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New Insights into the Pathogenesis of Desmin Myopathy

Desmin, or myofibrillar, myopathy (MFM) -- a rare and frequently misdiagnosed disorder -- is characterized by myofibrillar disruption and the accumulation of desmin and other proteins in muscle fibers (see J Neurol Neuropath Exp Neurol 1996; 55:549 and Neurology 1998; 51:1646). MFM is clinically and genetically heterogenetic. Patients may develop weakness in infancy or later in adulthood. Extremity weakness can be predominantly distal or proximal and can affect either the arms or the legs. MFM is also associated with a cardiomyopathy that may manifest as conduction defects or as congestive heart failure.

Most familial cases demonstrate autosomal dominant inheritance, although autosomal recessive or X-linked inheritance is suggested in some families. Recently, mutations in the desmin gene located on chromosome 2q35 were identified in 3 distinct families with autosomal dominant MFM. Some families have mutations in the B-crystallin gene located on chromosome 11q21-23, while still other MFM kinships have been linked to unidentified genes on chromosomes 12, 2q21, 2q24-31, or 10q (see, for example, Ann Neurol 1999; 46:681).

These authors evaluated 22 patients from 8 distinct families with autosomal dominantly inherited MFM and 2 patients with sporadic disease. Mutations in the desmin gene were identified in 4 families and in the 2 patients with sporadic disease. None of the patients had mutations in the B-crystallin gene. Transfected cells containing mutant desmin cDNA were unable to form a normal filamentous network. These transfected cells contained desmin-positive aggregates in the cytoplasm. The authors conclude that mutations in the desmin gene interfere with the proper assembly of the intermediate filament network, resulting in fragility of muscle fibers.

Comment: This report makes an important contribution to the unraveling of the pathogenesis of MFM. Desmin is the major intermediate filament protein of skeletal and cardiac muscle. This cytoskeletal protein links Z-bands with the sarcolemma and the myonuclei. B-crystallin is a heat-shock protein that is a "molecular chaperone" for desmin. The intermediate filament network is important in the stability of muscle fiber and during the mechanical stress of muscle contractions. The network may also have an important role in mitosis and regeneration of muscle cells. Mutations in the desmin, B-crystallin, and, perhaps, other genes encoding for intermediate filaments may disrupt the assembly and function of the intermediate filament network, leading to degeneration of muscle fibers.

— AA Amato

Anthony A. Amato, MD, is Chief, Neuromuscular Division, Department of Neurology, Brigham and Women's Hospital; Associate Professor of Neurology, Harvard Medical School, Boston, MA.

Published in Journal Watch Neurology June 1, 2000

Citation(s):

Dalakas MC et al. Desmin myopathy: A skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. N Engl J Med 2000 Mar 16 342 770 -780.

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