Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN),
includes two main subtypes of CMT1/HMSN I (demyelinating), and CMT2/HMSN II (axonal).
Further heterogeneity has been demonstrated by genetic molecular studies, with at
least four responsible genes for CMT1. As for CMT2, a mutation in the neurofilament-light
(NF-L) gene has been identified in a single family, and other CMT2 loci have been
mapped. We propose a clinical classification of the CMT2 phenotypes, and review the
features of the identified CMT2 genotypes. The following main subtypes of CMT2 are
considered in the phenotype classification: classical CMT2, the variants of CMT2 showing
atypical features that may represent either variance in the classical CMT2 phenotype
or separate entities; CMT2 plus, i.e. complex forms with involvement of additional
neural structures. The recognized CMT2 genotypes include: CMT2A (mapped to chromosome
1p35-36); CMT2B (3q13-22); CMT2C (with vocal cord paresis); CMT2D (7p14); CMT2E, related
to a mutation in the NF-L gene on chromosome 8p21; proximal CMT2, or HMSN P (3q13.1);
CMT2 with MPZ mutations; autosomal recessive CMT2 (1q21.2-q21.3); agenesis of the
corpus callosum with sensorimotor neuronopathy (15q13-q15); CMT2 X-linked with deafness
and mental retardation (Xq24-q26). The identified genotypes may correspond to previously
described clinical subtypes of CMT2. In particular, classical CMT2 presents in association
with NF-L gene mutation, in the only CMT2 family with known gene mutation, and in
CMT2A patients. However, the features of classical CMT2 have been paradoxically reported
also in families with MPZ mutation, and conversely several CMT2 families are not linked
to the known CMT2 loci. Further cloning of the CMT2 genes will ultimately shed light
on the pathogenic mechanism(s) implicated in the process of axonal degeneration, shared
by the different CMT2 genotypes.