Molecular genetics of autosomal-dominant demyelinating CMT

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Neuromolecular Med. 2006;8(1-2):43-62.

Molecular genetics of autosomal-dominant demyelinating charcot-marie-

tooth disease.

Houlden H, Reilly MM.

Centre for Neuromuscular Disease and Department of Molecular

Neurosciences, National Hospital for Neurology and Neurosurgery and

Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically

heterogeneous group of disorders and is the most common inherited

neuromuscular disorder, with an estimated overall prevalence of 17-

40/10,000. Although there has been major advances in the

understanding of the genetic basis of CMT in recent years, the most

useful classification is still a neurophysiological classification

that divides CMT into type 1 (demyelinating; median motor conduction

velocity < 38 m/s) and type 2 (axonal; median motor conduction

velocity > 38 m/s).

An intermediate type is also increasingly being described.

Inheritance can be autosomal-dominant (AD), X-linked, or autosomal-

recessive (AR). AD CMT1 is the most common type of CMT and was the

first form of CMT in which a causative gene was described.

This review provides an up-to-date overview of AD CMT1 concentrating

on the molecular genetics as the clinical, neurophysiological, and

pathological features have been covered elsewhere. Four genes (PMP22,

MPZ, LITAF, and EGR2) have been described in the last 15 yr

associated with AD CMTI and a further gene (NEFL), originally

described as causing AD CMT2 can also cause AD CMT1 (by

neurophysiological criteria).

Studies have shown many of these genes, when mutated, can cause a

wide range of CMT phenotypes from the relatively mild CMT1 to the

more severe Dejerine-Sottas disease and congenital hypomyelinating

neuropathy, and even in some cases axonal CMT2. This review discusses

what is known about these genes and in particular how they cause a

peripheral neuropathy, when mutated.