Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease

Abstract

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.