The earliest pathologic alterations in dysferlinopathy

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Abstract
Background: Dysferlinopathies are associated with proximal or distal muscular dystrophy. Dysferlin immunolocalizes to the muscle fiber periphery but does not associate with the dystrophin–glycoprotein complex; its function in humans, and the mechanism by which it causes muscle fiber injury, are not known. The authors therefore searched for pathogenetic clues by examining early abnormalities in nonnecrotic muscle fibers in dysferlinopathy. Five dysferlin-deficient patients were investigated. Weakness was distal in two, proximal in one, and both proximal and distal in two. Patient 5 was only mildly affected. Methods: Immunoblot analysis, membrane attack complex (MAC) immunolocalization, and quantitative electron microscopy. Results: In Patients 1 through 4, but not in 5, part or the entire surface of isolated nonnecrotic muscle fibers immunostained for MAC. Quantitative electron microscopy of 175 nonnecrotic muscle fibers revealed one or more of the following: 1) small (0.11 to 1.8 μm) plasmalemmal defects in 64% of fibers; 2) thickened basal lamina over some defects; 3) replacement of the plasma membrane by one to multiple layers of small vesicles in 57% of fibers; 4) papillary projections, frequently disintegrating, in 24 to 36% of fibers in Patients 1 through 4 but absent in fibers of Patient 5; 5) small subsarcolemmal vacuoles, some undergoing exocytosis, in 57% of fibers; and 6) infrequent subsarcolemmal regions containing rough endoplasmic reticulum and abundant free ribosomes. Conclusions: Dysferlin is likely required for maintaining the structural integrity of the muscle fiber plasma membrane, and plasma membrane injury is an early event in the pathogenesis of dysferlinopathy. MAC activation can participate in but is not an initial or primary event causing muscle fiber injury.