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Page 338 Estévez-Arias et al. J Transl Genet Genom 2022;6:333-52 https://dx.doi.org/10.20517/jtgg.2022.04

Table 1. CMT therapeutics: target cell processes and pathways and drug strategies
Cell process or mechanism of action Compound/therapeutic strategy
Reduction of gene expression Ascorbic acid
Reduction of protein synthesis Progesterone antagonists and modulators
Inhibition of Schwann cells proliferation and reduction of protein synthesis PXT3003 (baclofen, sorbitol, naltrexone)
(baclofen: GABA receptor modulator)
B
Partial silencing of gene expression Gene silencing
Gene insertion (AAV1-NT3) Gene therapy
Gene substitution
Regulation of myelin thickness Neuregulin pathways
UPR inhibition Curcumin, sephin-1
TRPA1 and TRPV1 channels activation FLX-787
Prevention of axonal degeneration SARM1 inhibitors
Reduction of microtubules acetylation (axonal transport) HDAC6 inhibitors
Myostatin pathway ACE-083
Reduction of abnormal calcium influx in Schwann cells P2X7 receptor modulators
Correction of defective lipid biosynthesis Dietary lipid supplementation
Nav 1.8 channel blocking Sodium channel blockers
Decreased number/activity of macrophages in the nerve CSF1R inhibitors
PIKfyve inhibition and decrease of PI3,5P2 levels PIKfyve enzyme inhibitors
Reduction of neurotoxic deoxysphingolipids L-Serine
Purine nucleotides supply S-adenosylmethionine (SAM)
Inhibition of aldose reductase Aldose reductase inhibitors
GABA : Gamma-aminobutyric acid B receptor; AAV1-NT3: adeno-associated virus-mediated neurotrophin-3; UPR: unfolded protein response;
B
TRPA1: transient receptor potential cation channel, subfamily A, member 1; TRPV1: transient receptor potential cation channel subfamily V
member; SARM1: sterile alpha and TIR motif-containing 1; HDAC6: histone deacetylase 6; CSF1R: colony-stimulating factor 1 receptor; PIKfyve:
phosphatidylinositol 3-phosphate 5-kinase. Summarized information in this table was extracted from Pisciotta et al. (2021) [50] .

The scenario of GDAP1 mutations is quite different from other CMT disease-causing genes due to its
heterogeneity: mutations in this gene have been related to axonal forms (AR-CMT2K with vocal cord
paresis (CMT2K), an intermediate form (CMTRIA), and a demyelinating (CMT4A) form of the disease.
Both recessive and dominant modes of inheritance have been reported . To date, more than 100 mutations
[56]
in GDAP1 gene have been related to CMT phenotype .
[59]
Clinically, CMT caused by mutations in this gene is characterized by severe distal motor and sensory
neuropathy. Nevertheless, a diverse spectrum of phenotypes should be considered due to the variability in
inheritance patterns [56,60,61] . It has been proposed that, while autosomal recessive mutations are responsible
for early-onset and severe neuropathies, dominant mutations cause a milder course of the disease .
[62]
Regarding the histological abnormalities, the sural nerve biopsy of severe affected segregating the disease in
an autosomal recessive manner shows a pronounced depletion of myelinated fibers, regenerative clusters
and signs of axonal atrophy. Additionally, a small proportion of thin myelinated fibers and proliferation of
Schwann cells forming onion bulb structures have also been found. The most relevant cytoplasmic feature
[63]
would be the mitochondrial abnormalities .
Although the explicit molecular mechanism underlying the GDAP1 function remains unclear, several
[59]
studies have explored its role in mitochondria physiology: morphology, function, and dynamics . Firstly,
the consequence of GDAP1 mutations can impair these mitochondrial functions through mitochondrial
membrane potential reduction, ATP production changes, or a disbalance of their dynamics [57,64,65] . Second,
GDAP1 may also interact with transport proteins involved in mitochondrial transport and movement.