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CMT (usually an osteo-arthropathic type of pain). This treatment includes physical therapy, as explained
above, but also drugs (both for neuropathic and non-neuropathic pain) [35,38,39] . Then, specific drug therapies
have been considered in the CMT research, mostly those related to commonly found mutated genes [40-43] ,
and several experimental models have been useful to explore different approaches (Available from:
https://www.jax.org/search?q=Charcot%20Marie%20Tooth).

Some clinical trials with pharmacologic agents aimed at reducing PMP22 expression in CMT1A patients,
such as ascorbic acid, which did not improve the patient condition . After preclinical assays in a CMT1A
[44]
rat model, the progesterone receptor antagonist onapristone was discarded because it was not safe in
humans . Recently, high-dose PXT3003 (baclofen/naltrexone/D-sorbitol) has demonstrated significant
[45]
[46]
therapeutic effects in patients with CMT1A and has emerged as a promising treatment option . HDAC6
inhibitors have shown positive effects on axonal defects in mouse models of several forms of CMT [47-49] ,
opening a new window in the pharmacological treatment of CMT disease [50,51] . Antioxidant therapy with
either the veterinary antibiotic florfenicol or mitoQ has also shown effectiveness in a knockout model of
GDAP1-related CMT when starting administration very early in mouse life, but not in older mice . Gene
[52]
therapy research in animal models is becoming more relevant. AAV9-mediated Schwann cell-targeted gene
therapy of Gjb1-null mouse improves motor performance and sciatic nerve conduction velocities along with
[53]
improved myelination and inflammatory processes in peripheral nerve tissues . Therefore, much work
remains to be done for the treatment of CMT. The discovery of cellular mechanisms underlying the disease
pathophysiology opens new options for preclinical studies searching for new treatments that include drug
[52]
repositioning . An in-depth overview of current research in the pharmacological and biological treatment
of CMT neuropathies is beyond the scope of this review. The current status of therapeutic investigations
and ongoing clinical trials in CMT disease and genetic neuropathies was recently reported by
Pisciotta et al. . In Table 1, we summarize the mechanisms of action and the type of therapies and
[50]
compounds that may be useful or indicated in the future treatment of CMT disease. Most candidate
therapies are based on an understanding of disease mechanisms and affected pathways in cellular
pathophysiology. In the next section, we address the pathogenic mechanisms involved in the different types
of CMT neuropathies.

PATHOGENIC MECHANISMS AND NERVE PATHOPHYSIOLOGY
CMT and related diseases constitute a very heterogeneous group of disorders. From clinical to genetic
diagnosis, variability among patients is very high and pathogenic mechanisms involve Schwann cell and
neuron/axon pathways. Figure 1 and Supplementary Table 1 provide information on CMT genes and
illustrate the cellular and molecular mechanisms that compromise the nerve physiology, either in the myelin
sheath or the neuron soma and axon.

The following sections explain, in more detail and alphabetical order, the pathogenic mechanisms related to
the genes that most frequently constitute the genetic cause of CMT. Together with this detailed description,
Table 2 summarizes this information and correlates with Figure 2, which illustrates in detail the subcellular
localization of the proteins and the mechanisms and pathways affected by the pathogenic variants.

GDAP1
Among the most commonly involved genes in the pathogenesis of CMT, we can find GDAP1. This gene
encodes ganglioside-induced differentiation-associated protein 1 (GDAP1), which is an atypical glutathione
[55]
S-transferase (GST) with glutathione-conjugating and membrane-remodeling functions . This protein
[54]
can be found in the outer mitochondrial membrane (OMM) and the mitochondria-associated membranes
(MAMs), and it is mainly expressed in neurons [56-58] .