Inherited peripheral neuropathies: a myriad of genes and complex phenotypes

Abstract

Inherited peripheral neuropathies form a sizable group of disorders that are known for their remarkable clinical and genetic heterogeneity. A common feature is the progressive length-dependent neurodegeneration in the peripheral nervous system (PNS). As a group, inherited peripheral neuropathies are the most common hereditary neuromuscular disorders with an estimated prevalence of one in every 2500 individuals. The inherited peripheral neuropathies are subdivided in hereditary motor and sensory neuropathy (HMSN), which is also known as Charcot–Marie–Tooth disease; hereditary motor neuropathy; and hereditary sensory and autonomic neuropathy (HSAN) based on clinical and electrophysiological findings. Further refinement of HMSN into demyelinating (HMSN-I), axonal (HMSN-II) and intermediate forms can be made when applying criteria to nerve conduction studies. These subdivisions stem from the pre-genetic era and were laid down in seminal reports based on detailed description in patients and families (Harding and Thomas, 1980; Dyck, 1993; Harding, 1993). The first and still major causal genetic defect for inherited peripheral neuropathies, the CMT1A duplication, was discovered two decades ago (Lupski et al. , 1991; Raeymaekers et al. , 1991). Since that time, our knowledge of the molecular genetic groundwork of this group of diseases has grown considerably with well over 40 causal genes now identified. Genetic heterogeneity is such that, for a given subgroup of phenotypes, numerous candidate genes still have to be considered. Conversely, pronounced clinical heterogeneity can be observed among patients carrying mutations in the same gene with phenotypes sometimes conforming more closely to another subgroup within the classification of inherited peripheral neuropathies. The interrelationship between mutations in the known genes and their respective clinical phenotypes has led to a highly intricate classification. There are countless examples of this clinical and genetic heterogeneity: dominant mutations in HSPB1, HSPB8 and GARS can cause …