What is muscular dystrophy? Forty years of progressive ignorance

This lecture traces recent advances in knowledge of the muscular dystrophie s, as well as their increasing complexity. They are described through the e yes of the author from his first exposure to and complete ignorance of the disease in the late 1950s, through the advent of modern techniques, to the molecular genetic revolution, with the recognition of individual genes and proteins for disorders within the muscular dystrophy umbrella. There initially seemed to be a logical sequence of linked membrane proteins from dystrophin in Duchenne and Becker dystrophy, through the dystrophin-a ssociated glycoproteins (sarcoglycans) in some of the limb girdle muscular dystrophies (LGMD), to the extracellular matrix protein merosin (alpha -2 l aminin) in congenital muscular dystrophy (CMD). The first spoke in the whee l came with the discovery of a calcium activated protease enzyme, calpain 3 , in one form of LCMD, and subsequently another novel non-membrane protein, dysferlin, in another. There are currently at least eight distinct genetic forms of LGMD alone, and another eight separate genetic entities in the CM D group. This has highlighted our ignorance of the pathogenesis of the musc ular dystrophies in relation to a diverse array of protein deficiencies. To compound things further, the X-linked and dominant forms of Emery-Dreifu ss muscular dystrophy have recently been linked to emerin and lamin A/C, re spectively, two proteins of the nuclear membrane, opening up yet another ne w ballpark of discovery.