Genetics and pathogenesis of distal muscular dystrophies

Distal myopathies are distal muscular dystrophies because they are genetic disorders with progressive loss of muscle tissue. The true distal dystrophies not only show a distal onset; they also remain more distal than proximal throughout the course of the disease. Currently almost 20 different entities of distal muscular dystrophies have been genetically determined, compared to just five entities delineated on clinical grounds in the 1980s. Half of the genes underlying these disorders have been associated with distal phenotypes only, whereas the other genes can manifest also with other than distal phenotypes such as proximal, scapuloperoneal or generalized phenotypes. Interestingly, most of the genes causing distal muscular dystrophies code for protein components of the sarcomere, in contrast to the proximal dystrophies in which most of the genes cause defects in sarcolemmal proteins. The reason for why some gene defects predominantly affect distal muscles is not well understood. The fact that the majority of these defects are due to structural and functional components of the sarcomere is intriguing but so far it does not provide further clues for understanding or for therapeutic approaches. The highly selective involvement of muscles in many of the distal dystrophies is even less well understood.