshift mutation of the dysferlin gene.2—Michael Rubin
1. Bushby KM, et al. Brain. 1999;122:1403-1420.
2. Illa I, et al. Ann Neurol. 2001;49:130-134.