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  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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 609308).

  7. Congenital muscular dystrophies form a third category of muscular dystrophies after the dystrophinopathies and the LGMDs. They include milder phenotypes such as Ullrich disease (COL6A1, COL6A2, COL6A3) (OMIM 254090) and rigid spine syndrome (SEPN1) (OMIM 602771). The most common congenital muscular dystrophy, traditionally referred to as merosin deficiency (MDC1A; LAMA2) (OMIM 607855), has a moderately severe phenotype. A mutation in FKRP may cause a moderate form of congenital muscular dystrophy (MDC1C) (OMIM 606612) as well as LGMD2I. The three classic severe congenital muscular dystrophies are Fukuyama congenital muscular dystrophy (FCMD) (OMIM 253800), muscle-eye-brain disease (POMGnT1) (OMIM 253280), and Walker-Warburg syndrome (POMT1, FCMD, FKRP) (OMIM 236670).

  8. Some distal myopathies have dystrophic features on histology, including Miyoshi myopathy (DYSF) (OMIM 254130), which is allelic to LGMD2B; and tibial muscular dystrophy (Udd myopathy; TTN) (OMIM 600334), which is allelic to LGMD2J.

  9. Several unique phenotypes do not easily fit into one of the above categories, including Bethlem myopathy (COL6A1, COL6A2, COL6A3) (OMIM 158810), Emery-Dreifuss muscular dystrophy (EMD, LMNA) (OMIM 310300, 181350, 604929), facioscapulohumeral muscular dystrophy (OMIM 158900), and oculopharyngeal muscular dystrophy (PABP2) (OMIM 164300).

  10. The natural history ranges widely in these disorders, from the most severe congenital muscular dystrophies that are rapidly fatal to very mild diseases that have onset in adulthood and do not cause significant disabilities. Other organ systems may be involved, depending on the specific disease, including the heart, lungs, spine, eyes, and brain. In the more severe forms, the usual cause of death is a cardiac or pulmonary complication.

  11. The protein products of the genes known to cause muscular dystrophy perform a variety of functions and are clustered in several specific locations within or outside the muscle fiber. One cluster forms the dystrophin-associated protein complex (DAPC), which is linked to a second cluster in the extracellular matrix complex through sarcolemmal proteins. Three other clusters lie in the sarcomere, Golgi apparatus, and nucleus. There are a few proteins that do not easily fall into these five main categories, such as enzymes. The functions range from structural to signaling to glycosylation, depending on the specific protein. Many of these proteins are also expressed in nonmuscle tissues, often leading to multiorgan involvement in the muscular dystrophies.

  12. The diagnosis of the muscular dystrophies has changed dramatically since the gene for DMD was cloned in 1986. Many children with DMD and BMD no longer require uncomfortable and invasive diagnostic tests such as electromyography and muscle biopsy. In about two-thirds of cases, deletion and duplication analyses on DNA obtained from blood lymphocytes suffice to confirm the diagnosis after an elevated creatine kinase (CK) level has been documented. Muscle biopsy may still be required in many of the remaining cases, as well as in many of the other forms of muscular dystrophy, although mutation analysis is increasingly being used to confirm the diagnosis.

  13. Many of the genes that cause the muscular dystrophies have homologues in other organisms. Three organisms that are commonly used as models of muscular dystrophy are the mouse, dog, and zebrafish. The mdx mouse is the most widely used model. The xmd dog more closely replicates humans in general and DMD in particular compared with the mdx mouse, but is a more difficult organism to work with. Zebrafish models of muscular dystrophy have recently been developed and show promise in certain settings due to their rapid reproductive cycle.

  14. Significant progress has been made in the therapy of the muscular dystrophies over the past two decades. Steroid therapy prolongs ambulation in DMD. Surgery for scoliosis alleviates the respiratory complications and makes the patient more comfortable. The development of portable respirators has preserved motility late in the course even when respiratory failure occurs. Angiotensin-converting enzyme (ACE) inhibitors improve the course of cardiomyopathy, which complicates DMD, BMD, and other muscular dystrophies. Physical and occupational therapy also have been helpful. The life expectancy and quality of life have both improved significantly for affected individuals. A definitive cure, however, remains elusive. A new generation of potential therapies has emerged from the laboratory, and hope remains that one of these will eventually develop into a cure.

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