The muscular dystrophies are a diverse group of inherited disorders characterized by progressive muscle weakness and wasting in which the primary defect becomes most symptomatic in skeletal muscle, with variable involvement of the heart. The clinical classification has been based largely on severity, distribution of affected muscles, and mode of inheritance. In the last 5 years, the molecular defect has been identified in many forms of the disease, and the clinical classification is giving way to a molecular classification.

Dystrophin is a high-molecular-weight cytoskeletal protein localized at the inner surface of the muscle membrane. It is part of a dystrophin-glycoprotein complex, including the dystroglycans and sarcoglycans. The complex provides a bridge across the muscle membrane, with dystrophin binding F-actin in the cytoplasm and dystroglycan binding merosin (laminin-2) in the extracellular matrix. Dystrophin deficiency results in destabilization of the complex and failure of the dystroglycans and sarcoglycans to localize in the membrane. The complex seems to be critical for the structural integrity of the muscle membrane.

Dystrophin is absent from the muscle of boys with Duchenne muscular dystrophy (DMD) and reduced or altered in the milder Becker muscular dystrophy (BMD) (see Tables 216-1 and 216-2 for complete lists of OMIM numbers; the corresponding GenBank numbers for cloned nucleotide sequences are given). Both are now classified as dystrophinopathies. X-linked dilated cardiomyopathy (XLDC) results from a cardiac-specific dystrophin deficiency. In each case, mutation of the large (2500-kb) dystrophin gene is responsible for the disease.

Several autosomal recessive forms of muscular dystrophy, including four of the eight autosomal recessive forms of limb-girdle muscular dystrophy (LGMD) have defects in the four muscle-specific sarcoglycans secondary to mutations in the corresponding genes and are now classified as sarcoglycanopathies.

Two other forms of autosomal recessive LGMD are due to mutations in genes unrelated to the dystrophin-glycoprotein complex. These include the gene encoding the muscle-specific, calcium-activated neutral protease calpain-3 and the gene encoding dysferlin, a protein of unknown function related to fer-1 (Caenorhabditis elegans spermatogenesis factor).

Of three known autosomal dominant forms of LGMD, the molecular defect in one is known to be in the gene encoding caveolin-3, the muscle-specific form of the principal protein component of caveolae in the plasma membrane.

The classic form of congenital muscular dystrophy is due to mutations in the gene encoding merosin (laminin-2) in the extracellular matrix, confirming the importance of merosin as part of the dystrophin-glycoprotein complex. Fukuyama congenital muscular dystrophy, common in Japan, is due to mutation in a gene encoding fukutin, a protein of unknown function, which results in a secondary and unexplained reduction in merosin in the extracellular matrix, the latter possibly explaining the disease phenotype.

Emery-Dreifuss muscular dystrophy (EDMD) is X-linked and distinct from DMD and BMD. It is caused by mutations in the ubiquitously expressed gene encoding emerin, a protein localized at the nuclear membrane of myonuclei with sequence similarity to the nuclear lamina-associated protein LAP2. Phosphorylation is critical to its putative role in anchoring the nuclear membrane to the cytoskeleton.

Autosomal dominant and recessive forms of oculopharyngeal muscular dystrophy (OPMD) are both caused by mutations in the gene encoding polyadenylation binding protein 2 (PABP2). The mutation is an expansion of a normal (GCG)6 triplet repeat, resulting in an elongated polyalanine stretch at the N-terminus of the protein and presumably a conformational change that induces the formation of characteristic intranuclear filaments. Homozygosity for a (GCG)7 allele is responsible for the autosomal recessive form, whereas heterozygosity for a longer expansion accounts for the autosomal dominant form.

Fascioscapulohumeral muscular dystrophy (FSHMD) is autosomal dominant and is due to deletion of multiple copies of a 3.2-kb tandem repeat in both sporadic and familial cases. No gene has been identified to be specifically altered in the disease, and the molecular consequences of the deletion are poorly understood.

With identification of the molecular defect in so many forms of muscular dystrophy, specific diagnostic tests are now available, and in familial cases, prenatal diagnosis for future pregnancies is available. A combination of DNA, RNA, and protein-based laboratory tests can be used to clearly distinguish between the many forms with overlapping phenotypes.

Naturally occurring animal models exist for three forms of muscular dystrophy, including the dystrophin-deficient mdx mouse and dog, the merosin-deficient dy/dy mouse, and the sarcoglycan-deficient cardiomyopathic hamster. In addition, several knock-out models have been created by homologous recombination in the mouse, and crossing with mice deficient in other molecules has resulted in animals with severe phenotypes, useful for testing novel therapies.

Despite the recent progress in understanding the basic defect, the muscular dystrophies are still largely untreatable. Corticosteroids are the only pharmacologic agents that have so far shown beneficial effect for DMD, but the improvement is minimal, and side-effects preclude long-term administration. Myoblast transfer of normal myogenic cells has been tried with very limited success, but overcoming the immune rejection may lead to new clinical trials. Gene therapy is a major research activity at present, and newly developed adenoviral vectors have shown considerable promise for gene delivery with sustained activity of the transgene. There is therefore reason to be optimistic about the future for gene therapy.