The age of single-gene neurological disorders is not dead

Abstract

This edition of Brain sees the first of a series of articles describing new genes responsible for inherited neurological disease, thus expanding the clinical neurogenetics portfolio. Sebahattin Cirak from the Institute of Child Health in London led a transcontinental consortium of clinical and basic science researchers who map the locus for a gene responsible for an autosomal dominant distal myopathy (Cirak et al. , 2010). Their work casts new light on the disease mechanisms of these poorly understood disorders; but at the same time, they broaden concepts on the potential mechanisms involved. Distal myopathies provide a classical example of the way that molecular genetics has revolutionized classifications in clinical neurology (Table 1). First described in the early part of the last century (Gowers, 1902), they were the focus of that old neurological chestnut ‘is the distal weakness due to muscle or nerve dysfunction?’ and were latterly subdivided into discrete entities based on astute clinical examination (reviewed in Barohn et al. , 1998). Early gene mapping studies identified several loci, highlighted the likely aetiological heterogeneity and led to the further delineation of different clinical groups (Udd, 2009). A major subgroup was associated with pathological myofibrils (myfibrillar myopathies) (Udd, 2009), overlapping with inherited limb girdle syndromes. Positional cloning and candidate gene analysis led to the rounding-up of some obvious culprits [ MYO7 , the myosin heavy chain 7 gene (Meredith et al. , 2004) and fast IIa myosin as recently published in Brain (Tajsharghi et al. , 2010)] and provided a satisfying explanation for the muscle group specificity of some distal myopathies [including the ophthalmoplegia in inclusion body myopathy-3, due to mutations in the myosin heavy chain IIa gene (Martinsson et al. , 2000)], but the real power of these ‘reverse genetic studies’ was in revealing new proteins required for intact muscle …