Abnormalities of dystrophin, the sarcoglycans, and laminin α2 in the muscular dystrophies

Abstract

Abnormalities of dystrophin, the sarcoglycans, and laminin α2 are responsible for a subset of the muscular dystrophies. In this study we aim to characterise the nature and frequency of abnormalities of these proteins in an Australian population and to formulate an investigative algorithm to aid in approaching the diagnosis of the muscular dystrophies. To reduce ascertainment bias, biopsies with dystrophic (n = 131) and non-dystrophic myopathic (n = 71) changes were studied with antibodies to dystrophin, α, β, and γ sarcoglycan, β dystroglycan, and laminin α2, and results were correlated with clinical phenotype. Abnormalities of dystrophin, the sarcoglycans, or laminin α2 were present in 61/131 (47%) dystrophic biopsies and in 0/71 myopathic biopsies, suggesting that immunocytochemical study of dystrophin, the sarcoglycans, and laminin α2 may, in general, be restricted to patients with dystrophic biopsies. Two patients with mutations identified in γ sarcoglycan had abnormal dystrophin (by immunocytochemistry and immunoblot), showing that abnormalities of dystrophin may be a secondary phenomenon. Therefore, biopsies should not be excluded from sarcoglycan analysis on the basis of abnormal dystrophin alone. The diagnostic yield was highest in those with severe, rapidly progressive limb-girdle weakness (92%). Laminin α2 deficiency was identified in 5/131 (4%) patients; 2/5 patients presented after infancy, indicating that abnormalities of laminin α2 are not limited to the congenital muscular dystrophy phenotype. Overall patterns of immunocytochemistry and immunoblotting provided a guide to mutation analysis and, on the basis of this study, we have formulated a diagnostic algorithm to guide the investigation of patients with muscular dystrophy.