Charcot-Marie-Tooth Disease and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

Literature and regulatory information updated: 4 October 2026.

Hereditary motor and sensory neuropathy (HMSN) · peroneal muscular atrophy · CMT1A (17p12/PMP22 duplication), CMT1B (MPZ), CMT2 (MFN2 and other axonal forms), CMTX1 (GJB1), CMT4 (autosomal recessive forms) · HNPP (17p12/PMP22 deletion) · 17p12 microduplication

0. Initial Reference Table

(Table sources: [2, 4, 11–14, 29–33].)

1. Introduction

Charcot-Marie-Tooth disease comprises chronic hereditary length-dependent sensorimotor peripheral neuropathies, the commonest hereditary neuromuscular disorder, with estimated prevalence approximately 1 in 2500 [1, 3]. Typical disease features slowly progressive distal weakness and atrophy beginning in peroneal (fibular)-innervated muscles and later affecting hands, with distal sensory loss, reduced or absent reflexes and pes cavus [4]. Genetic heterogeneity is central: GeneReviews lists more than 80 associated genes [4], and the Oxford Desk Reference describes their roles in myelin structure, transcription, mitochondrial function and intracellular membrane transport [1].

The eponym dates to 1886, when Jean-Martin Charcot and Pierre Marie in Paris described “a particular form of progressive muscular atrophy, often familial, beginning in the feet and legs and later affecting the hands” [34], while Howard Henry Tooth's Cambridge thesis argued for a neuropathic basis of the “peroneal type of progressive muscular atrophy” [35]. In 1968, Peter Dyck and Edward Lambert used conduction velocity and histology to distinguish hypertrophic demyelinating HMSN I from neuronal/axonal HMSN II [36]. Harding and Thomas's 1980 British series of 227 conduction-classified patients documented AD inheritance in most families of both types, some recessive and isolated cases, and greater male weakness [37]. Skre's 1974 western Norwegian population estimate of approximately 1:2500 remains cited [5].

In 1991, James Lupski's Houston and Christine Van Broeckhoven's Antwerp groups independently identified an approximately 1.5 Mb tandem 17p duplication causing CMT1A [38, 39]; in 1992, peripheral myelin protein 22 kDa (PMP22) was shown within the duplication [40, 41], arising through unequal recombination between flanking CMT1A-REP repeats [9]. Chance and colleagues demonstrated the reciprocal deletion causing HNPP in 1993 [42], clinically described by De Jong in a Dutch potato-picker family in 1947 [2, 43]. That year also identified connexin 32 (GJB1) in X-linked CMT [44] and myelin protein zero (MPZ) in CMT1B [45]; subsequent discoveries included MFN2 in CMT2A (2004) [46], SH3TC2 in CMT4C (2003) [47], NDRG1 in HMSN-Lom (2000) [48], and SORD in 2020 as the commonest recessive hereditary neuropathy cause [49].

Clinical assessment starts with neurophysiological classification (demyelinating, intermediate or axonal) and inheritance, followed by molecular diagnosis beginning with PMP22 duplication/deletion testing in every proband [4, 16]. Magy and colleagues proposed inheritance-, neuropathy- and gene-based nomenclature in 2018 (e.g. AD-CMTDe-PMP22), adopted by GeneReviews alongside historical alphanumeric names [4, 50]. CMT and its major subtypes (CMT1A, CMT1B, CMT2/MFN2 and other axonal forms, CMTX1, CMT4), genomic 17p12 microduplication and HNPP are considered together because reciprocal PMP22 dosage mechanisms link the two commonest entities [1, 2].

2. Molecular Genetics and Pathophysiology

2.1 General principles: Schwann cells, axons and neurophysiological classification

Classic classification distinguishes primary Schwann-cell pathology (demyelination with reduced conduction velocities) from primary axonal pathology (degeneration with preserved velocities and reduced amplitudes) [1]. Relative to normal motor velocity above 40–45 m/s, GeneReviews defines demyelinating CMT1 below 35 m/s, axonal CMT2 above 45 m/s, and dominant intermediate DI-CMT at 35–45 m/s [4]. Historical thresholds differ: Oxford Desk Reference usually gives 10–38 m/s for HMSN1 and 38–48 m/s for HMSN2 [1], while the Norwegian population study used 38 m/s with an intermediate 25–45 m/s range [6]. Term-newborn motor velocities are approximately 50% of adult values, approaching them around 3 years, requiring age-adjusted interpretation [1].

The 2020 French PNDS (French National Diagnosis and Care Protocol) proposes, based on Langlais and colleagues, a two-way grid crossing the electrophysiological phenotype with the mode of transmission: under AD inheritance it distinguishes AD-CMT1 (demyelinating), AD-CMT2 (axonal) and DI-CMT (intermediate); under AR inheritance, AR-CMT1 (CMT4), AR-CMT2 and RI-CMT; and the X-linked form (CMTX) lies mainly in the intermediate range [17]. Families with features of both patterns (intermediate forms) account for about 10% of the total [17]. The same document acknowledges the limits of any classification: a single gene may cause dominant and recessive forms, and several genes without a CMT acronym may present with an isolated peripheral neuropathy before the cardinal signs of the underlying disease; it therefore refers to the OMIM phenotypic series PS118220 as the reference list of loci [17]. Purely motor forms (“spinal” CMT, distal hereditary motor neuropathies, distal spinal muscular atrophy) and purely sensory or dysautonomic forms are treated as related disorders and are sometimes classified among the CMT2 forms [17].

CMT genes are grouped by cellular function: structural proteins of compact myelin (PMP22, MPZ, PRX), myelination transcription factors (EGR2), gap junctions (GJB1), mitochondrial dynamics and transport (MFN2, GDAP1), endosomal and lysosomal trafficking (RAB7A, LITAF, SH3TC2, MTMR2, SBF2, FIG4), cytoskeleton and axonal transport (NEFL, KIF1B, DYNC1H1), chaperones (HSPB1, HSPB8), aminoacyl-tRNA synthetases (GARS1, AARS1, YARS1) and metabolism (SORD) [1, 4]. Saudubray's chapter on disorders of cellular trafficking places many forms of CMT in this category: defects of the endoplasmic reticulum–Golgi exocytic pathway (TFG), of the endolysosomal pathway and autophagy (RAB7A in CMT2B, FIG4 in CMT4J, SH3TC2, MTMR2 and SBF2 in CMT4B), of kinesin- and dynein-dependent axonal transport (KIF5A, DCTN1) and of glial connexin trafficking (connexin 32 in CMTX1), and notes that the late-onset manifestations of these defects tend to be predominantly motor, with spastic paraparesis, motor neurone disease and peripheral neuropathy [51]. The same text describes DNM2 as a cause of CMT with neutropenia and MFN2 as a protein of the membrane contact sites between organelles [51], and the chapter of the same book on phosphoinositides places FIG4 (CMT4J, also Yunis-Varón syndrome) and the phosphatases MTMR2/MTMR13 (CMT4B1/B2) in the phosphatidylinositol phosphorylation pathway [52].

The PNDS organises the pathophysiology into nine mechanisms [17]. The first is myelin development and maintenance, disturbed by variants in about twenty genes (PMP22, MPZ and GJB1 being the best known); when the variant damages myelin and axon simultaneously, the result is an intermediate form. Next come protein biosynthesis and degradation, with protein aggregation in CMT2 due to NEFH and Golgi apparatus disruption due to FAM134B (RETREG1); the neuromuscular junction, with favourable effects of pyridostigmine described in CMT2D and in hereditary motor neuropathy due to SLC5A7, which encodes the presynaptic choline transporter; axonal transport (DCTN1, DYNC1H1, NEFL, spastin), whose variants combine central and peripheral signs; endocytosis and autophagy, with RAB7A, a GTPase in which five variants described up to 2020 caused sensory CMT2B with ulcers, through disturbance of endosomal trafficking and MAP kinase signalling; membrane dynamics and other transport proteins (SPTLC1, SPTLC2, MTMR2, SBF1, SBF2); ion channels (SCN9A, SCN10A, SCN11A in sensory and autonomic neuropathies, TRPV4 in CMT2C, GJB1 in CMTX1); the mitochondrial network (MFN2, GDAP1, COX6A1 in AR axonal and intermediate forms, SLC25A46 with optic and cerebellar atrophy, HSPB1 with a defect of axonal mitochondrial transport reversible in the mouse model by HDAC6 inhibition, PDK3 in CMTX6, DHTKD1 in CMT2Q, HK1 in CMT4G, MT-ATP6 and SURF1 in CMT4K); and alterations of transcription and translation, which include five aminoacyl-tRNA synthetases (GARS1, AARS1, HARS1, YARS1, MARS1), the methyltransferase DNMT1 and the transcription factor EGR2, whose variants alter the expression of myelin genes to a variable degree depending on the allele [17]. For most of these genes, how the abnormal protein produces a length-dependent neuropathy remains unclear [17].

2.2 PMP22 and 17p12: duplication (CMT1A), deletion (HNPP) and point variants

PMP22 encodes a 22 kDa integral membrane glycoprotein forming peripheral compact myelin and regulating Schwann-cell growth, with bidirectional dosage sensitivity [2, 29]. An approximately 1.4–1.5 Mb duplication containing PMP22 causes overexpression, uniform demyelination with repeated demyelination/remyelination and “onion bulbs”, and secondary axonal loss determining weakness [1, 29]. Reciprocal deletion reduces mRNA and protein, disrupts myelin junctions and causes focal instability with tomacula (sausage-like segmental sheath thickenings) and compression vulnerability; haploinsufficiency is supported by PMP22 frameshifts in HNPP families [2]. Point variants produce misfolded protein with effects beyond dosage, spanning CMT1E (often sensorineural deafness), infantile Dejerine-Sottas, Roussy-Lévy and approximately 20% of HNPP [2, 29]. Four PMP22 copies (homozygous duplication) produce the most severe phenotype; homozygous deletion was reported in a child with sensory neuropathy and facial paresis [29].

Non-allelic homologous recombination (NAHR) occurs between two flanking low-copy repeats (CMT1A-REP, >17 kb originally and approximately 24 kb in full sequence) around the 1.5 Mb interval [9]. The hotspot lies near a mariner-like transposon [53], with duplication and deletion reciprocal products of unequal crossing-over [1, 2]. Palau and colleagues' de novo duplications were all paternal, arising from unequal non-sister chromatid exchange during spermatogenesis [54]. Oxford Desk Reference presents CMT1A as a microduplication syndrome delineated before microarrays, noting that microduplications tend to be milder than reciprocal deletions because segmental trisomy is generally better tolerated than monosomy [10].

2.3 17p12 microduplication as a genomic alteration

Diagnostic 17p12 microduplication corresponds to recurrent CMT1A duplication; classic “17p11.2–p12” reflects early physical mapping to the band boundary [1, 38]. Adjacent proximal 17p11.2 contains RAI1, deleted in Smith-Magenis and duplicated in Potocki-Lupski syndrome; the Brazilian genetic syndromes text notes that changes in this approximately 40-gene region produce distinct phenotypes including these, with potential cardiac and pulmonary involvement [3, 55]. Yuan and colleagues characterised 23 individuals with contiguous non-recurrent duplications encompassing both PMP22 and RAI1 (“PMP22-RAI1 contiguous gene duplication syndrome”), whose junction microhomology and insertions suggested replication-based mechanisms, with combined Potocki-Lupski/CMT1A features and possibly earlier neuropathy [56]. A developmental-delay microarray may therefore identify a PMP22-containing duplication, requiring anticipation of demyelinating neuropathy and avoidance of neurotoxic drugs [56, 57]. Isolated 17p12 duplication also occurs incidentally on microarrays; Oxford Desk Reference stresses that recurrent copy-number variants (CNVs) may derive from a mildly affected unrecognised parent, making parental clinical and neurophysiological assessment part of interpretation [1, 10].

2.4 MPZ (CMT1B and axonal/intermediate forms)

MPZ encodes myelin protein zero (P0), the principal peripheral myelin protein, an immunoglobulin-superfamily adhesion molecule maintaining adjacent lamellar compaction [29]. Variants span demyelinating CMT1B, axonal CMT2I/CMT2J, intermediate DI-CMTD, congenital hypomyelinating neuropathy and Dejerine-Sottas; original Roussy-Lévy was attributed to MPZ c.393C>A [4, 29]. CMT1B velocity is bimodal (means 16.5 and 44.3 m/s), suggesting early demyelinating gain of function and late axonal loss of function; near-normal velocities more often accompany deafness and pupillary abnormalities (tonic pupil), as with p.Thr124Met [29]. Older MPZ numbering excluded the 29-amino-acid signal peptide: p.Thr124Met corresponds to historical “Thr95Met”, and Roussy-Lévy c.393C>A (p.Asn131Lys) to “Asn102Lys”. Both are ClinVar pathogenic on NM_000530.8 (VCV000014181, VCV000014186); reports should use normalised numbering and retain historical names only to facilitate literature searches [58]. De novo frequency was 25% for MPZ versus 1.3% for PMP22 duplication in a German series of 1206 index cases [59].

2.5 GJB1 (CMTX1)

GJB1 (Xq13.1) encodes connexin 32, forming “reflexive” gap junctions between a Schwann cell's non-compact lamellae at paranodes and Schmidt-Lanterman incisures, permitting radial diffusion of ions and small molecules [12, 51]. Loss produces mixed demyelinating/axonal neuropathy (axonal loss with regeneration, scattered onion bulbs and an enlarged adaxonal cytoplasmic collar on electron microscopy), differing from widespread CMT1A onion bulbs [12]. Connexin 32 also occurs in central myelin (oligodendrocytes), explaining fixed CNS findings and transient white-matter dysfunction [12, 51]; Saudubray lists connexin 32 mutations among white-matter disorders and glial-trafficking neuropathies [51], while Oxford Desk Reference includes them among leukoencephalopathies with peripheral involvement [55]. Sequencing identifies >99% of pathogenic variants, including non-coding promoter and 5'/3' untranslated variants potentially missed by coding-only panels [12]. c.-17G>A produces the severest phenotype among five common variants, while intracellular-domain missense variants are milder [60]; this 5' untranslated variant is ClinVar NM_000166.6:c.-17G>A, pathogenic/likely pathogenic (VCV000246014), illustrating coding-only-panel limitations [12, 58].

2.6 MFN2 and other axonal forms (CMT2)

MFN2 (1p36.22) encodes mitofusin 2, an outer mitochondrial membrane GTPase required for fusion, mitochondria–endoplasmic reticulum coupling and parkin recruitment in mitophagy; dysfunction fragments mitochondrial networks and impairs energy delivery along long axons, causing length-dependent axonal degeneration with preserved myelin [13, 51]. MFN2-HMSN is approximately 90% AD and 10% AR, with semidominant inheritance in two families; median onset is 12 years AD and 8 years AR, and optic atrophy approximately 7% and 20%, respectively [13]. Oxford Desk Reference's CMT2 table also includes KIF1B, RAB7 (CMT2B), GARS (CMT2D) and neurofilament light chain NEFL (CMT2E) [1]. Saudubray groups RAB7A (late endosome–lysosome), DNM2 (CMT with neutropenia), KIF5A (SPG10, CMT2, amyotrophic lateral sclerosis) and DCTN1 (distal hereditary motor neuropathy) among axonal/endosomal trafficking defects [51]. Recessive CMT-SORD results from biallelic sorbitol dehydrogenase loss, accumulating neurotoxic sorbitol through the polyol pathway; c.757delG (p.Ala253GlnfsTer27) is commonest, and fasting serum sorbitol is a reliable biomarker also useful for rare-variant classification [30, 49]. Normalised notation is NM_003104.6:c.757del (ClinVar VCV000929258, pathogenic/likely pathogenic); the original author manuscript used c.753delG because the deletion occurs in a G homopolymer and HGVS assigns the most 3' position, so both names describe the same allele [49, 58]. Highly homologous pseudogene SORD2P carries this deletion in >95% of control chromosomes; the authors acknowledged difficult SORD variant calling and required gene-specific PCR confirmation [49]. Saudubray includes SORD deficiency among inborn metabolic disorders presenting solely as peripheral neuropathy [61].

Other genes of intermediary metabolism and of the nuclear lamina explain rare axonal forms. Activating variants in the gene for pyruvate dehydrogenase kinase isoenzyme 3 (PDK3, on the X chromosome) cause dominant X-linked CMT type 6 (CMTX6); the available data attribute the neuropathy to reduced pyruvate flux caused by hyperphosphorylation of the pyruvate dehydrogenase complex by the mutant protein p.Arg158His [62]. In DHTKD1 (10p14), which encodes the E1 subunit of the 2-oxoadipate dehydrogenase complex, biallelic loss of function produces 2-aminoadipic and 2-oxoadipic aciduria, considered of little or no clinical significance (more than half of the more than 20 known individuals are asymptomatic); by contrast, a heterozygous nonsense variant, designated p.Tyr485Xaa in the source, was associated with CMT type 2Q in a large Chinese pedigree [63]. Neither the recessive metabolic form nor CMT2Q is accompanied by metabolic decompensation, so specific measures during intercurrent illness do not appear necessary; pharmacological doses of thiamine and pyridoxine and a low-lysine diet did not alter the pathological metabolites or show clinical benefit [63]. In an autosomal recessive subtype of CMT2, variants have been identified in the lamin A/C gene (LMNA), allelic with AD Emery-Dreifuss muscular dystrophy, limb-girdle dystrophy LGMD1B, dilated cardiomyopathy with conduction defects, familial partial lipodystrophy, mandibuloacral dysplasia, atypical Werner syndrome and Hutchinson-Gilford progeria [64, 65].

2.7 Autosomal recessive (CMT4) and other demyelinating forms

CMT4 comprises AR demyelinating neuropathies, generally beginning in early childhood and more severe than the dominant forms [1, 4]. SH3TC2 (CMT4C) encodes a protein with SH3 and TPR domains involved in Schwann-cell endosomal recycling [14, 47]. MTMR2 (CMT4B1) and SBF2/MTMR13 (CMT4B2) encode phosphatases (and their regulatory subunit) of phosphatidylinositol 3-phosphate and 3,5-bisphosphate; loss of function causes focal folds and outgrowths of myelin (myelin outfoldings), the histological signature of the CMT4B group [52, 66]. FIG4 (CMT4J) encodes a PI(3,5)P2 phosphatase; in CMT4J one allele is typically hypomorphic, whereas complete biallelic loss causes Yunis-Varón syndrome [51, 52]. NDRG1 (CMT4D, HMSN-Lom) has a founder variant (NM_006096.4:c.442C>T p.(Arg148Ter)) in the Roma population [31, 48]. GDAP1, an outer mitochondrial membrane protein, causes demyelinating (CMT4A), axonal (CMT2H/K) and intermediate forms, AR or AD, often with vocal cord paresis [4]. EGR2, a master transcription factor of myelination, causes AD CMT1D, Dejerine-Sottas disease and congenital hypomyelinating neuropathy [29, 67]. PRX (CMT4F) encodes periaxin, required for the formation of Cajal bands, and causes severe demyelinating neuropathy with a marked sensory component [4].

2.8 Phenotypic variability and modifiers

CMT1 severity varies among carriers of the same alteration, within families and between twins, indicating non-genetic and modifier-gene contributions [3]. Oxford Desk Reference estimates approximately 10% are asymptomatic and detectable only by careful examination or conduction studies [1]. CMT1A velocities decrease during the first 2–6 years, then remain relatively stable in adulthood; weakness correlates with reduced compound muscle action potential (CMAP) amplitude, reflecting secondary axonal loss rather than demyelination severity [29].

2.9 NDRG1 and CMT4D (HMSN-Lom): gene, variant spectrum and mechanism

Hereditary motor and sensory neuropathy type Lom (HMSN-Lom, HMSNL), classified as CMT4D, was mapped in 1996 by linkage and linkage disequilibrium analysis in endogamous Roma groups from Bulgaria, to a narrow interval of chromosome 8q24; haplotypes conserved across groups of different identity and migratory history indicated a single mutation predating the divergence of those groups [68]. Fine mapping in families from several European countries narrowed the critical region to about 200 kb [69], and in 2000 sequencing of the genes in the interval identified the premature stop codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1) [48]. The historical localisation was 8q24.3; the current cytoband of the gene is 8q24.22 [33]. In standardised notation, the founder variant is NM_006096.4:c.442C>T p.(Arg148Ter) (NC_000008.11:g.133258374G>A, GRCh38), validated in VariantValidator on the MANE Select transcript; it appears in the literature as R148X or p.R148*, and in later reports with older nucleotide numbering (C564T; g.631C>T on NM_006096.3) designating the same protein substitution [48, 70, 71].

NDRG1 encodes a cytoplasmic protein of about 43 kDa, with a central α/β-hydrolase fold domain, an N-terminal region of 30 residues and a C-terminal region with three 10-residue repeats [32]. It is expressed ubiquitously but reaches particularly high levels in the Schwann cell, where it is located in the cytoplasm and not in the myelin sheath [48, 72]. Proposed functions include vesicular trafficking and endosomal recycling, lipid metabolism and the Schwann cell–axon signalling required for axonal survival [32, 48]. In the Ndrg1-null mouse, myelination of the sciatic nerve is normal in the first two weeks of life and progressive demyelination begins at around 5 weeks, with weakness mainly of the hind limbs, pointing to a role in the maintenance, rather than the initial formation, of the myelin sheath [72]. Conditional ablation in oligodendrocytes compromises the maintenance of mature oligodendrocytes and the regenerative potential of central myelin, an experimental finding compatible with the central signs described in some patients [32].

The variant spectrum is dominated by loss-of-function alleles. The systematic review by Abati and colleagues (search to April 2025) gathered 22 pathogenic variants in 72 patients from 26 articles: p.(Arg148Ter) was found in 46 patients (64%), all of Roma ancestry; it was followed by c.538-1G>A (6 patients), c.327-2A>G (4) and the duplication of exons 6–8 (3), and the remainder were each described in a single patient [32]. The splicing variants NM_006096.4:c.538-1G>A and NM_006096.4:c.327-2A>G, validated in VariantValidator, lead mainly to skipping of exons 9 and 6, respectively, with minor use of cryptic acceptors that introduce a premature stop codon; complementary DNA analysis in blood and lymphoblastoid lines showed preferential exon skipping in 82% (c.327-2A>G) and 68% (c.538-1G>A) of transcripts [33]. c.538-1G>A was described in 2003 in a non-Roma Bulgarian patient, in the first NDRG1 screening of 104 patients with CMT of diverse ethnicities, and has conflicting classifications submitted without criteria in ClinVar (VCV000005121), although it meets the ACMG/AMP criteria PVS1, PS3 and PM2 in the Bulgarian functional study [33, 73]. Beyond these, frameshift variants have been described, such as NM_006096.4:c.739del p.(His247ThrfsTer74) in a non-Roma Italian woman [74] and NM_006096.4:c.508dup p.(Glu170GlyfsTer35) in compound heterozygosity with the founder variant [33], nonsense variants such as NM_006096.4:c.553C>T p.(Gln185Ter) and NM_006096.4:c.788C>A p.(Ser263Ter), splicing variants such as NM_006096.4:c.943+2T>C and NM_006096.4:c.537+2_537+10del, and two missense variants (p.Leu146Pro and p.Arg234Gln) [32] (all c. and p. designations confirmed in VariantValidator on NM_006096.4).

Two less common mechanisms have direct consequences for diagnosis and counselling. In a Turkish family, array comparative genomic hybridisation with exonic probes detected a homozygous intragenic duplication of about 6.25 kb, spanning exons 6–8 and reducing messenger RNA expression; this was the first example of a copy-number variant as a cause of recessive CMT [75]. In the Czech series of 12 patients, 11 were homozygous for p.(Arg148Ter) inherited from both parents, but in one patient the variant had been inherited only from the father and unmasked by uniparental isodisomy of the whole of chromosome 8 [76]. The 2026 review found no statistically significant association between variant type (truncating or non-truncating) and the presence of central or bulbar signs, but the number of patients limits any genotype–phenotype inference [32]. Natural animal models exist: in the stretcher mouse, deletion of exons 10–14 of Ndrg1 produces a more severe phenotype than targeted inactivation [77], and in Alaskan Malamute dogs a missense variant reduces the protein in nerve by more than 70% and causes a demyelinating neuropathy resembling human CMT4D [78].

3. Clinical Spectrum and Manifestations by Organ System

3.1 Common CMT phenotype

Classic onset is usually 5–15 years (5–25 in dominant demyelinating forms), with walking difficulty from impaired foot lifting (“foot drop”), progressive deformity, high arches and claw toes [1, 4]. Gradual distal-leg atrophy produces “inverted champagne-bottle” or “stork-leg” appearances, weak dorsiflexion/eversion and pes cavus; hand weakness follows and is rarely symptomatic before adulthood [1]. The Brazilian text describes distal-to-proximal progression, impaired finger adduction/abduction from intrinsic hand involvement, steppage gait, equinus contracture from weak dorsiflexors relative to triceps surae, and falls/ankle sprains [3]. Tactile, vibration and proprioceptive deficits are common on examination but rarely prompt presentation; hypoesthesia may cause pressure ulcers and proprioceptive loss sensory ataxia [3]. Some have postural tremor (historically Roussy-Lévy syndrome) [1]. Although traditionally described as painless, musculoskeletal and neuropathic pain are frequent [4].

The Brazilian text lists hammer toes, claw hands, equinovarus/cavovarus feet, tendon contractures, Charcot arthropathy, scoliosis, pain and balance impairment as principal abnormalities; occasional features include impotence, hip dysplasia, respiratory failure, sleep apnoea, deafness, vestibular disturbances, hand tremor, cramps, plantar calluses and acrocyanosis [3]. Sensorineural hearing loss occurs in several forms [4]; auditory processing disorders were described in >60% of children with CMT1/CMT2 [29]. Fatigue is highly prevalent [29]. Severity varies from asymptomatic adults to loss of independent walking; most have childhood limitations in sports and footwear and some middle-age mobility limitation, with <5% requiring wheelchairs [1, 4]. Life expectancy is preserved in dominant demyelinating forms [3, 4].

The PNDS adds frequency data to this picture [17]. First symptoms appear in the first decade in 60% of patients, but onset around the age of 60 occurs, and locomotor disorders have two peaks of onset, between 2 and 3 years and in adolescence. The history should look for sprains and fractures of the foot and ankle, difficulties in school sport, recurrent plantar lesions in sensory forms (ulcers, paronychia, calluses), use of insoles, scoliosis and previous foot surgery. Patients often underplay the steppage gait, and global atrophy of the legs gives the appearance of “stork legs”. In the Gudmundsson cohort, pes cavus, secondary to plantar flexion of the first metatarsal and attributed to selective denervation of the intrinsic muscles, was present in 70% and claw toes in 46%; pes planus is much rarer. Hip dysplasia occurs in 6–10% of patients, mainly in demyelinating forms, presents from the age of 8 with hip pain on walking (acetabular or femoral dysplasia, femoral anteversion, eccentric femoral head) and progresses without treatment to early coxarthrosis. Between 20% and 30% of patients with CMT1 report pain, mainly musculoskeletal and less often neuropathic; in a series of 211 patients, pain complaints were more frequent in CMTX than in CMT1 and in CMT1 than in CMT2, and about 30% of patients with CMT2 report pain, mainly in the feet. Hypoaesthesia with proprioceptive impairment is common on examination, but paraesthesiae are rarely reported; vasomotor acrosyndrome may occur, and bladder and sphincter involvement, possible in all types, never dominates the picture. Clinical examination does not distinguish a demyelinating from an axonal form, although palpable hypertrophy of nerve trunks points to some demyelinating forms [17].

Among associated signs, the PNDS highlights sleep disorders [17]. The prevalence of obstructive sleep apnoea-hypopnoea syndrome is increased in CMT1A, possibly due to laryngeal neuropathy, and warrants polygraphy or polysomnography in the presence of excessive daytime sleepiness, intense daily snoring, nocturia, unrefreshing sleep or predominantly morning fatigue; central apnoeas have also been described. Restless legs syndrome affected 40.9% of patients with CMT1 versus 16.4% of controls in the study by Boentert and colleagues (2014), and 37% of a series of 27 patients with CMT2 (1998), particularly in MPZ-related CMT2J [17]. A meta-analysis cited in the PNDS documented, compared with the general population matched for age and sex, poorer quality of life, increased risk of depression (linked to disability but also independent of it) and shorter total sleep time, and the document recommends systematic assessment of mood during follow-up [17]. Restrictive respiratory failure due to diaphragmatic involvement is rare in classic forms such as CMT1A, but occurs in severe paediatric forms (EGR2, PMP22 point variants) and in forms with thoracic deformity, such as CMT2C [17]. Facial palsies and glossopharyngeal involvement have been described in CMT1A, and axonal neuropathies predominate among patients with vocal cord paresis (9 of 11 in one series) [17].

3.2 CMT1A (PMP22 duplication)

CMT1A accounts for 70–80% of CMT1 and up to approximately 50% of all CMT [4] (31% in a large UK series [79]); CMT1A, CMT1X, CMT2A, CMT1B and HNPP comprised 89.2% of genetic diagnoses in the Inherited Neuropathy Consortium (1652 patients, 13 centres) [8, 29]. Symptoms usually begin in the first or second decade, but prolonged distal latencies may occur in early infancy and slow velocities were documented at 2 years; the full phenotype may emerge only in the second decade or later [29]. Among 57 patients, three had floppy-infant syndrome, two marked proximal/distal weakness, one severe scoliosis, five calf enlargement and three hand deformities [29]. Palpable great auricular or ulnar nerves at the elbow are frequent, with biopsy showing hypertrophy and onion bulbs [1, 3, 29]. Median nerve velocities are typically 10–30 m/s (range 5–38), with published means 16.5–21 m/s and uniform slowing across nerves [3, 29]. Progression is slow, with long stable periods [29]. Surgery, chemotherapy, trauma and pregnancy may accelerate disease or trigger symptoms in asymptomatic carriers [3].

The PNDS brings together data from classic CMT1A cohorts [17]. In the series by Birouk and colleagues, symptoms began in the first 10 years in 50% of patients and before 20 years in 70%, and 25% were asymptomatic, identified in the course of family genetic counselling; examination showed lower-limb areflexia in 100%, heel-walking difficulty in 66%, foot muscle atrophy in 50%, nerve hypertrophy in 50% and pes cavus in 33%, with cramps from childhood that increased with age and without paraesthesiae or dysautonomia. Severity correlated with early onset and with axonal loss in the median nerve, not with conduction velocity. In a cohort of 72 patients followed by Shy and colleagues, the CMTNS increased on average by 0.68 points per year (95% CI 0.46 to 0.91) and the NIS (Neuropathy Impairment Score) by 1.38 points per year (95% CI 0.61 to 2.12) [17]. The rare patients homozygous for the duplication have a more severe phenotype than heterozygotes [17]. The proportion of de novo duplications was 11% in a cohort of 118 patients with verified paternity, a figure discussed in section 8.1 [17].

3.3 CMT1B (MPZ)

CMT1B accounts for 6–10% of CMT1 [29]. One group begins in the first decade, sometimes with motor delay, very slow velocities and severe disease extending to congenital hypomyelinating neuropathy and Dejerine-Sottas; the other begins in adulthood, with near-normal velocities, lower motor amplitudes and more deafness/pupillary abnormalities [29]. Onset tends to be concordant within families [29]. Late axonal CMT2I/CMT2J shares a length-dependent phenotype with neuropathic pain in some families [4].

In a cohort of 103 patients with CMT1B cited in the PNDS, 61 used orthoses, 19 needed walking aids and 10 a wheelchair; 33 had no family history, 21 had deafness and 17 scoliosis, and the earlier the onset, the more severe the disease [17]. In 10 carriers of the variant NM_000530.8:c.116A>C p.(His39Pro), classified in ClinVar as pathogenic/likely pathogenic (VCV000217232), onset was in adulthood and progression slow, except for one subacute case with painful sensory neuropathy; 70% had deafness and 80% restless legs syndrome [17]. Acute or subacute onset with neuropathic pain and Adie pupil due to dysautonomia is characteristic of some MPZ variants, tonic pupil occurs in 35–70% of patients with CMT2J, and the variant NM_000530.8:c.371C>T p.(Thr124Met) is associated with marked dysautonomia and respiratory disturbances [17]. More than 80 MPZ variants have been described, with a spectrum ranging from Dejerine-Sottas disease and congenital hypomyelination to the intermediate form and the rapidly progressive late-onset axonal form [17]. Histologically, CMT1B is distinguished by decompaction of the myelin sheath and by focal folds of the myelin lamellae, different from tomacula, which may coexist in the same nerve [17].

The PNDS also describes the remaining dominant demyelinating forms [17]. CMT1C (LITAF/SIMPLE) accounts for about 1.6% of dominant CMT1 in France; it begins in the second decade, with reduced but present reflexes, motor deficit less frequent than in CMT1A (44%), moderate neuropathy on the CMTNS and median and ulnar nerve velocities higher than in CMT1A. CMT1D (EGR2) accounts for about 1% of CMT1; half of the 17 families initially described had a de novo variant, most patients have a severe phenotype (from infantile neuropathy without measurable velocities to classic CMT1), and the combination of severe distal motor deficit, ptosis and areflexia is suggestive; AR inheritance of the same gene gives rise to CMT4E. In CMT1E (PMP22 point variants), the spectrum ranges from the severe congenital form to moderate forms, with cases of axonal pattern described with the variant NM_000304.4:c.475C>T p.(Arg159Cys) (historical designation R159C), classified in ClinVar as of uncertain significance (VCV000637831). NEFL mainly causes CMT2E, but also demyelinating or intermediate forms (CMT1F) and muscle involvement. FBLN5 can cause AD demyelinating CMT, and GJB3, which encodes connexin 31 and causes erythrokeratodermia variabilis et progressiva and deafness, has been associated with demyelinating CMT with deafness and skin ulceration [17].

3.4 CMT2 (MFN2 and other axonal forms)

Axonal forms account for about one third of CMT cases [3] and, in the Norwegian population study, 49.4% of families [6]. Clinically they resemble CMT1 but are generally less disabling, with less sensory loss; velocities are normal or mildly reduced (38–48 m/s) with reduced amplitudes [1, 4]. MFN2-HMSN (CMT2A) is characterised by earlier and more severe lower-limb involvement, motor predominance, pes cavus, gait instability and frequent postural tremor [13]; in an international prospective study of 196 patients, childhood onset of the AD form was the principal predictor of severity, independently of disease duration, with greater use of orthoses and full-time wheelchairs [80], and MFN2 explains a much greater fraction of CMT2 cases with severe disability than of mild cases [13]. MFN2-associated phenotypes include HMSN VI (neuropathy with optic atrophy), HMSN V (with pyramidal signs) and, in biallelic cases, multiple symmetric lipomatosis with partial lipodystrophy [13]. Other axonal forms have distinctive hallmarks: RAB7A (CMT2B) with marked sensory loss, plantar ulcers and amputations (ulceromutilating neuropathy) [4]; GARS1 and other aminoacyl-tRNA synthetases (CMT2D) with hand predominance [4]; NEFL (CMT2E/1F), capable of producing axonal or demyelinating patterns [29]; HSPB1 and HSPB8, at the border with distal hereditary motor neuropathies [1]; TRPV4 (CMT2C) with vocal cord paresis and association with skeletal dysplasias [4]; and GDAP1 (CMT2K/CMT4A) with vocal cord paresis [4]. CMT-SORD, the most frequent recessive form, usually begins in the second decade, is axonal and motor-predominant (two thirds with a CMT2 phenotype and one third with distal hereditary motor neuropathy), affects dorsiflexion and plantar flexion similarly, and shows intermediate velocities in about one quarter of cases; about one quarter of patients use orthoses, usually from the fourth decade, but most remain independently ambulant [30]. In LMNA-related recessive CMT2, the 2020 cardiogenetics chapter allows that cardiac involvement similar to that of other laminopathies might be anticipated, but records that it has not yet been described [64]; the Oxford Desk Reference, which recommends cardiac surveillance in all patients with laminopathy-related muscle disease, excludes the partial lipodystrophy and CMT phenotypes from the strong evidence of age-related progressive heart disease [65]. In PRPS1 (Xq22–24), which encodes phosphoribosylpyrophosphate synthetase isoform 1, moderate loss of function causes the triad of peripheral neuropathy, hypotonia and deafness formerly called X-linked recessive CMT or Rosenberg-Chutorian syndrome (CMTX5); severe loss of function causes Arts syndrome (intellectual disability, hypotonia, ataxia, optic atrophy and peripheral neuropathy, X-linked), and missense variants with mild deficiency cause X-linked non-syndromic deafness, whereas enzyme superactivity manifests as hyperuricaemia, gout and, in some families, sensorineural deafness [81].

The PNDS estimates CMT2 at about 30% of CMT and records that the disease does not reduce life expectancy, with long periods without evident deterioration [17]. Most forms are AD; the forms due to DNAJB2, IGHMBP2, LMNA, MME and TRIM2 are recessive, and MFN2, GDAP1 and LRSAM1 give rise to dominant and recessive forms, the recessive ones generally more severe [17]. Although the typical picture is one of areflexia, there are CMT2 forms with brisk reflexes, Babinski sign and asymmetrical atrophy; sensory predominance is characteristic of RAB7A, LRSAM1 and, more rarely, SPTLC1, and optic atrophy occurs mainly with MFN2 and SLC25A46 [17]. Onset in or predominance of the upper limbs points to genes of the distal motor neuropathies (BSCL2, GARS1, REEP1, HSPB8), and a pyramidal syndrome with preserved reflexes to overlap forms with the spastic paraplegias (KIF5A), to genes of the distal motor neuropathies (GARS1, BSCL2, SETX) or to mitochondrial genes (MFN2, GDAP1) [17]. In HINT1-related AR-CMT2, motor-predominant axonal neuropathy is associated with clinical neuromyotonia (action myotonia in the hands) and electrical neuromyotonia (neuromyotonic discharges and myokymia); symptoms usually begin at the end of the first decade, with weakness of the foot and toe dorsiflexors, but may appear up to the age of 28, and CK is raised [17]. With MFN2 variants, onset ranges from 6 months to 50 years, and the spectrum includes early stroke with neuropathy, cognitive impairment, pyramidal syndrome, optic atrophy (with cases of acute optic neuropathy) and, in one homozygous family, lipodystrophy [17].

Annex 5 of the PNDS groups the features that guide molecular testing in CMT2, summarised in the following table with designations and modes of inheritance aligned with OMIM; the annex inverts the designations CMT2A2A and CMT2A2B, but in OMIM CMT2A2A is AD and CMT2A2B is AR.

The PNDS reference to exceptional cardiomyopathy or arrhythmia in LMNA-related CMT contrasts with the 2020 cardiogenetics chapter, which records that cardiac involvement has not yet been described in LMNA-related recessive CMT2, and with the Oxford Desk Reference, which excludes the CMT phenotype from the strong evidence of progressive heart disease; none of these sources formulates a specific cardiac surveillance recommendation for this form [17, 64, 65].

3.5 CMTX1 (GJB1)

CMTX1 is the second commonest CMT form and commonest X-linked form, accounting for at least 10–20% [12, 60]. Men typically present at 5–25 years with bilateral foot drop, symmetrical below-knee atrophy, pes cavus, intrinsic hand atrophy with thenar predominance, and four-limb areflexia; proximal muscles remain strong and the dominant hand may be worse [12]. Oxford Desk Reference suggests disproportionate thumb-abduction weakness relative to the first dorsal interosseous as a clue [1]. Forearm velocities are intermediate (30–40 m/s men, 30–60 women), with median more affected than ulnar nerves and inter-nerve heterogeneity [12]. Heterozygous women are not silent carriers: most have mild/moderate progressive signs, some only electrophysiological changes and few no manifestations; among 31 women, two thirds had mild and one third moderate CMT Neuropathy Score (CMTNS), with leucocyte X-inactivation no different from controls [82]. In 387 patients from 295 families internationally, men were initially more severely affected, but both sexes progressed similarly over up to 8 years [60].

CNS involvement is often overlooked: acute, self-limited, sometimes recurrent reversible stroke-like episodes produce pyramidal weakness, dysarthria, ataxia, dysphagia or altered consciousness lasting hours to weeks [12]. Most follow hyperventilation/exertion, readaptation after returning from altitude, fever, head trauma or minor infections; MRI shows diffusion and T2 changes in subcortical white matter and splenium, resolving within weeks on diffusion or potentially persisting on T2 [12]. Rarely, episodes precede neuropathy and mimic stroke or demyelinating disease [12]. Subclinical visual, brainstem auditory or somatosensory evoked-potential abnormalities are common, and fixed dysarthria, spasticity, hyperreflexia or Babinski signs may occur [12].

The PNDS places CMTX1 at about 10% of CMT and 90% of X-linked CMT, and describes the lesions of the central episodes as symmetrical, posterior and involving the corpus callosum, with signs that as a rule disappear within 48 hours, always reversible leucoencephalopathy, no correlation with particular GJB1 variants, and altitude or intercurrent infection as identified triggers [17]. In a Chinese cohort of 22 patients with GJB1 variants, these explained 23.9% of CMT, the mean age at onset was 15.6 ± 8.7 years and 4 patients (18%) had sudden fever-induced cerebral symptoms (aphasia, dysphagia, focal palsies or tetraplegia), reversible without treatment within hours to days, which were the first manifestation in two of them [17]. In men, conduction studies show a demyelinating or intermediate pattern (intermediate in 40–90% of cases, depending on the series), sometimes with temporal dispersion and blocks that wrongly suggest an inflammatory neuropathy; in women, the pattern is axonal or near-normal [17]. The French series of Dubourg and colleagues (2001; 93 patients from 37 families) quantified the difference between the sexes:

(Source of the table: [17], which reproduces the series of Dubourg and colleagues.)

3.6 CMT4 (recessive forms)

CMT4 usually begins in childhood, with greater severity, frequent scoliosis and cranial nerve involvement and, in some subtypes, laryngeal/phrenic involvement [1, 4]. SH3TC2-HMSN (CMT4C) usually presents with early severe scoliosis/kyphoscoliosis and cavus, flat or valgus foot deformity in the first decade or early adolescence; tongue involvement, facial paresis, hearing loss, dysarthria and respiratory problems (approximately 18%) may occur, with median velocities 4–37 m/s (mean 22), unrelated to disease duration [14]. CMT4B1 (MTMR2) is more severe than CMT4B2 (SBF2), with earlier onset and more motor delay, wheelchair use and respiratory involvement; vocal cords are often involved in both, but glaucoma occurs only in CMT4B2 [66]. CMT4D (HMSN-Lom, NDRG1) features sensorineural deafness with early auditory evoked abnormalities [48]. CMT4J (FIG4) may cause proximal/distal weakness and sometimes rapidly progressive asymmetrical weakness, conduction blocks and temporal dispersion resembling chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [83]. Rare complex forms with deafness, retinitis pigmentosa or vocal cord paralysis require alternative diagnoses in sporadic cases [1].

The PNDS stresses that CMT4 forms are rare, described in isolated families, in regions of high consanguinity or in particular populations (Roma), with much earlier onset than in the dominant forms, sometimes from birth with motor delay [17]. By subtype, it adds [17]: in CMT4A (GDAP1, 8q21), motor delay in the second year of life, severe motor-predominant neuropathy with proximal involvement by the end of the first decade and wheelchair use usually in the second decade, with respiratory failure and scoliosis; in AR axonal forms due to GDAP1, vocal cord and diaphragmatic paralysis and wheelchair dependence before the age of 20, or rapidly progressive motor neuropathy with paradoxically brisk reflexes (except the ankle jerks); in CMT4B1 (MTMR2), equinovarus foot, scoliosis, possible diaphragmatic, facial and bulbar involvement, and wheelchair use from the third decade; in CMT4B3 (SBF1, 22q13), a picture similar to that of CMT4B1, with a more severe axonal form involving several cranial nerves and progressive microcephaly; in CMT4C (SH3TC2), about 16% of recessive forms in Caucasian patients, with a spectrum from delayed walking with respiratory and cranial involvement to mild forms with only scoliosis and foot deformity; in CMT4D (NDRG1), deafness in the second or third decade and tongue atrophy; in CMT4E (EGR2), from a slowly progressive picture to congenital hypomyelination with respiratory and cranial nerve dysfunction; in CMT4F (PRX, 19q13.2), walking after 18 months, severe distal amyotrophy, early scoliosis, disabling neuropathic pain, ocular abnormalities, deafness and respiratory failure; in CMT4G (HK1, 10q22, formerly HMSN-Russe), distal deficit in childhood with severe sensory loss; in CMT4H (FGD4, 12p11.21), early onset with delayed walking and marked scoliosis, and less severe forms; in CMT4J (FIG4, 6q21), onset between early childhood and the sixth decade, with proximal and distal involvement, sometimes asymmetrical; in CMT4K (SURF1), severe childhood demyelinating neuropathy with scoliosis, deafness, nystagmus and cerebellar ataxia, raised serum lactate, mitochondrial abnormalities on muscle biopsy and putaminal hyperintensity on magnetic resonance imaging; and, in AR intermediate and axonal forms, COX6A1 [17]. The cytobands of PRX and FGD4 follow OMIM (the PNDS gives 10q22 and 12q12, respectively).

3.7 Early-onset forms: Dejerine-Sottas and congenital hypomyelinating neuropathy

Dejerine-Sottas describes severe childhood demyelinating neuropathy with very slow velocities, elevated CSF protein, marked weakness and hypertrophic onion-bulb nerves, without specifying inheritance or gene [4]. It may arise from AD de novo MPZ/PMP22/EGR2 variants or AR forms; most have been reclassified genetically as HMSN1 [1]. Congenital hypomyelinating neuropathy (EGR2, MPZ) presents from birth with hypotonia, areflexia and velocities as low as 3 m/s [29, 67].

The PNDS treats the Dejerine-Sottas forms as a continuum between CMT1 and the congenital hypomyelinating neuropathies, which are distinguished by a primary defect of myelin formation, without signs of demyelination [17]. Severe early forms may be life-threatening through respiratory failure, may be associated with sensory deficits and may result from AD or AR inheritance or from a de novo variant, mainly in PMP22, MPZ, EGR2 and FIG4; in the presence of early foot deformities, recessive variants of FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 are the most frequent [17]. In paediatric forms with onset in the first decade, the warning signs are difficulty in achieving standing or delayed walking with very marked joint hyperlaxity, a foot deformity that is not always typical, and areflexia; foot drop may precede the classic deformity, and hip dysplasia with an unusual course or late appearance should raise the possibility of CMT [17]. The child's history should look for dysaesthesiae, neuropathic pain and fatigability when writing, which are rarely reported spontaneously, and for language or learning difficulties suggesting auditory neuropathy [17]. In retrospective studies of children over 3 years assessed with the CMTPedS scale, progression only becomes measurable after 2 years of follow-up, and the most sensitive items are foot dorsiflexion angle, balance and standing long jump; the phenotype and the course depend on variant type and age [17].

3.8 HNPP (PMP22 deletion)

HNPP is characterised by recurrent acute sensory and motor neuropathies in one or several nerves; the most common initial manifestation is an acute painless focal mononeuropathy at a compression site [2]. The first episode usually occurs in the second or third decade (range 2 to 70 years; mean 37 years), with increasing reports of paediatric onset since molecular testing became widespread [2]. The most commonly affected sites, in descending order, are the peroneal nerve at the fibular head (foot drop), the ulnar nerve at the elbow, the median nerve at the wrist (carpal tunnel syndrome) and the brachial plexus and radial nerve; less often, the motor brachial plexus, the hypoglossal nerve (including after carotid endarterectomy), the sciatic nerve, and the laryngeal, phrenic and facial nerves [2]. Complete recovery occurs in about 50% of episodes, over days to months; incomplete recovery is associated with prolonged compression and usually leaves mild disability [2]. The PNDS describes episodes of sudden onset with painless paraesthesiae and adds that the palsy leaves severe long-term motor deficit in 9% of cases [17]. Mild to moderate pes cavus occurs in 4–40% of cases, and some patients develop a mild to moderate CMT-like polyneuropathy [2]. Pain, formerly considered rare (“painless palsy”), is now recognised as frequent: in one study, 74% reported pain persisting for more than a week, three quarters of them with neuropathic pain and almost 90% with probable central sensitisation [2, 84]; a 2026 systematic review supports this reassessment [85]. Penetrance is complete, but expressivity is highly variable, and men have more palsies and electrophysiological abnormalities than women [2]. Asymptomatic cerebral white-matter lesions, CIDP-like presentations and, in individuals with PMP22 point variants (for example, NM_000304.4:c.281dup p.(Arg95GlnfsTer128)), phenotypes combining HNPP with CMT1-type polyneuropathy have been described [2].

3.9 Manifestations by system

3.10 CMT4D (HMSN-Lom): natural history and clinical spectrum

The original clinical description, in Bulgarian Roma, defined the typical sequence: gait disturbance in the first decade, upper-limb weakness in the second decade and, in most, deafness noticed mainly in the third decade, with sensory loss of all modalities and distal predominance, frequent skeletal deformities (mainly of the feet) and greatly reduced motor conduction velocities [86]. Nerve biopsy showed a hypertrophic neuropathy with onion bulbs in the three youngest patients, which was no longer evident in the oldest patient, presumably through regression secondary to axonal loss [86]. In an extended family with 27 affected individuals, onset was in early childhood, one third had bulbar involvement and deafness appeared in the second or third decade [87]. In a Serbian family of two siblings, lower-limb weakness began at 7 years, hearing problems at 12 and hand weakness at 15, with dysarthria and mild proximal atrophy [70].

The 2026 systematic review gives the broadest aggregate picture, with the limitations inherent in a compilation of heterogeneous reports (median of 1 patient per article; clinical data unavailable for 7 of the 72 patients) [32]. The median age at onset was about 7 years, and 67 of 70 patients (96%) began with lower-limb weakness and walking difficulty; at the first neurological assessment, all had walking difficulty, distal weakness and atrophy in all four limbs, generalised areflexia and skeletal deformities [32]. Seventy-five per cent of patients were of Roma ancestry; the remaining 18 came from Bulgaria (9), China (3), Turkey (3), Italy (2) and India (1) [32].

(Source of the table: [32]; BAEPs, brainstem auditory evoked potentials.)

The deafness of CMT4D is an auditory neuropathy. In a Slovenian Roma family, otoacoustic emissions and cochlear microphonics were preserved, indicating normal outer hair cell function, but the neural components of the brainstem auditory evoked potentials (BAEPs) were absent; speech comprehension was affected disproportionately to the pure-tone loss, and caloric testing elicited no vestibular response, without vestibular complaints [88]. BAEPs suggest demyelination of the eighth cranial nerve and abnormal conduction in the central auditory pathways of the brainstem [86] and are abnormal before hearing complaints and already in childhood [33, 89]. In the 2024 Bulgarian cohort, 4 of 7 patients with splicing variants had hearing complaints, with sensorineural loss predominantly at high frequencies; the two siblings without complaints, aged 30 and 31, had normal audiograms but prolonged BAEP latencies [33].

Cranial nerve and respiratory involvement can be severe. The two Italian siblings described in 2026 had dysphagia (severe in one of them, requiring percutaneous endoscopic gastrostomy), bilateral vocal cord paralysis in adduction and a restrictive syndrome with chronic respiratory failure requiring non-invasive ventilation, as well as cognitive delay not formally assessed and visual evoked potentials with low-amplitude P100 [32]. The authors attribute adductor paralysis to preferential involvement of the longer recurrent laryngeal nerve, with relative sparing of the cricothyroid, innervated by the superior laryngeal nerve, and point out that vocal cord paralysis is also described in GDAP1- and MFN2-related neuropathy [32]. Central signs include subcortical white-matter lesions, first described in a French family without Roma ancestry carrying p.(Arg148Ter) [90], and mild atrophy of the cerebellum, medulla and upper cervical cord in a non-Roma Italian woman with the c.739del variant [74].

Neurophysiology distinguishes CMT4D from the dominant forms. It is a demyelinating neuropathy with severe, early axonal loss: slowing also affects proximal (musculocutaneous, axillary) and cranial (facial, hypoglossal) nerves, sensory potentials are absent, M waves are frequently multiple, the blink reflex has an unusual three-component response, and slowing worsens during childhood, in contrast to the static reduction of CMT1 [87]. In the 2026 review, among 68 patients with median or ulnar motor conduction data, 17 had no obtainable motor potential, and in the remainder the mean median nerve velocity was 13.2 m/s [32]. In the Bulgarian cohort, sensory potentials in all four limbs and motor potentials in the lower limbs were unobtainable in all patients, except in a child assessed at 2.5 years (peroneal at 12.8 m/s), and parameters worsened on serial reassessment [33]. Histology shows depletion of myelinated fibres, with the few preserved fibres of small calibre and poorly developed onion bulbs [33, 91].

4. Clinical Recognition and Red Flags

Oxford Desk Reference recommends at least a three-generation pedigree, extended for earlier affected generations, actively seeking high arches, abnormal gait and mobility limitation (sticks/wheelchairs); motor milestones, running/walking or school sport difficulties; impaired buttoning, clumsiness/falls; current disability; and vision/hearing assessment [1]. Examination should observe foot slap or steppage gait, test heel walking (usually difficult) and finger abduction, seek calf atrophy, high arches, claw toes and thickened nerves, particularly the great auricular nerve behind the earlobe (frequent in CMT1A), and intrinsic hand atrophy; assess foot/hand vibration, noting sensory signs exceeding complaints as evidence of longstanding progression; and test reflexes, lost first at Achilles tendons but potentially retained despite substantial weakness [1]. Sporadic cases warrant pigmentary retinopathy assessment (Refsum), and learning difficulties suggest chromosomal microarray (e.g. Smith-Magenis) [1].

Blindness, seizures, dementia and intellectual disability are outside the CMT phenotype and suggest alternatives such as metachromatic leukodystrophy, Krabbe disease, Pelizaeus-Merzbacher disease or Lowe syndrome [4]. Negative family history does not exclude CMT because of subclinical relatives, recessive inheritance or de novo variants [4, 59].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Clinical criteria

The diagnosis of CMT in a symptomatic individual is based on the characteristic findings of peripheral neuropathy on history and physical examination, supplemented by neurophysiological study and confirmed by molecular testing [4]. For CMT1, the Brazilian textbook reproduces the GeneReviews criteria: progressive sensorimotor peripheral neuropathy; slow nerve conduction velocity (typically 10–30 m/s, range 5–38 m/s; normal above 40–45 m/s); palpable nerve thickening, especially of the ulnar nerve in the groove and of the great auricular nerve on the lateral aspect of the neck; and a family history compatible with AD inheritance [3, 29]. The Spanish guideline recommends that clinical assessment be followed by a neurophysiological study with defined parameters and that genetic diagnosis be approached sequentially; follow-up is exclusively clinical, without the need for routine additional investigations [16]. The French PNDS bases the diagnosis on the triad of progressive distal motor deficit (with steppage), skeletal deformities (pes cavus, claw toes, scoliosis) and generalised hyporeflexia or areflexia, which may be limited to the ankle jerks, common to all subtypes and to many acquired polyneuropathies; the pedigree is mandatory, electroneuromyography confirms and classifies the neuropathy, and subtype diagnosis depends on identification of the genetic alteration [17]. When the diagnosis is suspected, the attending physician should refer the patient to a neurologist, preferably at a reference or competence centre for rare neuromuscular diseases [17].

5.2 Neurophysiology and conduction-velocity classification

Median motor conduction velocity separates demyelinating and axonal forms and guides gene selection [1]. CMT1A slowing is uniform and diffuse, whereas acquired and some hereditary forms (CMT4C, CMT4J, EGR2, CMTX1) may be non-uniform or multifocal [12, 29, 67, 83]. HNPP typically shows prolonged distal latencies (median at wrist, peroneal at fibular head) in most symptomatic and asymptomatic carriers, aiding relative assessment; Dubourg criteria require bilateral prolonged median distal motor/sensory latencies with at least one additional peroneal motor abnormality (89% sensitivity). One third have absent/reduced sural potentials, and compression-site slowing with conduction block may occur [2, 93].

The PNDS assigns five functions to electroneuromyography: to confirm the neuropathy, to define it as axonal, demyelinating or intermediate, to distinguish within a demyelinating form the acquired (segmental and focal) from the hereditary (usually diffuse) pattern, to guide genetic testing and to help with prognosis, as shown by the longitudinal series of 69 patients with CMT1A followed for 15 years by Dyck and colleagues [17]. On needle electromyography in the Birouk series (CMT1A), fibrillation potentials at rest were present in 15% of patients, recruitment was reduced in the first dorsal interosseous in all and in the tibialis anterior in 92%, and 6% had no motor potential in the tibialis anterior; in chronic neuropathies, motor unit potentials frequently have amplitudes above 2 mV and durations above 15–20 ms [17]. Neuromyotonia or myokymic discharges (frequency 50–80 Hz) in a motor-predominant axonal neuropathy suggest HINT1: this gene explained 10% of 174 patients with AR axonal CMT, and biallelic HINT1 variants are present in 76–80% of AR axonal neuropathies with neuromyotonia (the PNDS gives both values in different passages) [17].

5.3 Genetic testing algorithm

GeneReviews defines three steps [4]. Step 1 recommends PMP22 duplication/deletion testing in every CMT proband, since duplication explains up to approximately 50% overall; because MLPA (multiplex ligation-dependent probe amplification), quantitative PCR or targeted microarray differs from many panels' sequencing, request it separately unless explicitly included [4]. Step 2 uses a panel with the eight commonest genes (GDAP1, GJB1, HINT1, MFN2, MPZ, PMP22, SH3TC2, SORD) and other table 4 genes, maximising yield while limiting uncertain variants in phenotype-irrelevant genes [4]. Step 3 considers exome/genome sequencing if previous steps are negative [4]. Oxford Desk Reference adds pedigree guidance: AD history suggests PMP22 duplication; absent father–son transmission suggests GJB1, recognising that later symptomatic women can make inheritance appear AD; heterogeneity warrants panel/exome/genome [1]. With typical disease and slowing, PMP22 duplication testing may reasonably precede complete conduction studies [1].

HNPP testing first targets PMP22 deletion (approximately 80%), then sequencing (approximately 20%) if negative, or a neuropathy panel including deletion/duplication analysis [2]. CMTX1 sequencing should cover promoter, untranslated regions, non-coding exons and splicing sites potentially missed by conventional panels [12]. Adapted American College of Medical Genetics criteria increased pathogenic/likely pathogenic GJB1 classifications in the international 387-patient study [60]. Fasting serum sorbitol supports rare CMT-SORD variant pathogenicity [30].

The PNDS describes the French pathway [17]. The law requires the prescriber to inform the patient about the nature of the test and to record in the file a consent signed by both, and the laboratory receives a certificate of consultation; the request must be accompanied by a clinical letter and pedigree, with a precise description of the phenotype (age at onset, topography, additional signs, electroneuromyography results), on dedicated forms for CMT and for distal motor forms. In the absence of these data, laboratories restrict themselves to the minimum analysis, testing for duplication/deletion of the PMP22 region; if this is negative, high-throughput panel sequencing is proposed, and exome or genome sequencing is discussed collegially between clinician and geneticist when the panel is negative [17]. The request forms offer targeted requests (CMT1A duplication, GJB1, MPZ, MFN2, familial variant) and four panels: CMT1 for demyelinating or intermediate forms, defined by an upper-limb motor velocity below 40 m/s (26 genes, including PMP22, MPZ, GJB1, EGR2, LITAF, NEFL, GDAP1, SH3TC2, MTMR2, SBF1, SBF2, NDRG1, PRX, FGD4, FIG4, HK1, INF2, DNM2, FBLN5, GNB4, KARS1, PLEKHG5, PMP2, SURF1, AARS1 and YARS1); CMT2 for axonal forms (37 genes); distal hereditary motor neuropathies (26 genes); and pure sensory neuropathies (17 genes) [17]. The same forms advise against first-line panels in patients without a family context and with onset of neuropathy after the age of 60 [17]. According to the document, exome or genome sequencing led to a molecular diagnosis in about 30% of panel-negative cases, with a yield that rose the more feasible segregation analysis was, and the overall diagnostic rate was about 60% in CMT and 20% in distal hereditary motor neuropathies [17]. For a novel variant, segregation analysis, coordinated by a geneticist in collaboration with the neurologist so that the clinical status of each person is well defined (with electroneuromyography in paucisymptomatic individuals), requires samples from at least three people [17]. The 40 m/s threshold separating the French panels is higher than the 35 m/s of GeneReviews and the historical 38 m/s; the difference mainly affects patients with velocities between 35 and 40 m/s, whom the PNDS directs to the demyelinating/intermediate panel and GeneReviews classifies as intermediate [4, 17]. The 2020 panels do not include SORD, whose association with neuropathy was published that year, and include HINT1 only in the distal motor panel, whereas GeneReviews places both among the eight core nuclear genes of any CMT panel; a negative French panel predating this update therefore excludes neither CMT-SORD nor HINT1-related neuropathy [4, 17, 49].

Clinical CMT suspicion (family history + examination) → exclude acquired causes → conduction studies
                │
                ▼
Step 1 (all probands): PMP22 duplication/deletion testing (MLPA or equivalent)
                │ negative
                ▼
Step 2: multigene panel (8 commonest genes + others), guided by conduction studies and inheritance
   ├── Demyelinating (<35–38 m/s): no ♂→♂ transmission → GJB1; panel with MPZ, PMP22 (sequence),
   │       EGR2, LITAF, SH3TC2, GDAP1, PRX, MTMR2, SBF2, NDRG1, FGD4, FIG4
   ├── Intermediate (35–45 m/s): GJB1 (including non-coding regions); MPZ, DNM2, INF2, GDAP1
   ├── Axonal (>45 m/s): MFN2, GDAP1, SORD (+ serum sorbitol), HINT1, MPZ, NEFL, HSPB1, GARS1, RAB7A...
   └── Recurrent focal palsies: PMP22 deletion → PMP22 sequencing (HNPP)
                │ negative
                ▼
Step 3: exome or genome (with CNV analysis); periodic variant reassessment; DNA banking

GeneReviews recommends PMP22 dup/del testing in every CMT proband regardless of neurophysiological phenotype [4]; the algorithm derives from [1, 2, 4, 12, 16].

Overall yield is approximately 60%: genetic diagnoses were obtained in 60.4% of 1652 Inherited Neuropathy Consortium patients [8] and 66% of 776 German CMT1 patients (51% CMT1A, 9% CMTX1, 5% CMT1B) [29]. Demyelinating yield exceeds axonal yield; only 27.2% of Norwegian population-study families had identified variants in genes then tested [6]. Consider proband DNA banking without molecular diagnosis [4]. Pandey and colleagues' case illustrates false-negative risk and the importance of repeated or expanded testing with strong suspicion [94].

5.4 Other investigations

Sporadic childhood-onset cases warrant parental conduction studies for asymptomatic carriers, Friedreich testing (frataxin GAA expansion), eye assessment for pigmentary retinopathy/optic atrophy, phytanic acid (Refsum), brain MRI with regression, seizures or other CNS abnormalities, and sural biopsy only after inconclusive DNA studies [1]. Biopsy shows CMT1 onion bulbs and Schwann-cell hyperplasia [3], HNPP tomacula (non-specific and occasionally seen elsewhere) [2], CMT4B outfoldings [66] and CMTX1 adaxonal collar changes [12]; CMT1 autopsies showed posterior spinal column degeneration [3]. HNPP ultrasound shows multifocal nerve cross-sectional enlargement within and outside compression sites, while MRI may show increased calibre and fascicular hyperintensity [2]. Diffusion MRI is key for CMTX1 central episodes [12]. Functional assessment uses validated CMTNS version 2 and CMTES scales [95].

The PNDS adds data on ancillary investigations [17]. CK was raised in 30% of a cohort of 205 patients, and elevation is typical of HINT1-related AR-CMT2 and of some NEFL variants (up to 1440 IU/L); lumbar puncture is not recommended, although the same cohort showed raised cerebrospinal fluid protein in 76%. Assessment of autonomic and small-fibre involvement includes orthostatic hypotension on examination, RR interval variability on deep breathing and on the Valsalva manoeuvre, and electrochemical skin conductance (Sudoscan). Magnetic resonance imaging of the sciatic and tibial nerves with diffusion tensor imaging distinguishes a demyelinating profile in CMT1A, and muscle magnetic resonance imaging quantifies neurogenic atrophy and detects progression over 12 months, but neither forms part of routine diagnosis or follow-up. Ultrasound, which shows very homogeneous nerve hypertrophy in CMT1A, helps to separate it from CIDP, and computed tomography has documented hypertrophy and, in one case of CMT1, calcification of the cervical roots. Nerve biopsy is now exceptional, reserved for difficult diagnoses (acquired cause, non-CMT familial neuropathy such as amyloidosis), with the indication discussed at a reference centre and processing in an appropriate facility [17]. In forms with diaphragmatic weakness, the PNDS proposes blood gas analysis and pulmonary function tests in the presence of dyspnoea or orthopnoea, and polysomnography if sleep apnoea is suspected; orthopaedic examination looks for foot deformities, hip dysplasia and scoliosis, with radiographs if there is a clinical abnormality [17]. Hearing assessment is recommended in all children, with pure-tone audiometry, auditory evoked potentials and a test of speech perception in conversation: in a study of 26 children (18 with CMT1 and 8 with CMT2) compared with 26 controls, all had abnormal auditory evoked potentials (delayed latency or low amplitude) and normal pure-tone thresholds, but 61% of school-age children with CMT1 and 87% of those with CMT2 had difficulty with speech perception, with repercussions on daily communication [17].

5.5 Genetic test limitations and report content

Each method covers only part of the spectrum, requiring explicit tested/untested scope. MLPA, quantitative PCR and targeted microarray detect recurrent 17p12 duplication/deletion but not PMP22 point variants causing approximately 20% of HNPP and CMT1E; sequencing panels detect CNVs only with validated calling, which must be stated [2, 4]. Non-recurrent 17p11.2–p12 rearrangements (e.g. PMP22-RAI1 duplications) have variable breakpoints requiring microarray/genome delimitation [56]. Many panels omit GJB1 promoter, untranslated and non-coding exon regions [12]; homologous pseudogenes, such as SORD/SORD2P, require specific alignment/amplification [49]; and parental blood cannot detect germline mosaicism documented in MPZ, limiting recurrence-risk exclusion [4]. Negative testing does not exclude convincing CMT/HNPP: case 10.1 initially tested negative for PMP22 changes before sequencing identified a point variant [94].

Reports should include gene, versioned transcript (preferably MANE Select: PMP22 NM_000304.4, MPZ NM_000530.8, GJB1 NM_000166.6, MFN2 NM_014874.4, SORD NM_003104.6, SH3TC2 NM_024577.4, GDAP1 NM_018972.4), DNA/protein HGVS, zygosity (heterozygous, homozygous, phased compound heterozygous, or male GJB1 hemizygous), ACMG/AMP classification and technical limitations [24, 96]. Recurrent CNVs require genomic coordinates, reference genome version and copy number. Historical MPZ numbering without signal peptide or SORD c.753delG should be normalised, optionally retained parenthetically [58].

A VUS does not become pathogenic through treatment response or occurrence in some affected relatives: partial cosegregation in a small family has limited statistical weight, and segregation studies are research rather than diagnostic confirmation [96]. International CMTX1 GJB1 reclassification used gene-adapted ACMG criteria and aggregated many-family evidence rather than isolated observations [60]. Elevated CMT-SORD serum sorbitol is supportive functional evidence requiring experienced laboratory interpretation [30]. Variable expression and X inactivation affect phenotype prediction in hemizygous GJB1 men and heterozygous women, without changing variant classification [12, 82].

5.6 Diagnosis of CMT4D

Suspicion rests on the combination of severe demyelinating neuropathy with onset in the first decade, inheritance compatible with AR (affected siblings, consanguinity or endogamy) and sensorineural deafness or abnormal BAEPs, especially in patients of Roma origin [86, 89]. BAEPs abnormal from childhood help to separate HMSN-Lom from HMSN-Russe (CMT4G, HK1), which is clinically similar in children, and conduction velocities are lower in HMSN-Lom; even so, the definitive diagnosis is genetic [89]. In a Roma patient, or in a family with AR inheritance and unknown ethnicity, the Serbian algorithm proposes targeted testing for c.442C>T immediately after exclusion of the PMP22 duplication [92], and the Slovak group recommends including NDRG1 and HK1 in the routine diagnostic work-up of Roma patients with demyelinating neuropathy [71]. Outside this context, CMT4D should be considered in any recessive demyelinating neuropathy, because it has been described in several non-Roma populations [33, 74].

The first-line test in a non-Roma patient is a multigene neuropathy panel including NDRG1, or exome sequencing, with CNV analysis [4]. This gene has three specific limitations. The intragenic duplication of exons 6–8 escapes conventional sequencing and requires copy-number methods with exonic resolution [75]. A homozygous result should be confirmed in both parents, because uniparental isodisomy of chromosome 8 mimics homozygosity and reduces the recurrence risk [76]. And canonical intronic splicing variants benefit from complementary DNA analysis when classification is conflicting, as happened with c.538-1G>A [33]. Staging investigations at diagnosis include pure-tone and speech audiometry, otoacoustic emissions and BAEPs, swallowing assessment and laryngoscopy, spirometry and, in the presence of visual complaints, visual evoked potentials and fundoscopy [32, 88].

5.7 Severity and functional impact scales

The reliability of scales in CMT was studied in 40 patients (2008) and, by an expert group, in 479 patients (2014); five CMTNS items and three clinical tests (10-metre timed walk, nine-hole peg test and ankle dorsiflexion dynamometry) were the eight items that best discriminated between severity grades [17]. The PNDS lists the available instruments, summarised in the table, and notes that some scales, such as the CMTNS and the ONLS, are not validated in all languages [17].

6. Differential Diagnosis

GeneReviews groups alternatives into systemic diseases with neuropathy, other hereditary neuropathies, distal myopathies, hereditary sensory/autonomic neuropathies and acquired neuropathies [4]. Acquired causes include alcoholism, vitamin B12 deficiency, thyroid disease, diabetes mellitus, HIV, vasculitis, leprosy, neurosyphilis, amyloidosis, occult malignancy, heavy metals and inflammatory/immune neuropathies, including CIDP [4]. Inborn metabolic neuropathies are usually syndromic, unlike classic CMT: lipid storage disorders affect central/peripheral myelin with slow velocities and leukoencephalopathy, energy-metabolism defects mainly cause normal-velocity axonal neuropathy, and SORD deficiency, late riboflavin defects or trifunctional protein defects may present with neuropathy alone [61]. Sphingosine-1-phosphate lyase deficiency differs from AR-CMT2 by acute/subacute onset and improving mononeuropathies, resembling acquired neuropathy, HNPP or hereditary neuralgic amyotrophy [61].

In recessive demyelinating neuropathies of childhood onset, particularly in patients of Roma origin, the practical differential lies between the founder forms of this population and some non-founder forms with deafness:

7. Treatment and Risk Management Strategies

7.1 General principles

As of October 2026, no FDA- or EMA-approved disease-modifying treatment exists for any CMT form or HNPP; treatment is symptomatic and preventive [4, 20, 21]. GeneReviews recommends neurologist, rehabilitation physician, orthopaedic surgeon, physiotherapist and occupational therapist involvement [4]; the Brazilian text adds clinical genetics and psychology, targeting symptoms, secondary complications and aggravating situations such as pregnancy [3]. The international paediatric guideline, developed through systematic review of 10 questions, modified Delphi and GRADE, includes 3 evidence-based and 31 consensus recommendations on weakness, balance/mobility, sensory symptoms, cramps, upper-limb and respiratory function, range of movement and non-surgical deformity management [15]. Spanish guidance favours early rehabilitation/orthopaedic management with individualised exercise, orthoses and conservative surgery assessment, including tendon transfers [16]. Persistent hand/foot weakness has occupational implications requiring early counselling [4].

ERN EURO-NMD links European hereditary neuropathy centres, supporting complex cases, trials and harmonised care [25]. Patient associations support families, professionals, registries and trials: Portugal's APN; the US Charcot-Marie-Tooth Association, maintaining the neurotoxic-drug list cited in 7.5; and Charcot-Marie-Tooth UK [26–28]. Brazilian/Australian professionals produced a practical paediatric rehabilitation summary in Portuguese, Spanish and English [15, 101].

In France, the 2020 PNDS (French National Diagnosis and Care Protocol), coordinated by the reference centre for rare neuromuscular diseases and amyotrophic lateral sclerosis in Marseille (La Timone Hospital), defines the care pathway [17]. In the absence of aetiological treatment, the aims are to prevent complications with motor and proprioceptive rehabilitation, foot-lifting orthoses, podiatry and occupational therapy; to maintain autonomy with human and technical aids and home adaptation; to offer psychological support to the patient and family; and to ensure regular follow-up, with regular practice of adapted moderate physical activity [17]. The neurologist establishes the diagnosis, discloses it and coordinates follow-up; the general practitioner follows the patient in the community, applies the recommendations and treats intercurrent illnesses; physical medicine and rehabilitation physicians, orthopaedic surgeons, podiatrists, orthotists, geneticists, physiotherapists, occupational therapists, psychologists and nurses complete the team, ideally coordinated by a reference centre [17]. The diagnosis is disclosed in a dedicated consultation, in a reference or competence centre, preferably in the presence of a trusted person, with explanation of the diagnosis and of the therapeutic goals, planning of follow-up, offer of psychological support and physiotherapy, information on genetic counselling and patient associations, and time for the patient's questions; the general practitioner promptly receives a report of the information given, and a post-disclosure consultation may be offered in the following month [17]. Therapeutic education covers the disease and warning signs, transmission and genetic counselling, treatments and their adverse effects, the importance of annual assessments, professional and family life and travel preparation, access to social rights, institutional resources (including Orphanet and associations), and the management of fatigue, stress, musculoskeletal self-care and technical aids [17].

The French organisation is linked to the European network [17]. The FILNEMUS health filière, one of the 23 rare disease filières created under the second national rare diseases plan (2011–2016), brings together diseases of muscle, of the neuromuscular junction and of peripheral nerve, and the spinal muscular atrophies, through reference centres (CRMR) and competence centres (CCMR) distributed across six networks (PACARARE, NNERF for familial amyloid neuropathies and other rare peripheral neuropathies, Atlantique-Occitanie-Caraïbe, Nord/Est/Ile-de-France, CALISSON and CARAMMEL), and seven molecular diagnostic laboratories (Angers, Lille, Limoges, Lyon, Marseille, Kremlin-Bicêtre and Pitié-Salpêtrière), whose gene lists are available on Orphanet [17]. CMT may be recognised as an “off-list” long-term condition (ALD), with 100% coverage of related care after a care protocol validated by the medical adviser [17]. The Maison départementale des personnes handicapées (MDPH) assesses applications for compensation, decided by the CDAPH committee: mobility inclusion card (with the “invalidity” mention from 80% permanent disability), recognition of disabled worker status (with a 6% quota in companies with more than 20 employees), vehicle adaptation, disability compensation benefit (human and technical aids and adaptation of the home or vehicle), disabled adult allowance and its supplements, disabled child education allowance and school adaptations, such as extra time in examinations; after 60 years, the personalised autonomy allowance covers dependency grades 1 to 4 of the AGGIR scale [17]. The CMT-France association, founded in 1990 and with about 2000 members, has a multidisciplinary medical board, regional delegates, a quarterly magazine, a medical alert card and an annual national congress (about 400 participants), and is a member of Eurordis and of the patient representative group (ePAG) for peripheral neuropathies of the ERN EURO-NMD; it works with AFM-Téléthon, Alliance-Neuro and Alliance Maladies Rares [17]. Specific spa treatment programmes exist for CMT, with a rehabilitation pool, adapted physical activity and lectures by neurologists [17]. The PNDS notes that occupational therapy assessments in private outpatient practice and upper limb technical aids are not reimbursed by health insurance, which limits their use [17].

7.2 Rehabilitation, orthoses and mobility

Recommended measures include ankle-supportive footwear, ankle–foot orthoses (AFOs) for foot drop, daily Achilles tendon stretching to prevent shortening, grip exercises for hand weakness and individually adapted activity; controlled trials found no ankle-range benefit from night splints [4]. Some need crutches/sticks and <5% wheelchairs [1, 4]. Oxford Desk Reference adds insensate-foot ulcer prevention, adolescent scoliosis surveillance, mobility aids/handrails and UK DVLA notification by affected drivers [1]. The Brazilian text encourages activity, fall prevention, aquatic exercise, gait training and weight control [3]; avoid obesity because it impairs walking [4]. Dufek and colleagues evaluated customised composite orthoses in CMT [3].

The PNDS details the orthoses [17]. In pes cavus, the aim is to address the complaints (plantar pain, conflict of the toes and dorsum of the foot with footwear, ankle instability with sprains and falls): thermoformed insoles for the cavus or unstable foot and, in more advanced cases, custom-made footwear with a rigid high upper, slight elevation of the forefoot to ease the roll-off of the step and, if necessary, lateral flaring of the sole for varus, reinforcement of the upper or an integrated lifter, the latter at the cost of greater weight. Foot-lifting (ankle-foot) orthoses improve balance, stability and control of steppage in the swing phase, and are available as off-the-shelf or moulded models, in fabric with an elastic strap, polypropylene or carbon. In a comparison in 26 patients, only the conventional rigid orthosis improved balance, and both orthoses tested increased step length; the rigid orthosis suits severe deficits, and the dynamic orthosis is preferable when the plantar flexors have MRC strength ≥4 and the toe extensors ≥3 [17]. In other studies, orthoses reduced steppage and proximal compensations (14 patients), patients who used them daily walked more slowly and with greater energy cost, because they were the most severely affected (32 patients), the rate of use was only 20% in 25 patients with severe steppage, owing to discomfort, lack of perceived need or stigma, and an anterior elastic orthosis reduced energy cost at comfortable speed without altering speed (7 patients) [17]. In the upper limb, occupational therapy can make custom positioning orthoses, worn at rest against flexor contracture of the fingers and pain, and functional thumb opposition orthoses [17].

According to the PNDS, physiotherapy is the mainstay of management in children and adults [17]. In children, the lesions follow a predictable sequence, aggravated by growth: weakness of the intrinsic and then extrinsic muscles, reduced extensibility and contracture of the soft tissues (muscles, plantar aponeurosis, periarticular structures), bone deformity and, finally, compensations; the foot deformities (cavus, cavovarus, equinovarus and, less often, planovalgus) progress from reducible to fixed, and only then become surgical. Physiotherapy seeks to prevent this fixation, through stretching of the triceps surae, toe flexors and plantar aponeurosis and mobilisation of all the joints of the foot and ankle, in individual sessions combined with massage; the proposed frequency is 2 to 3 sessions per week, adjusted to the type, stage and course of the disease and to school and family constraints, with parents taught the exercises [17]. It is not prescribed automatically at diagnosis: children are followed in a physical medicine and rehabilitation clinic, which decides the appropriate time [17]. Rehabilitation should be gentle, below the pain threshold, with passive and active aerobic exercise; moderate muscle exercise is effective and safe, improving gait and strength, endurance and muscle rehabilitation programmes improve autonomy, aerobic training improves functional capacity, stretching maintains range of motion, and dynamic training improves proprioceptive complaints, although harmonisation of modalities and long-term safety data are lacking [17]. The same document advises against weight training and intense exertion and recommends activities such as cycling, walking, gymnastics, swimming, aqua aerobics or dancing, adjusted to the patient's abilities [17]. Disability progresses more through the loss of compensatory mechanisms and the progression of deformities than through worsening of the motor deficit [17]. Walking aids (sticks, crutches, more rarely a walking frame) prevent falls in combination with orthoses; a manual or powered wheelchair maintains independent outdoor mobility in severe forms; the occupational therapist may suggest cutlery and pen holders, long-handled reachers, dressing aids and adapted utensils; and, in advanced forms, adaptation of the driving position may be needed [17].

7.3 Orthopaedic surgery

Severe pes cavus warrants surgery, preferably decided jointly by neurology, physiotherapy and orthopaedics; a 45-patient study found benefit, and hip dysplasia sometimes requires surgery [4]. Laurá and colleagues review cavovarus, claw toes and ankle instability, clinical assessment and conservative, surgical/postoperative options, highlighting absent evidence-based guidelines and variable osteotomy, tendon transfer (e.g. tibialis posterior) and fusion techniques [102]. CMT4C scoliosis may require bracing and surgery before linear growth ends [14]. HNPP decompression remains controversial because spontaneous recovery is common and controlled studies absent [2].

The PNDS prioritises conservative treatment whenever possible and lists the surgical indications (scoliosis, pes cavus, claw toes and claw hand, steppage) and the techniques described [17]: posterior tibial tendon transfer (described in 1982); triple arthrodesis of the hindfoot, with retrospective series of 16 patients with CMT (1989) and of 57 patients, 6 with CMT (1999); nerve decompression, including microvascular decompression in trigeminal neuralgia; and, for symptomatic hip dysplasia, for which only surgery is effective, the Bernese periacetabular osteotomy, which seeks to delay arthroplasty. In the most recent comparative series (2016), 27 operated patients with CMT had improvement in pain, but more complications than 54 patients with developmental dysplasia (33% versus 13%: sciatic neurapraxia or palsy, heterotopic ossification, infection, pubic non-union, persistent pain, arthroplasty) [17].

7.4 Pain, cramps and fatigue

Identify pain's cause precisely [4]. Musculoskeletal pain may respond to paracetamol or NSAIDs; neuropathic pain to tricyclic antidepressants (amitriptyline, clomipramine), carbamazepine, gabapentin or pregabalin; modafinil has been used for fatigue [3, 4, 13]. HNPP treatment ranges from topical analgesics to pregabalin, carbamazepine or duloxetine, with insoles/AFOs potentially relieving recovery-phase pain [2]. None has a CMT-specific indication; NICE adult neuropathic pain guidance offers amitriptyline, duloxetine, gabapentin or pregabalin initially [103]. The doses below derive from labels for other peripheral neuropathic pain.

Extrapolation of evidence must be distinguished from off-label use. The efficacy of these drugs has been demonstrated in other painful neuropathies (mainly diabetic and postherpetic), and their application to pain in CMT or HNPP is an extrapolation, without specific trials [4, 103]. Whether such use falls within the indication depends on the wording of the label and on the jurisdiction. In the European Union, pregabalin (Lyrica®, centrally authorised) is indicated for peripheral and central neuropathic pain in adults, and the harmonised summary of product characteristics for gabapentin refers to peripheral neuropathic pain in adults, “such as” painful diabetic neuropathy and postherpetic neuralgia; neuropathic pain due to CMT in an adult therefore falls within the wording of these indications [113, 114]. In the United States, gabapentin (Neurontin®) is approved only for postherpetic neuralgia and pregabalin for pain of diabetic neuropathy, postherpetic neuralgia, fibromyalgia and neuropathic pain associated with spinal cord injury, so use in CMT is off-label [104, 106]. Duloxetine is restricted to diabetic peripheral neuropathic pain on both sides of the Atlantic, so its use in CMT is off-label, and amitriptyline has no indication for neuropathic pain in the US label (off-label use in the USA), but the Portuguese SmPC indicates it for the treatment of neuropathic pain in adults, so in Portugal its use in an adult with CMT falls within the wording of that indication [108, 110, 111, 115]. In children and adolescents none of these drugs has an indication for neuropathic pain in the labels cited, and in pregnancy the choice should be individualised on the basis of each product's label; in these groups any prescription for neuropathic pain is off-label [104, 106, 113].

The French PNDS (French National Diagnosis and Care Protocol) recommends treating pain, a frequent complaint, with antiepileptics and antidepressants, acknowledges that they have not been evaluated specifically in CMT, provides for referral to a pain centre and gives no dosages; the doses in the table above, based on the labels and on NICE guidance, do not diverge from the PNDS, which is silent on this point [17, 103]. For fatigue, the PNDS advises against ascorbic acid in CMT1A, given the absence of effect in randomised trials, and recommends looking for another cause: predominantly morning fatigue and excessive daytime sleepiness should prompt investigation for sleep-disordered breathing (obstructive apnoea, more frequent in CMT1, and central apnoeas), restless legs syndrome and periodic limb movements may fragment sleep, and depression and nutritional deficiencies should be excluded [17]. The PNDS expresses the ascorbic acid doses of two trials in milligrams per day; the published trials used grams per day (1.5 g/day for 24 months in adults aged 18 to 70 years in CMT-TRIAAL/CMT-TRAUK; 4 g/day for 2 years in patients aged 13 to 70 years in the North American trial), values given in section 7.9 [17, 116, 117].

7.5 Neurotoxic drugs to avoid or monitor closely

The Oxford Desk Reference recommends avoiding neurotoxic drugs such as vincristine, taxanes (paclitaxel), cisplatin, isoniazid and nitrofurantoin [1]; the MFN2 GeneReviews includes vincristine, isoniazid and nitrofurantoin, as well as excessive alcohol and malnutrition [13]. Vincristine can severely worsen CMT: Graf and colleagues described three families with AD CMT1 in which a member with cancer developed severe, rapidly evolving neuropathy after the first doses of vincristine, with a 17p11.2–12 duplication documented in all, and recommended testing for the duplication before starting vincristine in patients with familial or unexplained neuropathy [57]. The systematic review by Cavaletti and colleagues (2023) found evidence that vincristine, and possibly paclitaxel, may occasionally induce atypical and more severe neurotoxicity in patients with CMT, but found no convincing evidence for similar recommendations regarding the other drugs, and stressed that patients should not be deprived of effective treatments but should instead be closely monitored [118]. Following this review, the Charcot-Marie-Tooth Association reduced its list of neurotoxic medications to vincristine (contraindicated in the demyelinating forms) and paclitaxel [27].

The review by Weimer and Podwall (2006), the basis of later lists, combined a literature search with the North American CMT database (CMTNA, Indiana University) [119]. In the literature they found only 26 publications on CMT and drug toxicity, 22 of them on vincristine, with 30 patients (15 adults and 15 children); 26 of the 30 had no diagnosis of CMT before treatment, although 10 showed, in retrospect, evident signs (pes cavus, distal atrophy) or an affected first-degree relative. Of the 16 patients studied genetically, 13 had the 17p duplication and one had the HNPP deletion. In the general population, vincristine sensory neuropathy usually appears from a cumulative dose of 5–8 mg; in patients with CMT, 18 of the 30 developed marked sensory symptoms or new weakness after 2 to 4 mg (or the equivalent paediatric dose of 1.5 mg/m² per administration), sometimes with tetraparesis of a pattern similar to Guillain-Barré syndrome, dysarthria and dysphagia; almost all improved, often without returning to their previous state. The few reports with other agents (cisplatin and doxorubicin tolerated in one CMTX; paclitaxel with carboplatin with worsening and docetaxel with carboplatin subsequently tolerated; nucleoside analogues for HIV infection in two patients with CMT1A and one with HNPP) did not allow these drugs to be classified as either safe or excessively risky. In the CMTNA, with 996 drug records from 209 people in 190 families, 19 drugs were associated by patients with worsening, 18 of which were already on published lists; the most frequent were nitrous oxide (3 of 6 exposures), metronidazole (3 of 13), nitrofurantoin (2 of 11), phenytoin (2 of 11), statins (2 of 20) and sertraline (5 of 21), with 1 or 2 reports for isoniazid and high-dose intravenous penicillin and one for gabapentin; of the 150 anaesthetics recorded, 12 (8%) were followed by some worsening, without sufficient detail to distinguish neuropathy from a postoperative effect. Doxorubicin, chloramphenicol, dapsone, disulfiram, hydralazine, lithium and pyridoxine at conventional doses were used without any recorded adverse effect. No difference between subtypes was observed, with small numbers (22 patients with a confirmed genetic subtype, 12 of them with CMT1A). The authors stressed that these data are patient-reported, without serial examinations, and that the final classification is partly subjective [119].

The practical recommendations of the same review are: do not use vincristine in known or probable CMT1A and, very probably, in HNPP; before vincristine, take a targeted family history and look for clinical signs of CMT, with genetic testing in suspected cases; use metronidazole with caution and for a limited time; reserve nitrofurantoin for when no suitable alternative exists; prefer another antiepileptic to phenytoin, reassessing individually those well controlled on it; monitor for myopathy and neuropathy with statins; choose, in HIV infection, a less neurotoxic nucleoside analogue; and consider measuring vitamin B12 or, preferably, methylmalonic acid before a planned anaesthetic with nitrous oxide [119]. In HNPP, the GeneReviews specifically mentions vincristine [2].

The Weimer and Podwall (2006) classification arranges drugs into four categories of probable risk for patients with CMT; annex 8 of the French PNDS (2020) reproduces it with changes, shown in the last column [17, 119]. Since 2023, the Charcot-Marie-Tooth Association retains only vincristine and paclitaxel, and the systematic review by Cavaletti and colleagues found no convincing evidence for the others [27, 118]:

The designation “nitric oxide” in the PNDS annex corresponds to nitrous oxide (N₂O), as confirmed by the original text of Weimer and Podwall, which justifies its inclusion by the irreversible oxidation of the cobalt of cobalamin, capable of precipitating myeloneuropathy when vitamin B12 is at the lower limit or with chronic abuse [119]; subacute combined degeneration and neuropathy after N₂O anaesthesia have been described mainly with pre-existing B12 deficiency [121]. This list diverges from more recent guidance. The systematic review by Cavaletti and colleagues (2023) found convincing evidence only for vincristine and, possibly, paclitaxel, and the Charcot-Marie-Tooth Association reduced its list to these two drugs, whereas the PNDS, which predates that review, retains dozens of drugs in the moderate or uncertain risk categories [17, 27, 118]. Isoniazid, too, which the Oxford Desk Reference and the MFN2 GeneReviews advise avoiding, appears in the PNDS as of uncertain or minor toxicity [1, 13, 17]. In practice, vincristine is the only drug for which all sources agree on a contraindication in the demyelinating forms; for the others, the PNDS list serves to identify the drugs that warrant clinical monitoring of nerve function, without depriving the patient of an effective treatment [17, 118].

Regarding anaesthesia, the SH3TC2 GeneReviews states that suxamethonium is usually contraindicated, that neuromuscular blocking agents should be used with caution and that local or regional anaesthesia, including epidural analgesia in labour, has been used without problems, each case to be discussed with the anaesthetist [14]. The French PNDS, by contrast, sees no contraindication to suxamethonium or to malignant hyperthermia triggering agents in CMT, considers thiopental, thiamylal and propofol safe, does not contraindicate epidural anaesthesia (bupivacaine, fentanyl and morphine without worsening of the disease) and prefers locoregional anaesthesia in neurological diseases, with no additional complications described, although without randomised trials or large cohorts; in a series of 4 patients with ropivacaine block, one had a prolonged 12-hour block, fully reversible [17]. The divergence regarding suxamethonium persists between the two sources; the GeneReviews caution was formulated for an early-onset recessive form with extensive denervation (CMT4C), and the decision rests with the anaesthetist, who weighs the degree of denervation in each patient [14, 17].

7.6 Subtype-specific management

CMT4D. There is no targeted or disease-modifying therapy: the sources consulted describe no interventional trials, gene therapy or oligonucleotides in clinical phase for NDRG1, and the only registered study including CMT4D is the Hereditary Neuropathy Foundation's international natural history registry of hereditary neuropathies (NCT05902351), currently recruiting [123]. The murine and canine models described in section 2.9 are, for now, tools for studying myelin maintenance rather than therapeutic platforms with published results [72, 78]. Management follows the general principles of CMT (physiotherapy, orthoses, foot and spinal surgery, avoidance of neurotoxic drugs) with four additions specific to CMT4D [4, 32]. The first is auditory rehabilitation: because the deafness is an auditory neuropathy, speech comprehension falls below that expected from the audiogram and the benefit of conventional hearing aids is limited [88]; in a multicentre series of 5 patients with CMT and sensorineural hearing loss or auditory neuropathy (genotypes not individualised), cochlear implantation brought the mean pure-tone threshold from 84.1 to 33.0 dB and sentence recognition to 5%, 65% and 74% in the three patients tested, and the authors considered the procedure safe [122]. The second is laryngeal and swallowing assessment, with adaptation of diet texture or gastrostomy when there is aspiration, and the third is respiratory monitoring (spirometry, maximal respiratory pressures, cough peak flow, overnight oximetry), with non-invasive ventilation and mechanical cough assistance if there is ventilatory failure [32]. The fourth is community-directed genetic counselling, described in section 8.1. Surgical correction of pes cavus may be needed early (at 5 years in one of the Italian patients), and loss of ambulation occurs in some patients between the third and fourth decades [32, 33].

7.7 Pregnancy

CMT appears to be an independent risk factor for maternal complications: in the Italian national registry (193 pregnancies, 157 deliveries), CMT manifestations appeared or worsened in 9.3% of pregnancies, sometimes persistently, and placenta praevia (1.6%), non-cephalic presentation (8.4%) and preterm birth (20.3%) were more frequent [4, 124]. The Brazilian textbook lists pregnancy among the situations that may exacerbate symptoms [3]. The PNDS (French National Diagnosis and Care Protocol) describes worsening of the neuropathy during pregnancy in CMT1A, possibly linked to the rise in progesterone, and considers the obstetric complications of delivery moderate and controversial: a 2012 study of 33 patients found no complications, whereas a 2005 cohort of 108 parturients with hereditary neuropathy showed a twofold risk of caesarean section, a threefold risk of forceps delivery, more abnormal presentations and more postpartum haemorrhage due to uterine atony (p = 0.04) [17]. On the basis of these data, the PNDS advises medical surveillance of pregnancy and delivery in a level 3 maternity unit, and does not contraindicate epidural analgesia [17]. The results of the Italian registry, published after the PNDS, reinforce obstetric surveillance [124].

7.8 Clinical trials and investigational treatments

PXT3003 (low-dose baclofen, naltrexone hydrochloride and D-sorbitol). This oral network-pharmacology combination acts on GABA-B, opioid and muscarinic receptors to reduce intracellular cyclic AMP and Schwann-cell PMP22 expression [20]. Phase 2 (80 adults, 1 year) confirmed safety and improved CMTNS and Overall Neuropathy Limitations Scale (ONLS) at the highest dose; EMA's Committee for Orphan Medicinal Products issued a positive designation opinion in February 2014 [125], with EU CMT1A orphan designation EU/3/14/1260 dated 26/03/2014, recognising rarity/plausibility rather than efficacy [126]. Phase 3 PLEO-CMT (323 patients, 15 months) found high-dose baclofen 6 mg/naltrexone 0.70 mg/D-sorbitol 210 mg, 5 mL twice daily, improved ONLS by −0.37 versus placebo (97.5% CI −0.68 to −0.06; p = 0.008), but crystallisation caused early high-dose arm termination, high attrition and statistical-plan adaptation [127]. International confirmatory PREMIER (NCT04762758; approximately 350 patients, 52 centres; modified ONLS change at 15 months) missed its primary endpoint according to Chinese-trial authors; results were neither peer-reviewed nor posted in the registry, with status “unknown” since April 2024, limiting evidential weight [20, 128, 129]. Conversely, Chinese phase 3 (NCT05092841; 176 patients aged 16–65, 25 centres; 5 mL twice daily for 2 weeks then 10 mL twice daily, 15 months) found ONLS difference −0.249 (95% CI −0.467 to −0.030; p = 0.0257), improved lower-limb subscore and dorsiflexion strength, and no related serious adverse events; authors attributed discordance to genetic, severity and environmental differences [20]. A 2026 commentary highlights the limitations from unavailable programme results [129]. PXT3003 is not FDA/EMA approved, with no accepted marketing application identified [20, 21, 126].

Govorestat (AT-007) in CMT-SORD. Oral aldose reductase inhibition blocks the polyol pathway's first step and normalised intracellular sorbitol in fibroblasts/Drosophila [49]. Phase 2/3 INSPIRE (NCT05397665; 56 patients aged 16–55, randomised 2:1 to once-daily govorestat/placebo) used 12-month 10-metre walk/run as the clinical primary endpoint and blood sorbitol reduction as pharmacodynamic endpoint [22, 130]. Sponsor-reported 12-month interim data (49 evaluable) showed sorbitol reduction versus placebo (p < 0.001), correlation with 10-metre change (p = 0.031), and improved secondary CMT Health Index (CMT-HI); no significant between-group primary clinical difference was reported [130, 131]. Only 24 and 15 evaluable patients contributed 18- and 24-month analyses before open-label extension, and muscle-MRI progression-slowing claims lack peer review [131]. A 2025 FDA type C meeting identified unresolved pathophysiological evidence, sorbitol surrogate use, future phase 3 endpoint choice and carcinogenicity studies; no NDA was submitted [131]. Cycle Pharmaceuticals completed acquisition in February 2026, and phase 3 confirmatory NCT07191912 (CMT-HI at 36 months) was withdrawn before recruitment by sponsor decision [22, 132]. EU orphan designation dates to 22/05/2023 (EU/3/23/2783), without a CMT application; the European classic galactosaemia application (Nugalviq®) was withdrawn [126, 133]. A 2025 review suggested interim data might make govorestat CMT's first approved drug [21]; it remains unapproved and its CMT-SORD future uncertain.

Ignaseclant (NMD670). Skeletal-muscle ClC-1 chloride-channel inhibition enhances excitability and compensates demonstrated CMT1/CMT2 neuromuscular transmission deficits (single-fibre EMG jitter/blocks); murine CMT1A/CMT2D models showed improved strength/endurance [134]. Exploratory phase 2a SYNAPSE-CMT in genetically confirmed ambulatory CMT1/CMT2 adults (NCT06482437; 81 patients; 21 days of twice-daily oral treatment, day-28 assessment) missed its day-21 6-minute walk primary endpoint [23, 135]. February/June 2026 sponsor releases reported prespecified secondary improvement in grip strength on days 21 (p = 0.02) and 28 (p < 0.01), and day-28 composite CMT-FOM, without serious adverse events [23, 136]. These preliminary sponsor/conference findings lack peer review; a 3-week study cannot establish neuropathy progression effects. NMD670 received FDA orphan designation in January 2025 [137].

Gene and silencing therapies. ELP-02, a functional FIG4 AAV9 vector delivered by lumbar intrathecal injection, began a phase 1/2 study in CMT4J patients aged 3–20 in 2026 (NCT07447557) [138]. Novartis EDK060, a single IV infusion, is in phase 1 ascending-dose CMT1A adults (NCT07140614) [139]. De Grado and colleagues described PMP22 silencers and HDAC6 inhibitors approaching clinical trials [21]; gene therapy faces safety/cell-targeting challenges [21, 140]. A personalised GARS1 antisense oligonucleotide is being studied in one patient (NCT07226297) [141].

Cell therapies. Intramuscular CLZ-2002 (Schwann cells differentiated from tonsil-derived mesenchymal stem cells) was safe in phase 1 CMT1, with exploratory CMTNSv2 and ONLS-leg signals at 24 weeks [142]; EN001 is in placebo-controlled phase 1/2 CMT1A (NCT06328712) [143].

Approaches without demonstrated benefit. Ascorbic acid, effective in the murine model, did not improve CMT1A in the randomised CMT-TRIAAL/CMT-TRAUK and North American trials [116, 117]; ACE-083 was discontinued for failing to meet functional endpoints [144]. The 2020 PNDS summarises the 2015 Cochrane review (six trials in CMT1A with 1 to 4 g/day of vitamin C versus placebo, one of them paediatric), all without efficacy, and the 2008 Cochrane review, according to which no specific treatment had shown efficacy in CMT [17].

Preclinical approaches cited in the PNDS. Sephin1, a selective inhibitor of a holophosphatase of the integrated stress response pathway, prevented the morphological and motor abnormalities in mouse models of CMT1B and amyotrophic lateral sclerosis, and had not been tested in patients with CMT at the time of the PNDS; HDAC6 inhibition reversed the mitochondrial axonal transport defect in a mouse model of HSPB1 neuropathy; and favourable effects of pyridostigmine have been described in CMT2D, in which there is neuromuscular junction dysfunction [17].

7.9 Clinical trial interpretation

These trials cannot rank efficacy: endpoints differ (ONLS, modified ONLS, CMTNS, 10-metre and 6-minute walk, muscle volume), populations differ (mild/moderate CMT1A, CMT-SORD, combined CMT1/CMT2), and duration ranges from 21 days to 2 years, invalidating indirect comparisons. PXT3003's positive absolute differences are small (approximately one quarter to one third of a point on a 12-point scale), against very slow CMT1A progression with little 15-month placebo change; clinical importance is unestablished [20, 127]. Positive PLEO-CMT findings came from an early-terminated arm, missing data and modified analyses; negative international confirmatory PREMIER means the programme is not two concordant trials [20, 127, 129]. INSPIRE sorbitol reduction is pharmacodynamic; within-treatment correlation with function cannot replace a primary between-group difference, and FDA questioned sorbitol's surrogate validity [131]. SYNAPSE-CMT secondary effects in an exploratory 3-week study measure muscle performance rather than neuropathy progression [23]. Negative ascorbic acid, PREMIER and ACE-083 findings show that animal CMT1A efficacy does not necessarily transfer clinically [116, 117, 144].

7.10 Comparative regulatory status and evidence hierarchy

As of October 2026, no FDA/European Commission medicine is authorised to treat the cause or modify progression of any CMT/HNPP form; neuropathic analgesics used in practice have other indications [4, 133]. The table summarises the agents discussed.

(Table sources: [104, 106, 108, 111, 113–115, 126, 128, 131, 133, 137].)

Evidence levels include peer-reviewed PLEO-CMT/Chinese/ascorbic acid trials; registries giving status/design without PREMIER/INSPIRE results; sponsor/conference INSPIRE/SYNAPSE-CMT reports; orphan designations recognising rarity/plausibility rather than efficacy; and authorisation decisions, absent for these agents in CMT. Future authorisation would not guarantee marketing, reimbursement or national access; INFARMED assesses Portuguese access, ANVISA Brazilian registration and CONITEC inclusion in the Sistema Único de Saúde.

7.11 Divergences between the French PNDS and the other sources

8. Reproductive Options and Family Counselling

8.1 Inheritance and recurrence risks

Counselling depends on the molecular diagnosis, the mode of inheritance and the test results in each family [4]. In AD inheritance (CMT1A, CMT1B, AD CMT2A, HNPP), each child of an affected person has a 50% probability of inheriting the variant [2–4]. The proportion of de novo variants depends on the gene: 1.3% of PMP22 duplication carriers and 25% of MPZ variant carriers in the German series of 1206 index cases [59]; the historical GeneReviews chapter estimated that 20–33% of probands with CMT1A had a de novo duplication [29]; and about 20% of patients with HNPP have a de novo deletion [2]. The PNDS cites a third estimate for CMT1A, 11% de novo duplications in a cohort of 118 patients with verified paternity, and up to 25% de novo variants in CMT1B [17]. The three values are not directly comparable, because they use different denominators (all index cases referred for testing in the German series, clinical cohorts in the others); in an isolated case, only clinical, electrophysiological and molecular study of the parents distinguishes a de novo variant from one inherited from a mildly symptomatic parent [17, 29, 59]. When the variant is not detected in the leucocytes of either parent, the risk to siblings is slightly above that of the population because of the possibility of germline mosaicism, documented in MPZ [4]. An apparently negative family history can only be confirmed after clinical and/or molecular evaluation of the parents [4]; the Oxford Desk Reference recommends conduction studies in the parents of sporadic cases [1].

For AR CMT4/AR-CMT2/CMT-SORD, parents are asymptomatic obligate carriers and siblings have 25% affected, 50% carrier and 25% unaffected non-carrier probabilities [4]. SH3TC2-HMSN carrier testing may identify homozygotes because Spanish Roma carrier frequency is approximately 4% and onset may be late [14]. MFN2-HMSN is approximately 90% AD/10% AR; severe/early heterozygous cases warrant a second-allele search because prognosis and recurrence risk change (25% rather than 50%) [13]. CMTX1 men transmit to all daughters and no sons; heterozygous women transmit to 50% of offspring, with affected boys and heterozygous girls whose manifestations may be absent, mild or moderate [4, 12].

The French PNDS (French National Diagnosis and Care Protocol) places genetic counselling within a clinical genetics clinic [17]. In adults, the aim is to inform about the genetic nature of the disease and to organise the information of relatives about the risk and the possibility of testing, under the French decree of 20 June 2013, bearing in mind that testing relatives may reveal presymptomatic heterozygotes or homozygotes. In AR inheritance, when there is a reproductive plan and particularly when there is consanguinity, the partner is tested for the familial variant or variants; the partner is rarely a carrier, but if so, the risk for each child becomes 1 in 4. In children, counselling informs the parents about the mode of inheritance, the recurrence risk and the possibility of prenatal diagnosis [17].

In CMT4D, inheritance is AR and the recurrence risk for each sibling of a patient is 25% [4]. In Roma communities, endogamy and the high frequency of carriers of the founder variant make partner carrier testing, cascade testing of siblings and cousins, and the offer of prenatal or preimplantation diagnosis once both familial variants have been identified relevant [4, 99, 145]. In Croatia, the c.442C>T carrier frequency was 1.5% in a population sample of Bayash Roma from Baranja, lower than in other Vlax groups, and the differences between Croatian groups of the same migratory category show that the risk varies between subgroups and should not be extrapolated from one community to another [99]. Confirmation of carrier status in both parents avoids a counselling error when homozygosity results from uniparental isodisomy of chromosome 8, a situation in which only one parent is a carrier and the recurrence risk is far below the 25% of classical AR inheritance [76]. In Bulgarian Muslims, the founder variants c.538-1G>A and c.327-2A>G justify the same community approach [33].

8.2 Predictive testing, prenatal and preimplantation diagnosis

Predictive testing of at-risk adults is possible once the familial variant has been identified, with formal counselling on consequences and limitations [1, 4]. In asymptomatic minors with adult-onset conditions without beneficial early intervention, predictive testing is considered inappropriate, but in families with an established diagnosis it is appropriate to test symptomatic children at any age [1, 4]. In HNPP and SH3TC2-HMSN, clarifying the genetic status of asymptomatic relatives has practical benefit: it allows counselling on circumstances to avoid and early detection of scoliosis [2, 14]; in CMTX1 it allows information about the triggers of central episodes [12]. Prenatal diagnosis (chorionic villus sampling) and preimplantation genetic diagnosis are possible when the familial variant is known, but are rarely requested for typically adult-onset diseases that affect neither intellect nor life expectancy [1, 3, 29]. The ideal time for discussion is before pregnancy [4]. In France, prenatal diagnosis, performed mainly in forms of particular severity, requires that the variants of the index case and of both parents have been identified, and is carried out by chorionic villus sampling from 11 weeks of gestation or by amniocentesis from 15–16 weeks; when the fetus is affected, termination of pregnancy for medical reasons may be requested by the pregnant woman, after discussion in a multidisciplinary prenatal diagnosis centre [17]. Intrafamilial variability (including between twins) should be explained, as it gives parents an idea of the range of possible severity, but does not allow the phenotype of a child to be predicted [1, 3].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Global and European prevalence

The prevalence of 1 in 2500 derives from Skre's study in western Norway (1974) [1, 5]. The population study by Braathen and colleagues (Akershus, Norway) found 245 affected individuals from 116 families, corresponding to 1 in 1214 people (95% CI 1 in 1062 to 1 in 1366); CMT1, CMT2 and intermediate CMT accounted for 48.2%, 49.4% and 2.4% of families, and PMP22 duplication and GJB1, MPZ and MFN2 variants were found in 13.6%, 6.2%, 1.2% and 6.2% of families, respectively [6]. Orphanet records validated point prevalences of 28.2/100,000 in Spain, 17.5 in Italy, 16.0 in Cyprus, 12.0 in Iceland, 10.8 in Japan, 9.7 in Serbia and 6.1 in Denmark; for CMT1A, 15.2/100,000 in the United Kingdom and 82.37/100,000 in Norway; and for HNPP, 16/100,000 in Finland and a European estimate of 3.5/100,000 [7, 146]. The Norwegian figure assigned by Orphanet to CMT1A comes from the Braathen study and in fact corresponds to the prevalence of all CMT (1 in 1214, or about 82/100,000), not to that of CMT1A, which in that study represented only 13.6% of families; it should therefore not be used as the prevalence of CMT1A [6, 7]. GeneReviews estimates the overall prevalence of hereditary neuropathies at about 30/100,000, of CMT1 at 15–20/100,000 and of CMT1A at about 10/100,000, values that hold in diverse regions, including China [29]. The distribution of variant types and the phenotypic spectrum of HNPP are homogeneous across populations [2]. The French PNDS (French National Diagnosis and Care Protocol) gives a range of 9.7 to 82.3 cases per 100,000 inhabitants in populations of European origin, supported by the Norwegian studies and by a Brazilian systematic review, and estimates CMT2 at about 30% and CMTX1 at about 10% of CMT; PMP22 and GJB1 together account for about 60% of cases, MPZ is relevant in the demyelinating forms, MFN2, GDAP1, GJB1 and MPZ in the axonal forms, and GDAP1 and SH3TC2 are the most frequent recessive genes [17]. The only France-specific figure is the fraction of CMT1C, about 1.6% of dominant CMT1 [17]; the PNDS gives no national prevalence. No population prevalence studies of CMT in Portugal, nor national genetic diagnosis series, were found in the targeted search carried out for this review; absence from the sources consulted does not prove that unindexed data do not exist. The indexed Portuguese literature consists mainly of family reports, for example with CMT1E due to a PMP22 point variant, with NEFL-associated CMT2 and with CMT4B2 due to an SBF2 variant [147–149].

9.2 Non-European populations

The Brazilian reference notes no CMT1 epidemiological studies [3]; a 503-patient referral-centre series comprised 353 demyelinating, 39 intermediate and 111 axonal cases. Among 197 diagnosed probands, commonest genes were PMP22 duplication (58.88%), GJB1 (11.67%), MFN2 (6.09%), GDAP1 (3.55%), MPZ (3.05%) and PMP22 point variants (3.05%) [150], representing referral gene distribution rather than population prevalence. Among 100 unrelated Brazilians, GDAP1 explained 7.14% (5/70) of axonal cases, all recessive, severe and early onset, considered higher than elsewhere [151]. Thirty Brazilian children/adolescents followed longitudinally worsened by mean 2.25 CMTPedS points/year (2 in CMT1A) [152]; a Brazilian 2023 review covers research history, genes, pain, pregnancy and respiration [153]. An African systematic review found only 107 families (185 patients), mainly North African, with 91.2% AR and predominant LMNA/GDAP1/SH3TC2, reflecting consanguinity and limited research [154]. A South African cohort with 50% African genetic ancestry had 44% genetic-neuropathy yield (PMP22 in 4, MFN2 in 3, isolated rare genes), with substantial differences from the Global North [155]. SORD deficiency occurs in European, Hispanic, Chinese, Near Eastern and North African ancestry, most commonly c.757delG [30]. Population prevalence data were not found for most sub-Saharan African, Middle Eastern or Latin American countries; hospital series cannot establish per-100,000 rates.

9.3 Founder effects

The Roma (Gypsy) population has four private founder variants associated with three AR demyelinating forms: NDRG1 NM_006096.4:c.442C>T p.(Arg148Ter) (CMT4D/HMSN-Lom), SH3TC2 p.Cys737_Pro738delinsTer (published designation) and NM_024577.4:c.3325C>T p.(Arg1109Ter) (CMT4C), and a G>C change in an alternative untranslated exon of HK1 (CMT4G/HMSN-Russe) [31]. In 29 Spanish Roma families with AR demyelinating CMT, CMT4C accounted for 57.14%, HMSN-Russe for 25% and HMSN-Lom for 17.86%; the HK1 variant shares a founder haplotype that probably reached Spain at the end of the eighteenth century [31]. The SH3TC2 p.Arg1109Ter variant predominates in Spanish Roma with CMT4 [156], and the carrier frequency of SH3TC2-HMSN in this population is about 4% [14]. The NDRG1 p.Arg148Ter mutation was mapped in Roma families to 8q24.3 with a conserved haplotype, indicating a single founder [48]. The Oxford Desk Reference describes Friedreich ataxia, the main paediatric differential diagnosis, as rare in African and Asian populations [1].

The distribution of CMT4D follows the migratory history of the Roma. The disease was identified in Bulgaria and later in Roma families in Italy [157], Spain [91], Slovenia [88], Hungary [100], Serbia [70], the Czech Republic [76], Slovakia [71] and France [158]. European Roma groups form a founder population with subisolates: the coalescence ages of the haplotypes of five private mutations place the founding of the population about 32–40 generations ago, with secondary and tertiary founder events 16–25 generations ago [145]. The available proportions measure different things and are not prevalences: 17.86% of the 29 Spanish Roma families with AR demyelinating CMT [31]; 11 of 150 Bulgarian probands with demyelinating CMT selected by CMT4 criteria, including Roma families (7.3%) [33]; 2.88% of 104 patients with CMT of diverse ethnicities in whom the common causes had been excluded (4.68% of the demyelinating forms) [73]; 1.5% of all patients in a Hungarian series of 531 cases, in which NDRG1 was tested only for the founder variant in Roma patients [100]; and 12 patients from 8 Czech families, with HMSN-Russe twice as frequent as HMSN-Lom in the same country [76, 98]. Orphanet gives no validated prevalence for CMT4D (ORPHA:99950) [11]. Outside the Roma, there are two founder splicing variants in the Muslim Bulgarians of the Rhodopes, on shared haplotypes of 2.4 Mb (c.538-1G>A) and 9.6 Mb (c.327-2A>G) [33], and isolated cases in Turkey, Italy, China, India, Saudi Arabia and France [32, 33, 74, 75, 90]. In Brazil, the series of 503 patients from the Rio de Janeiro reference centre included patients with the variants c.943+2T>C (early-onset CMT with scoliosis, vocal cord paralysis and restrictive lung disease) and c.788C>A p.(Ser263Ter), according to the table of the 2026 review [32, 150]. The sources consulted include no Portuguese data on CMT4D, which does not demonstrate its absence, given the presence of Roma communities in Portugal.

9.4 Sex differences

In CMTX1 men are more severely affected [60]; in HNPP men have more palsies and electrophysiological abnormalities [2]; in CMT-SORD male sex is associated with greater distal weakness and greater decline [30]. Harding and Thomas described higher weakness scores in men in both types of HMSN [37]. The PNDS records more male than female patients, which it attributes to X-linked inheritance but not to it alone, and the French series of Dubourg (section 3.5) quantifies the difference in CMTX1: weakness in 87% of men versus 52% of women and median motor velocity of 34.5 versus 44.4 m/s [17].

10. Illustrative Clinical Case

10.1 Published case: a PMP22 point variant with overlapping CMT/HNPP and delayed diagnosis

Pandey and colleagues described in 2026 a 68-year-old woman with neuropathic symptoms since adolescence and a family history of CMT, seen because of multiple falls in the preceding year (one with complete loss of consciousness and another with partial loss accompanied by transient visual and speech disturbances), recurrent right foot drop and progressive weakness of the right limbs [94]. She had a history of bilateral carpal tunnel release, chronic migraine, tricuspid regurgitation and marked weight loss after bariatric surgery [94]. Examination revealed pes cavus, hammer toes, moderately severe loss of vibration sense in the lower limbs predominantly on the right, sensory changes at the right wrist and below the right knee, and right-sided weakness of grip, iliopsoas and tibialis anterior [94]. Brain computed tomography and magnetic resonance imaging showed no acute lesion (MRI showed only mild, non-specific white matter changes, interpreted by the authors as chronic microvascular), and moderate lumbar stenosis at L4-L5 did not explain the diffuse picture [94]. The conduction study showed prolonged distal latencies and reduced sensory velocities in the median nerves (about 28–30 m/s), absent ulnar and lower limb sensory responses, and, in the peroneal nerves, prolonged distal latencies, reduced amplitudes and velocities of 22–26 m/s [94]. Initial genetic testing was negative for PMP22 alterations; given the strong clinical suspicion, next-generation sequencing identified the heterozygous nonsense variant NM_000304.4:c.396C>A p.(Tyr132Ter) in PMP22, classified as pathogenic and confirmed on repeat testing [94]. The final diagnosis was CMT with overlapping features of HNPP; management included an ankle-foot orthosis, gabapentin 300 mg/day for neuropathic pain, referral to a neuromuscular disease clinic and genetic counselling, since her daughter had neuropathic symptoms; at follow-up, gait improved with consistent use of the orthosis [94].

The case demonstrates PMP22 point variants causing approximately 20% of HNPP and CMT1-like overlap [2]; PMP22 MLPA dup/del testing missing point variants and requiring sequencing after negative results [2, 4]; rapid post-bariatric weight loss and previous tunnel surgery as relevant HNPP history, with rapid weight loss an avoidable trigger and HNPP a compression-neuropathy differential [2]; and molecular confirmation enabling counselling of a symptomatic daughter [94]. Normalised NM_000304.4(PMP22):c.396C>A (p.Tyr132Ter) is ClinVar pathogenic/likely pathogenic (VCV003381154) [58]. The reported gabapentin dose is case-specific rather than a recommendation. Original figures: brain CT (https://pmc.ncbi.nlm.nih.gov/articles/PMC13476126/figure/FIG1/), brain MRI (https://pmc.ncbi.nlm.nih.gov/articles/PMC13476126/figure/FIG2/) and lumbar CT (https://pmc.ncbi.nlm.nih.gov/articles/PMC13476126/figure/FIG3/); conduction studies appear in original tables 1, 2 and 4 [94].

10.2 Published series: severe vincristine neuropathy in undiagnosed CMT1A

Graf and colleagues described three AD-CMT1 families in which a relative with malignancy developed rapidly severe neuropathy after initial vincristine doses in routine chemotherapy; each family had at least one affected individual with 17p11.2–12 duplication [57]. They concluded that duplication predisposes to severe vincristine toxicity, advised avoidance in CMT1A, detailed histories for all oncology patients, and pre-vincristine duplication testing in familial/unexplained neuropathy [57]. This remains the basis of the sole contraindication retained alongside paclitaxel caution in the current Charcot-Marie-Tooth Association list [27, 118].

10.3 Composite teaching case: CMTX1 with a transient central episode

A 15-year-old boy with pes cavus and recurrent sprains since 10 years presents with dysarthria/right hemiparesis developing over hours, two days after a mountain-resort trip and with fever. MRI shows symmetrical bilateral subcortical/splenial diffusion restriction outside a vascular territory; symptoms resolve in ten days and diffusion within weeks. Examination reveals disproportionate thenar atrophy, absent Achilles reflexes and median motor velocity 34 m/s. A maternal uncle has “thin legs”, the mother mild pes cavus, and no father–son transmission. PMP22 dup/del testing is negative; GJB1 sequencing identifies a pathogenic hemizygous variant, heterozygous in the mother. This matches GeneReviews reversible CMTX1 central dysfunction triggered by fever, exertion or post-altitude readaptation, with characteristic diffusion/T2 changes [12]; management includes supportive treatment for self-limited episodes, trigger information and assessment of at-risk female relatives, recognising symptomatic heterozygotes [1, 12].

10.4 Published case: two Roma siblings with CMT4D, bulbar involvement and respiratory failure

Abati and colleagues described in 2026 two Italian siblings of Roma ancestry, a 40-year-old woman and a 38-year-old man, homozygous for NM_006096.4:c.442C>T p.(Arg148Ter), children of healthy, apparently non-consanguineous parents [32]. The patient began walking at 1 year, but with an abnormal gait, predominantly on tiptoe; at 5 years difficulty with fine hand movements appeared and she underwent surgery for bilateral pes cavus; she walked unaided until 20 years, used a stick from that age, a walking frame at 27 and a wheelchair at 36 [32]. Deafness began in childhood and dysphagia at 18 years, with three aspiration pneumonias at 33, 36 and 38 years; at 36 bilateral vocal cord paralysis in adduction was diagnosed, causing dyspnoea [32]. On examination she had severe deafness, dysarthria and hypophonia, reduced visual acuity, kinetic head tremor, mild facial and jaw weakness, generalised areflexia and severe atrophy and weakness with a distal-to-proximal gradient; she could not stand unaided and had no scoliosis [32]. Distal sensory and motor potentials were unobtainable; the axillary nerve had a distal latency of 19.0 ms with an amplitude of 0.2 mV, and the facial nerve latencies of 9.8–11.4 ms with amplitudes of 0.1–0.2 mV; the CMTNSv2 score was 31/36 [32]. Fibreoptic endoscopic evaluation of swallowing confirmed the vocal cord paralysis, absence of the cough reflex and severe dysphagia for solids and liquids, which led to percutaneous endoscopic gastrostomy; spirometry showed a forced vital capacity of 44% of predicted and a cough peak flow of 29%, and non-invasive ventilation and mechanical cough assistance were proposed [32]. Her brother had a similar but milder picture: he walked with two sticks, had mild dysphagia for solids (soft diet), a forced vital capacity of 70% and reduced maximal respiratory pressures (52% and 40% of predicted), a CMTNSv2 of 32/36 and torsional nystagmus [32]. Both had visual evoked potentials with low-amplitude P100 and cognitive delay since childhood; of their three sisters, two had clinical features compatible with CMT, one of whom died at 36 years from complications of a tracheotomy, and segregation confirmed the variant in an affected sister and its absence in a healthy sister [32]. The case shows that CMT4D may extend to the cranial nerves and respiratory muscles, and supports the authors' recommendation to assess swallowing, vocal cords and respiratory function systematically [32]. The figures of the original article have not been reproduced.

11. Prognosis and Long-Term Follow-Up

Life expectancy is not reduced in CMT1 and in most dominant forms [3, 4]. Progression is slow, with long periods of stability; over time, some patients need sticks, but fewer than 5% need a wheelchair [1, 29]. The Brazilian textbook states that in severe cases (fewer than 5%) there may be wheelchair dependence and respiratory failure, and that prognosis may depend on the age at onset, itself influenced by external events [3]. Scoliosis is more frequent in early-onset forms and rarely severe outside CMT4 [1, 14]. Severity varies by subtype: in AD CMT2A, childhood onset is the main predictor of severity [80]; CMT4B1 is more severe and progresses more rapidly than CMT4B2 [66]; in CMTX1, the CMTES increases over up to 8 years, with maximal responsiveness at 3 years and greater sensitivity to change in mild phenotypes [60]; in CMT-SORD most patients retain independent ambulation [30]; and in HNPP disability in activities of daily living is usually mild, but chronic neuropathic pain occurs as a sequel in 50–75% of those affected [2]. The PNDS (French National Diagnosis and Care Protocol) adds that the course may be progressive or relapsing, with acute worsening described in pregnancy and with neurotoxic drugs such as vincristine, that disability is generally moderate and subtype-dependent (difficulty walking and climbing stairs, ulcers of the extremities in forms with marked sensory deficit) and that, in CMT1A, the CMTNS progresses on average by 0.68 points per year [17].

The Spanish guideline considers follow-up to be exclusively clinical and routine investigations unnecessary [16]. The French PNDS agrees that there are no consensus data on paraclinical follow-up, but organises clinical follow-up in a reference centre, in a clinic, day hospital or short admission, so that the patient sees all professionals in the minimum time, with annual frequency initially, six-monthly and then three-monthly when complications or dependence arise, and six-monthly in adolescence because of the risk of deformity during growth [17]. The annual frequency of GeneReviews remains the baseline for stable patients; the difference lies in the increased frequency provided for by the PNDS for adolescence and for patients with complications [4, 17]. The PNDS also recommends systematic assessment of mood, given the higher frequency of depression, and provides for a psychological interview at every visit [17]. Validated scales (CMTNSv2, CMTES, the paediatric CMTPedS scale, ONLS) are used in monitoring and in clinical trials [60, 80, 95]. In cases without a molecular diagnosis, periodic reassessment with new technologies and review of the classification of variants of uncertain significance are recommended, as illustrated by the case described in section 10.1 [60, 94].

In CMT4D, the prognosis is more guarded than in the dominant forms: weakness extends from the lower limbs to the hands in the second decade, some patients lose ambulation between the third and fourth decades (at 23 years in a Bulgarian patient and wheelchair use at 36 in an Italian patient), and bulbar and respiratory involvement, although rarely reported, may cause aspiration pneumonia and respiratory failure [32, 33, 86]. There are no survival studies; the death at 36 years of a sister of the Italian patients was due to complications of a tracheotomy, and does not allow the mortality of the disease to be estimated [32].

12. Summary and Concluding Remarks

CMT comprises hereditary length-dependent sensorimotor neuropathies, approximately 1 in 2500 with >80 genes, assessed through neurophysiology (demyelinating <35–38 m/s, intermediate 35–45, axonal >45), inheritance and sequential molecular testing [1, 4]. PMP22 dosage at 17p12 is central: recurrent 1.4–1.5 Mb microduplication through CMT1A-REP NAHR causes CMT1A, 70–80% of CMT1 and up to half overall; reciprocal deletion causes recurrent compression-site HNPP, and point variants cause CMT1E, Dejerine-Sottas and approximately 20% of HNPP [2, 9, 29, 38, 42]. Every proband therefore starts with PMP22 dup/del, followed by GDAP1/GJB1/HINT1/MFN2/MPZ/PMP22/SH3TC2/SORD panel and exome/genome [4].

The main subtypes are distinguished by clinical markers with practical consequences: in CMTX1, intermediate velocities, frequently affected heterozygous women and transient central episodes triggered by fever, exertion or altitude [12, 60]; in CMT1B, bimodal distribution of velocities and a high rate of de novo variants [29, 59]; in CMT2A, early and severe onset, optic atrophy and AD or AR inheritance [13, 80]; in CMT4C, early scoliosis and a founder effect in the Roma population [14, 31]; in CMT-SORD, a serum biomarker (sorbitol) and a therapeutic target [30]. The 17p12 microduplication may be detected by microarray in non-neurological contexts, and the contiguous PMP22-RAI1 duplication combines the Potocki-Lupski and CMT1A phenotypes [10, 56]. CMT4D (HMSN-Lom), caused mainly by the Roma founder variant NM_006096.4:c.442C>T p.(Arg148Ter) in NDRG1, combines severe demyelinating neuropathy of the first decade, deafness due to auditory neuropathy and, in some patients, bulbar, respiratory and central involvement; targeted testing in Roma patients, CNV analysis and parental confirmation of homozygosity are the critical points of diagnosis, and management is supportive, with auditory rehabilitation and surveillance of swallowing and breathing [32, 33, 75, 76].

Treatment remains symptomatic and multidisciplinary — orthoses, exercise, foot and spinal surgery, pain treatment, respiratory, laryngeal and ophthalmological surveillance according to the gene — and preventive, with avoidance of vincristine and caution with paclitaxel, prevention of nerve compression in HNPP and pregnancy planning [2, 4, 15, 16, 118, 124]. The 2020 French PNDS (French National Diagnosis and Care Protocol) adds organisation in reference centres of the FILNEMUS filière, surveillance of sleep disorders, mood and childhood hearing, six-monthly follow-up in adolescence and an extended list of potentially neurotoxic drugs, longer than the guidance issued after 2023 [17, 118]. There is no approved disease-modifying therapy; PXT3003 has two positive phase 3 trials, with small absolute differences, and an unpublished negative confirmatory trial; govorestat reduced sorbitol without a reported difference in the primary clinical endpoint and its confirmatory trial was withdrawn; ignaseclant missed its primary endpoint in a 3-week exploratory study, with signals in secondary endpoints reported by the sponsor; and gene therapies (AAV9-FIG4 in CMT4J) and PMP22 silencing therapies have entered the clinical phase [20, 22, 127, 138, 139]. The scarcity of population data outside Europe and the absence of prevalence studies in Portugal and in most African and Latin American countries are gaps to consider in service planning [3, 154].

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