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Major advances in the genetic understanding of the limb-girdle (LGMD) and congenital (CMD) muscular dystrophies have led to a new, genetically based classification of these disorders. The definition of the complex of dystrophin-associated proteins on a biochemical and subsequently genetic level has greatly accelerated this progress by providing candidate genes to complement or replace the process of linkage analysis either in families with muscular dystrophy or in sporadic cases. The major components of the dystrophin-associated proteins now known to be involved in muscular dystrophy besides dystrophin itself are the sarcoglycan complex and the α2-chain (merosin) of laminin-2 in the extracellular matrix. Mutations in the various sarcoglycans account for four types of autosomal recessive LGMD of varying severity (types 2C through 2F), including severe childhood-onset presentations. One type of autosomal recessive LGMD (type 2A) is caused by mutations in the protease calpain-3, whereas the gene for type 2B has not yet been identified, although the responsible locus has been assigned to chromosome 2p13. There are different autosomal dominant forms as well, one of which has been mapped to chromosome 5q31. With regard to CMDs, the major breakthrough involves a type of “classic” CMD with abnormalities of the white matter on magnetic resonance imaging of the brain. These patients show deficiencies of the laminin α2-chain, and mutations in the corresponding gene have been identified. The group of laminin α2-chain-positive classic CMD likely is heterogeneous. Among the group of CMDs with abnormalities of brain formation and mental retardation, genetic, immunohistochemical, and clinical differences are now beginning to emerge to help in the distinction between Fukuyama muscular dystrophy, the Walker-Warburg syndrome, and muscle-eye-brain disease.