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Estévez-Arias et al. J Transl Genet Genom 2022;6:333-52 https://dx.doi.org/10.20517/jtgg.2022.04 Page 335

The increasing knowledge of CMT genetics and pathophysiology has led to changes in the way the different
types were classified initially. Some efforts have been made to simplify its nomenclature, reducing the risk of
denomination errors [20,21] , since the discovery of newly associated genes susceptible to being the cause made
the classification more and more difficult. Specifically, Mathis et al. in 2015, opened a way for a precise
denomination including: (1) the inheritance pattern; (2) the pathophysiological phenotype (by using “de” or
“ax” for demyelinating and axonal forms, respectively); and (3) giving more importance to the causal
gene . Based on it, CMT1A 17p11.2 duplication would be AD-CMTde-PMP22dup or CMT4A would
[21]
[21]
become AR-CMTde-GDAP1 . This is an informative denomination that, in fact, is helpful and
understandable for both patients and clinicians. These types of proposals are an example of all the efforts
[20]
that the scientific community has made to manage such a heterogeneous group of diseases . In any case, in
our ambit, we still maintain the traditional nomenclature that, moreover, can be found in clinical databases
such as OMIM. This is the reason this denomination is used in this review.

The molecular genetics of CMT began in 1991 with the discovery of the 1.4 Mb duplication in the short arm
of chromosome 17, which contains the dose-sensitive peripheral myelin protein 22 (PMP22) gene, causing
CMT1A and became the most common cause of genetic neuropathies [15,22] . By 1992, point or indel
mutations in GJB1 (encoding connexin 32 [Cx32]), PMP22, and MPZ had also been discovered [17,23] . Loci
and genes for CMT and related peripheral neuropathies were initially identified using linkage studies,
positional cloning, or candidate gene approaches . Since the publication of the first draft of the human
[22]
genome in 2001, the development of high-throughput technologies, such as genome mapping, whole-exome
sequencing, and whole-genome sequencing, have accelerated the gene and mutation discovery in CMT
research [14,23] . As the Human Genome Project reached completion, the identification of CMT genes
increased markedly, so the number of genes associated with the disease has been increasing in the last years.

Currently, around 100 genes have been identified in Mendelian inheritance of genetic neuropathies.
Although there are myriad gene associations and pathophysiologic mechanisms, it is clear that the
mutations associated with the disease are closely related to the formation, compaction, and maintenance of
myelin (PMP22, P , Cx32, EGR2, NDGR1, PRX, etc.), the neuronal soma, axon and cytoskeleton
0
conservation (NEFL, LMNA, MORC2, etc.), the axonal transport (RAB7), and the mitochondrial dynamics
[3,7]
(MFN2, GDAP1, GARS, HSP22, HSP27, etc.) . This means that, independently of the defect (metabolic,
cytoplasmic, or structural) that primarily affects the myelin or axon, as well as the Schwann cell-axon
structure, the axonal degenerative process is the final common pathway in neuropathies that primarily affect
[24]
the largest and longest fibers .

CMT genes and their corresponding proteins have been classified according to their localization in the
neuron, and general information about their main biological function and proposed pathomechanisms is
explained here. The well-established proteins and their proposed pathogenic mechanisms for the nerve
(either in myelin or in the neuronal axon and soma) are summarized in Supplementary Table 1. The code of
the MIM genes (*) and their mode of inheritance are indicated together with the MIM phenotype (#) of the
neuropathy caused by the pathogenic variants of the corresponding gene. Information is updated each year
in the context of all neuromuscular disorders .
[25]
Genetic diagnosis
Due to the high heterogeneity in terms of gene associations, the approach to the diagnosis of CMT and
genetic neuropathies has evolved from a purely clinical approach in the past to a combined clinical/genetic
approach. As happens in many other diseases, genetic testing can also be used on the patient and their
family for predictive, antenatal, or preimplantation assessment.