Distal muscular dystrophies.

Distal muscular dystrophies are a group of inherited primary muscle disorders showing progressive weakness and atrophy preferentially in the hands, forearm, lower legs, or feet. Extensive progress in understanding the molecular genetic background has changed the classification and extended the list of confirmed entities to almost 20 different disorders, making the differential diagnostic procedure both easier and more difficult. Distal phenotypes first have to be differentiated from neurogenic disorders. The axonal form of Charcot-Marie-Tooth disease with late-onset distal weakness and distal forms of chronic spinal muscular atrophy may mimic those of the distal dystrophies. Increasing numbers of reports suggest increasing awareness of distal phenotypes in muscular dystrophy. Some disorders regularly progress eventually to involve proximal muscle, whereas others, such as tibial muscular dystrophy titinopathy (Udd), Welander distal myopathy, and distal myosinopathy (Laing), remain distal throughout the patient's lifetime. Pathologically there is a gradual degeneration and loss of muscle fibers with replacement by fibrous and fatty connective tissue, similar to the proximal forms of muscular dystrophy, frequently, but not always with rimmed vacuolar degenerative change. Strikingly, many of the genes involved in distal dystrophies code for sarcomeric proteins. However, the genetic programs leading to preferential involvement of distal muscles have remained unknown.