limb-girdle muscular dystrophies

Classification

 limb-girdle muscular dystrophy 1A (LGMD1A) (MIM.159000)

Etiology

Limb girdle muscular dystrophies are caused by mutations in several genes that encode for proteins with divergent functions.

The most common LGMD forms result from sarcolemmal adhesion complex defects (sarcoglycans), but also other sarcolemmal molecules (caveolin-3 and dysferlin), nuclear membrane (lamin A/C) components and other types of molecules underlie LGMD.

Three sarcomeric proteins have been to shown to be directly involved in this form of muscular dystrophy.

Mutations in myotilin cause dominant LGMD (1A), whereas mutations in telethonin and titin result in recessive LGMD (2G and 2J, respectively). A fourth molecule, the protease calpain-3, may also be linked to sarcomeric abnormalities, as many of its substrates are cytoskeletal proteins.

Sarcomeric protein mutations may also result in other clinical phenotypes, such as nemaline myopathies.

For titin, two different disease forms exist; homozygous mutations cause LGMD, whereas heterozygous mutations of titin gene result in distal myopathy.

Mutations in the known disease-associated sarcomeric proteins are a rare cause of LGMD and their pathogenetic mechanisms remain to be elucidated.

References

 Bushby KM. The limb-girdle muscular dystrophies-multiple genes, multiple mechanisms. Hum Mol Genet. 1999;8(10):1875-82. PMID: 10469840