Spectrum of muscular dystrophies associated with sarcolemmal-protein genetic defects

Abstract

Muscular dystrophies are heterogeneous genetic disorders that share progressive muscle wasting. This may generate partial impairment of motility as well as a dramatic and fatal course. Less than 30 years ago, the identification of the genetic basis of Duchenne muscular dystrophy opened a new era. An explosion of new information on the mechanisms of disease was witnessed, with many thousands of publications and the characterization of dozens of other genetic forms. Genes mutated in muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, several of which are part of the dystrophin-associated complex. Other gene products localize at the sarcomere and Z band, or are nuclear membrane components. In the present review, we focus on muscular dystrophies caused by defects that affect the sarcolemmal and sub-sarcolemmal proteins. We summarize the nature of each disease, the genetic cause, and the pathogenic pathways that may suggest future treatment options. We examine X-linked Duchenne and Becker muscular dystrophies and the autosomal recessive limb-girdle muscular dystrophies caused by mutations in genes encoding sarcolemmal proteins. The mechanism of muscle damage is reviewed starting from disarray of the shock-absorbing dystrophin-associated complex at the sarcolemma and activation of inflammatory response up to the final stages of fibrosis. We trace only a part of the biochemical, physiopathological and clinical aspects of muscular dystrophy to avoid a lengthy list of different and conflicting observations. We attempt to provide a critical synthesis of what we consider important aspects to better understand the disease. In our opinion, it is becoming ever more important to go back to the bedside to validate and then translate each proposed mechanism. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

Keywords: Duchenne muscular dystrophy; Dysferlin; Dystroglycan; Dystrophin; Sarcoglycan; limb-girdle muscular dystrophy.