More surprises in sarcomeric protein diseases

Abstract

In this issue of Brain, three papers (Wallgren-Pettersson et al ., Griggs et al . and Walter et al .) expand the horizons of skeletal muscle diseases caused by mutations in sarcomeric proteins. Two of the papers (Wallgren-Pettersson et al ., and Griggs et al .) deal solely with distal myopathies. One of the most unexpected discoveries in the sarcomeric protein disease field has been that mutations in sarcomeric proteins can cause distal myopathies. Each distal myopathy preferentially affects what can be a bizarre collection of specific, restricted muscles. In the early-onset distal myopathy, MPD1, this starts with the tibialis anterior and later extends to the flexor hallucis longus, long finger extensors, sternocleidomastoids and the medial head of the gastrocnemius (Lamont et al ., 2006). What sort of gene can do that to a patient? One might think of genes involved in positional information. However, we now know that specific mutations in the rod-domain of the slow myosin heavy chain, the myosin expressed in every slow skeletal muscle fibre and in the heart, cause this disease (Meredith et al ., 2004). The pathophysiological cascade from myosin mutation to disease phenotype remains a mystery. Equally, mutations in titin, expressed in every muscle fibre in the body, cause tibial muscular dystrophy—a late onset distal myopathy affecting another restricted group of muscles, including some of the same muscles as MPD1 (Hackman et al ., 2002). In the first paper, Wallgren-Pettersson et al . (page 1465) report that homozygosity for missense mutations in nebulin causes an early onset mild distal myopathy. Wallgren-Pettersson and her colleagues had previously shown that mutations in nebulin are the commonest cause of recessive nemaline myopathy (Pelin et al ., 1999). Nebulin nemaline myopathy, like other congenital myopathies, …