Genes for peripheral neuropathy and their relevance to clinical practice.

I dentification of neurological disease genes has expanded and transformed the neurologist’s nosology in the last decade. Yet some clinicians see the resultant overload of detail as merely making the diagnosis and management of patients more cumbersome with little tangible benefit. Using the example of inherited peripheral neuropathy it is timely for a clinician’s perspective of where neurogenetics has taken present day neurological practice and what the future might hold. Prior to molecular genetics, most neurologists kept a simple classification of inherited peripheral neuropathy in mind: demyelinating and axonal forms of hereditary motor and sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth disease (CMT); the hereditary sensory and autonomic neuropathies (HASN); hereditary liability to pressure palsies; and the hereditary amyloiditic polyneuropathies. Although workaday, this classification’s deficiencies were apparent. For example, a significant minority of patients with HMSN could not be categorised cleanly as either Type 1 (demyelinating) or Type 2 (axonal) on the basis of electrophysiology, leading to the notion of intermediate forms. A range of severe HMSN—recessively inherited and affecting infants and children, and including the category known as congenital hypomyelinating neuropathy— seemed to evade consistent classification. Our inability to make definitive diagnoses for these rare infantile disorders was particularly distressing given the family implications, profound motor disability, and sometimes death, which could result. So, when the chromosome 17 reduplication of the PMP-22 gene in CMT was described, a new dawn promised accurate diagnosis of genetic neuropathy and its implications. Since that first flush of promise, everything has become complicated by detail. There are more genetic neuropathies than we had ever imagined, and philately seems as useful as neurology for practising this subspecialty. We should be grateful to colleagues who have taken the trouble to distil this genetic literature and provide us with contemporary classifications. A brief look at their contemporary classifications for HMSN—now named CMT again—shows 37 identified genes or loci. Of these, 22 reflect demyelinating forms, 13 axonal and 2 intermediate, with a range of autosomal dominant and recessive, and sex-linked recessive transmission. At last the causes of the severe childhood and congenital hypomyelinating forms are emerging. The deluge continues apace. New interesting forms of CMT associated with mutations of the lamin A/C gene that encodes a nuclear envelope protein have been described, and of the gangliocideinduced differentiation-associated protein 1 (GDAP1). Also, different mutations affecting the same gene can produce demyelinating, intermediate or axonal forms of CMT—examples being CMT1B (myelin protein P0 mutations) and GDAP1 mutations. Reviews get out of date quickly—the website http:// molgen-www.uia.ac.be/cmtmutations/ provides a real time encyclopaedia. A similarly burgeoning range of genetic abnormalities seems to underlie other types of genetic neuropathy; acromutilating neuropathies of the HSAN type have been associated with the genetic locus for CMT Type 2B, or with the serine palmitoyltransferase long-chain base subunit 1 (SPTLC1) gene; the Riley-Day syndrome of familial dysautonomia is associated with mutations in the IkB kinase complexassociated protein (IKAP) gene; and selective neuropathies affecting small myelinated and unmyelinated fibres are associated with mutations in the tyrosine kinase A receptor for nerve growth factor (TRKA) gene. Memorising all of this is near impossible, even for academic clinicians subspecialising in peripheral neuropathy. The numerical classification has reached almost ridiculous proportions, whilst biochemical classifications have limited appeal for the non-cognoscenti. Identification of these myriad genetic abnormalities underlying CMT has led to one surprising, but important intellectual realisation. At the beginning of this voyage of molecular genetic discovery, many had anticipated that each new gene would add a logical piece to the jigsaw of understanding the development of peripheral nerve and the maintenance of its structure. However, in reality no all-embracing view of the biology of peripheral nerve development and structure has emerged from this wide range of naturally occurring human mutations. Indeed, few mutations seem to affect processes or proteins unique to peripheral nerves. Most seem to affect functions likely to be fundamental to the biology of the cells of many different tissues. Even in the case of mutations affecting the protein responsible for peripheral nerve myelin compaction—the myelin protein zero (MPZ) gene—we find that the 80 different point mutations cause a bewildering array of CMT Type 1B (demyelinating), CMT Type 2 (axonal), forms intermediate between CMT1 and CMT2, congenital hypomyelinating and childhood onset forms of CMT, and a late onset form of progressive demyelinating neuropathy with features resembling chronic inflammatory demyelinating polyneuropathy. Clinically similar phenotypes of CMT1 (demyelinating) can be associated with abnormalities of the various genes for the growth arrest protein peripheral myelin protein 22 (PMP-22), early growth response element 2 (EGR2), ganglioside-induceddifferentiation associated-protein-1 (GDAP1), myotubularin-related-protein-2 (MTMR2), n-myc-downstreamregulated-gene-1 (NDRG1), epithialgrowth-factor-related-protein-2 (EGR2), and periaxin (PRX). Thankfully the inability to develop or maintain an axon in CMT2 is founded in straightforward neurobiological logic when due to mutations in the genes for kinesin-motor-protein-1-B (KIFIBb) and neurofilament light chain (NFL), which involve axonal transport motor proteins and axonal structural intermediate filament proteins, respectively. But why do you get autosomal recessive CMT2 with one mutation of the laminin A/C nuclear envelope protein whilst other mutations produce the EmeryDreyfus muscular dystrophies, limb girdle muscular dystrophies, cardiomyopathy, and partial lipodystrophy Molecular genetic analysis of diseases has taught us something of the specific biology maintaining the structure of the peripheral nervous system, but it EDITORIAL 1371