[Different phenotypes of Charcot-Marie-Tooth disease caused by mutations in the same gene. Are classical criteria for classification still valid?]

Abstract

Molecular genetic research is leading to the continuous discovery of new genes and protein involved in peripheral nerves function. Simultaneously, extended clinical, neurophysiological and pathological research has yielded new genotype-phenotype correlation on Charcot-Marie-Tooth disease (CMT). This has made it possible to know that several genes can cause both demyelinating (CMT1) and axonal (CMT2) phenotypes. Those observations have questioned the validity of some current criteria for CMT classification and raise the need for new strategies for diagnosis. The discovery of Schwann cell-axon interaction is a challenge for coming years. In this review, we extensively analyzed mutations of genes that give rise to CMT1 or CMT2 phenotypes. There are at least three forms of genetic variability. MPZ gene mutations yield a real allelism, that is, CMT1 or CMT phenotypes associated to specific mutation by site or quality. GADP1 and probably NF-L gene manifest different phenotypes but only in terms of nerve conduction velocity (CV). Evidence is provided that indicates that CV reduction in GADP-1 neuropathy may be the result of axonal loss. Finally a third form of variability is present in CMTX due to the degree of clinical expression in females related with the inactivation of chromosome X.