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ABSTRACT

  • The muscular dystrophies are a broad class of primary muscle disorders with a diverse range of genetic etiologies, clinical presentations, and natural history. The disease generally arises through a loss of function of the affected protein product. They share a common histopathologic picture of muscle degeneration and regeneration, characterized by fiber necrosis, inflammation, and fibroadipose replacement of muscle fibers. This distinguishes them from the congenital myopathies, which are associated with muscle fiber dysmorphology, often due to abnormal accumulations of various proteins.

  • The first description of Duchenne muscular dystrophy (DMD) (OMIM 310200), the most common form, is generally attributed to Duchenne de Boulogne in 1861, although there are several reports published earlier in the nineteenth century by Edward Meryon and others that appear to present the same disease. A major milestone in the genetics of this disorder came in 1986, when the gene causing DMD was cloned. A year later, its protein product, dystrophin, was identified. Since then, several dozen genes have been associated with various forms of muscular dystrophy (gene sequences available at http://www.dmd.nl/).

  • The complexities of the genotype-phenotype correlations in the muscular dystrophies make it difficult to classify them. Two different schemas are presented, one organized by categories of the various proteins encoded by the causative genes, the other organized by phenotype. The former will be more useful for scientific researchers, the latter for clinicians.

  • In a phenotypic classification, the X-linked dystrophinopathies DMD and Becker muscular dystrophy (BMD) (OMIM 300376) are the most common forms of muscular dystrophy. Both are caused by mutations in the gene DMD (also known as dystrophin). The classic form of BMD has a milder phenotype than DMD, but the boundary between the two phenotypes is not always easy to determine, as there is a spectrum of clinical manifestations.

  • The autosomal dominant limb girdle muscular dystrophies (LGMDs) are to some extent phenotypically similar to the milder forms of dystrophinopathy. There are three autosomal dominant LGMDs for which causative genes have been identified. LGMD1A (myotilinopathy) (OMIM 159000) is caused by mutations in TTID. Mutations in LMNA cause a variety of phenotypes, including LGMD1B (laminopathy) (OMIM 159001), Emery-Dreifuss muscular dystrophy (OMIM 310300, 181350, 604929), cardiomyopathy, lipodystrophy, and Hutchinson-Gilford progeria. LGMD1C is also known as caveolinopathy (OMIM 607801) and is caused by mutations in CAV3. There are three other forms of autosomal dominant LGMD for which causative genes have not yet been identified: LGMD1D, LGMD1E, and LGMD1F.

  • The autosomal recessive LGMDs tend to be more severe, and have some phenotypic similarities to the more severe end of dystrophinopathy spectrum. They include LGMD2A (calpainopathy; CAPN) (OMIM 253600), LGMD2B (dysferlinopathy; DYSF) (OMIM 253601), LGMD2C (γ-sarcoglycanopathy; SGCG) (OMIM 253700), LGMD2D (α-sarcoglycanopathy; SGCA) (OMIM 608099), LGMD2E (β-sarcoglycanopathy; SGCB) (OMIM 604286), LGMD2F (δ-sarcoglycanopathy; SGCD) (OMIM 601287), LGMD2G (telethoninopathy; TCAP) (OMIM 601954), LGMD2H (TRIM32) (OMIM 254110), LGMD2I (FKRP) (OMIM 607155), LGMD2J (TTN) (OMIM 608807), and LGMD2K (POMT1) (OMIM ...

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