The muscular dystrophies: from genes to therapies

Abstract

The genetic basis of many muscular disorders, including many of the more common muscular dystrophies, is now known. Clinically, the recent genetic advances have improved diagnostic capabilities, but they have not yet provided clues about treatment or management. Thanks to better management strategies and therapeutic interventions, however, many patients with a muscular dystrophy are more active and are living longer. Physical therapists, therefore, are more likely to see a patient with a muscular dystrophy, so understanding these muscle disorders and their management is essential. Physical therapy offers the most promise in caring for the majority of patients with these conditions, because it is unlikely that advances in gene therapy will significantly alter their clinical treatment in the near future. This perspective covers some of the basic molecular biological advances together with the clinical manifestations of the muscular dystrophies and the latest approaches to their management.

Figure 1

Immunofluorescent images of control muscle (A) and dystrophic (mdx) muscle (B) from mice illustrate the presence of dystrophin at the sarcolemmal membranes of normal muscle and its loss from the sarcolemmal membranes in dystrophic samples (muscle sections were processed together and labeled for dystrophin, but because mdx muscle lacks dystrophin, the field remains completely dark). Hematoxylin and eosin staining of control (C) and dystrophic muscle (D) from mice show abnormal variance in fiber size, fibrosis, inflammatory cell infiltration, and degenerating and regenerating muscle fibers that are typically of abnormal size and contain centrally located nuclei (arrow). Although they are not as severely affected as humans with Duchenne muscular dystrophy, dystrophic (mdx mice) serve as a model for that disease, which also is due to a lack of dystrophin.

Figure 2

Schematic model showing the molecular linkages of the sarcolemma via the dystrophin-associated protein complex (DAPC) to the underlying contractile apparatus. Cytoskeletal components that are affected in the more common muscular dystrophies are indicated.