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Page 334 Estévez-Arias et al. J Transl Genet Genom 2022;6:333-52 https://dx.doi.org/10.20517/jtgg.2022.04

Keywords: Charcot-Marie-Tooth disease, genetic diagnosis, genetic neuropathies, inherited peripheral
neuropathies, pathogenic pathways

THE CLINICAL AND GENETIC FEATURES
Charcot-Marie-Tooth (CMT) disease was described and named in 1886 by Charcot, Marie, and Tooth .
[1,2]
Originally described as peroneal muscular atrophy, CMT is a hereditary motor and sensory neuropathy
(HMSN) that primarily affects either myelin or the axon of peripheral nerves . This review is focused on
[3]
CMT as well as other related genetic neuropathies, which include distal hereditary motor neuropathies
(dHMN) with minimal or absent sensory involvement, and hereditary sensory and autonomic neuropathies
(HSN and HSAN), with significant sensory involvement.

CMT is the most common inherited disorder of the peripheral nervous system (PNS), with an estimated
prevalence of 28-40 individuals per 100,000 inhabitants, with global distribution and no ethnic
[4-6]
predisposition . Individuals with CMT show symmetric, slowly progressive in a length-dependent
manner, distal neuropathy of the legs and arms. CMT disease usually begins in the first to third decade of
life, causing slowly progressive distal muscle weakness and atrophy, weak ankle dorsiflexion, depressed
tendon reflexes, and pes cavus deformity [7-11] . Other symptoms are ataxia, pyramidal signs, and hypoacusia.
More aggressive phenotypes, in which the symptoms appear within the first two years of life, are
characterized by hypotonia, areflexia, and ataxia that represent greater disability in patients, and in some
cases, limit the patient’s autonomous ambulation and can lead to significant motor disability .
[12]
CMT types and classification
There is a remarkable heterogeneity in the spectrum of CMT and related disorders. In the very first
[3,8]
instance, heterogeneity can be observed in symptomatology and severity of the disease . Once the
symptoms are detected, ancillary tests (electrophysiologic and neuropathologic studies) help clinicians to
classify patients into those with demyelinating or axonal primary involvement and, in some cases,
intermediate forms . Clinical or phenotypic heterogeneity is complemented with high genetic
[13]
heterogeneity [3,14] . Since the discovery of the 1.4 Mb duplication in chromosome 17p11.2 [15,16] , the number of
CMT-associated genes has been increasing, and today almost 100 genes causing CMT disease and other
genetic neuropathies are now known. The identification of the responsible gene and its inheritance pattern
also helps the clinical practice make a correct classification of patients [7,17] . The observed inheritance patterns
include autosomal dominant, autosomal recessive, and X-linked (partially dominant and recessive) forms.
However, many patients present apparent sporadic diseases, attributable to de novo mutations .
[18]

We can distinguish two CMT neuropathies according to the type of cells primarily affected and the nerve
conduction velocities (NCVs): demyelinating CMT which affects the myelin-forming Schwann cells and
with NCVs below 38 m/s, and axonal CMT which affects the axons of neurons and usually presents NCVs
above 38 m/s [13,19] . Intermediate forms with overlapping demyelinating and axonal features, especially within
the same family, are defined by NCVs lying between 25 and 45 m/s [3,4,7,13] . Taking together the conduction
velocity parameters and the mode of inheritance, we can stratify CMT into five different categories:
demyelinating plus autosomal dominant inheritance (CMT1); axonal plus autosomal dominant or recessive
(CMT2); demyelinating plus autosomal recessive (CMT4); and X-linked (dominant or recessive) (CMTX).
The term CMT3 has been reserved to designate Dejerine-Sottas syndrome or neuropathy, which is a specific
category related to a congenital or infantile-onset and a severe (usually demyelinating) phenotype. Further
subdivision of these CMT types is based mainly on causative genes and assigned loci.