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Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis

Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis
Literature review current through: Jan 2024.
This topic last updated: Jan 20, 2022.

INTRODUCTION — The hereditary peripheral neuropathies have been classified based upon clinical characteristics, mode of inheritance, electrophysiologic features, metabolic defects, and specific genetic markers. The primary hereditary neuropathies predominantly affect peripheral nerves and produce symptoms of peripheral nerve dysfunction.

Historically, the primary hereditary neuropathies were designated by eponyms that had the connotation of specific clinical features (eg, Charcot-Marie-Tooth disease [CMT] or Dejerine-Sottas disease). However, phenotypic variability resulted in substantial diagnostic confusion.

The Dyck classification developed in the 1970s helped to define specific types based upon clinical and electrophysiologic features [1]. Many of the primary hereditary neuropathies were divided into hereditary motor sensory neuropathy (HMSN) and hereditary sensory autonomic neuropathy (HSAN). However, the eponym Charcot-Marie-Tooth disease has had a resurgence in popularity, and today the term "CMT" is regarded as being synonymous with HMSN.

CMT/HMSN is the focus of the current review and for the sake of simplicity will be referred to as CMT for the remainder of this review. This topic will review the genetics, clinical features, and evaluation of CMT. Management and prognosis are reviewed separately. (See "Charcot-Marie-Tooth disease: Management and prognosis".)

The primary hereditary sensory autonomic neuropathies, the neuropathies not included in this classification, and the disorders affecting both the central and peripheral nervous systems are discussed elsewhere. (See "Overview of hereditary neuropathies" and "Hereditary sensory and autonomic neuropathies" and "Neuropathies associated with hereditary disorders".)

OVERVIEW — CMT consists of a spectrum of disorders caused by pathogenic variants in various genes whose protein products are expressed in myelin, gap junctions, and/or axonal structures within peripheral nerves [2]. A variety of pathogenic variant types has been associated with CMT, including whole-gene duplications and deletions as well as point pathogenic variants [3,4]. For example, duplication of the PMP22 gene causes CMT1A, the most common subtype (approximately 40 percent overall).

The association of different pathogenic variants within the same gene with various clinical phenotypes is a common finding in this group of peripheral neuropathies. This variability suggests that these disorders represent a spectrum of related phenotypes caused by an underlying defect in peripheral nervous system myelination and axonal function.

The major categories of CMT are CMT types 1 through 7 as well as an X-linked category, CMTX. Within each category, a specific disease associated with a particular gene is assigned a letter (eg, CMT1A, CMT1B, etc). CMT is genetically heterogeneous with numerous causative genes identified to date [5,6], but the vast majority of cases are attributed to pathogenic variants in just four genes: PMP22, MPZ, GJB1, and MFN2. This genetic distribution was first described in a large cohort of 1024 CMT patients from the United States [7] and confirmed in a subsequent cohort of 1005 patients from Japan [8]. The overall estimated prevalence of CMT is 40 per 100,000 [9], which varies from 10 to 82 per 100,000 in different reports [10]. There is no known ethnic predisposition [6]. CMT types 1 and 2 represent by far the largest proportion of patients, as documented in several studies, including ones from Russia [11] and France [12].

The most common initial presentation of CMT is distal weakness and atrophy manifesting with foot drop and pes cavus. Sensory symptoms are often present but tend to be less prominent. Later in the course, foot deformities such as hammertoes ensue, along with hand weakness and atrophy (table 1).

The diagnostic evaluation, despite the widespread availability of genetic testing, still centers on electromyography (EMG) in many cases. Genetic testing is key to confirming the diagnosis after EMG. However, it may be appropriate to skip EMG and go directly to genetic testing in a patient with a strong family history of confirmed CMT, especially when a relative has a known pathogenic variant.

CMT1 — CMT1 is characterized by peripheral nerve demyelination and an autosomal dominant pattern of inheritance. CMT1A, due to duplication of the PMP22 gene, accounts for approximately 70 to 80 percent of CMT1 cases [11,13]. Affected patients typically present in the first or early second decade [14]. Infants with this pathogenic variant may be symptomatic, but these cases are generally classified as congenital hypomyelinating neuropathy or Dejerine-Sottas disease. (See 'CMT3' below.)

Early complaints may include frequent sprained ankles caused by distal muscle weakness or difficulty running and keeping up with peers. Physical findings may include areflexia, pes cavus, and distal lower extremity weakness and atrophy.

Distal calf muscle atrophy often occurs, causing the classic "stork leg deformity," which tends to become more prominent with disease progression. Walking is clumsy because of both muscle weakness and sensory loss. Sensory loss progresses gradually and may be detected on physical examination via loss of proprioception and vibration.

Late changes include atrophy of the intrinsic hand and foot muscles. Palpable enlargement of the peripheral nerves may occur secondary to nerve hypertrophy. In addition, kyphosis or scoliosis may develop at later stages of the disease.

Ambulation may be significantly affected, but complete loss of ambulation is uncommon. Life expectancy is normal.

Disease exacerbation can occur in pregnancy, an effect that may be mediated by increased plasma progesterone [15]. (See 'Management' below.)

Nerve conduction studies (NCS) show severe slowing of conduction velocity in both the motor and sensory nerves, typically with values less than 60 percent of normal. The pattern of slowing is generally uniform, with no conduction block or temporal dispersion. In some cases, sensory responses may be absent. Nerve conduction velocity slowing is present even in asymptomatic infants [16]. Needle electromyography (EMG) examination is typically normal. Frequently, little correlation exists between the electromyographic and clinical findings, as the latter are probably produced primarily by secondary axonal dysfunction [4,17,18].

Sural nerve biopsy shows demyelination that affects primarily the large nerve fibers. Onion bulbs are a characteristic feature; they reflect repeated demyelination and remyelination and represent redundant Schwann cells, collagen, and fibroblasts. Secondary axonal changes may be present.

Genetics of CMT1 — CMT1 is caused by mutations in genes that are expressed in Schwann cells, the myelinating cells of the peripheral nervous system [4]. The most common types exhibit autosomal dominant inheritance and have been subdivided into types 1A, 1B, 1C, etc. However, autosomal recessive and X-linked forms also occur [19-22]. (See 'X-linked CMT' below.)

CMT1A — CMT1A is associated with a 1.5 Mb duplication or, less commonly, a single nucleotide variant of the peripheral myelin protein 22 (PMP22) gene on chromosome 17p11.2-p1; duplication leads to overexpression of PMP22, while single nucleotide variants alter distribution of the protein [3,23,24]. Interestingly, patients with a 1.5 Mb deletion at this site develop hereditary neuropathy with pressure palsy. (See "Hereditary sensory and autonomic neuropathies".)

Patients with single nucleotide variants usually have more prominent clinical manifestations. In these patients, PMP22 partially accumulates in the Schwann cells rather than being inserted in the myelin sheath, as occurs with gene duplication [24].

In addition to the typical findings discussed above, patients with CMT1A may have associated sleep apnea [25,26]. In one report, 13 asymptomatic family members of an index patient with CMT and sleep apnea were investigated for these disorders. Eleven of the 14 (including the index patient) had PMP22 duplications on chromosome 17; all 11 also had sleep apnea [25].

Hereditary neuropathy with liability to pressure palsy — Hereditary neuropathy with liability to pressure palsy (HNPP; tomaculous neuropathy), a recurrent, episodic demyelinating neuropathy, is an autosomal dominant disorder associated with PMP22 deletions and single nucleotide variants that is allelic to CMT1A. Affected patients typically present with isolated nerve palsies in areas frequently affected by compression or mild trauma. Symptoms first appear in the second decade in most patients, but they can occur in younger children or be delayed until into the third decade [27-29]. Single nerve palsies typically appear sequentially, resolving in days to months, and may be associated with persistent motor deficits in various nerve distributions.

The most frequently affected nerves are those at common sites of trauma or entrapment and include the axillary, median, radial, ulnar, and peroneal nerves, along with the brachial plexus. Other findings may include cranial nerve involvement, sensorineural deafness, and scoliosis. In one series of 70 patients, nerve involvement in episodes of palsy occurred with the following frequencies [28]:

Peroneal nerve – 36 percent

Ulnar nerve – 28 percent

Brachial plexus – 20 percent

Radial nerve – 13 percent

Atypical phenotypes of HNPP include a polyneuropathy resembling chronic inflammatory demyelinating polyneuropathy [30] and presentations involving generalized weakness and muscle cramps [31], musculoskeletal pain [32], or low back pain with radicular symptoms [33]. Central nervous system white matter lesions have been reported in isolated patients as well as several members of a large family with HNPP [34,35].

HNPP results in focal slowing of motor nerve conduction velocities. Sural nerve biopsy shows focal myelin thickening (tomacula) on light microscopy. These lesions are best seen with teased fiber preparations and appear as enlarged sausage-shaped thickenings of the myelin sheath [36].

HNPP is an autosomal dominant disorder associated with PMP22 gene pathogenic variants. In approximately 80 percent of HNPP cases, there is a 1.5 Mb deletion in chromosome 17p11.2 that results in reduced expression of PMP22 [28,37-39]. The deletion corresponds to the duplicated region of PMP22 present in CMT1A. Approximately 20 percent of patients with HNPP have single nucleotide variants or small deletions in PMP22, and sporadic cases with de novo deletions have been described [28,39-41]. PMP22 pathogenic variants may slow nerve conduction by disrupting myelin junctions [42]. In one report of seven children with PMP22 deletions and early-onset HNPP, a coexisting Ile92Val polymorphism in the LITAF gene was present in six children, suggesting that this polymorphism leads to an early-onset HNPP phenotype when accompanied by a PMP22 deletion [29].

On electrodiagnostic testing, patients with HNPP will typically display signs of a demyelinating neuropathy even while asymptomatic, including subclinical carpal tunnel syndrome. There should be multiple signs of demyelination if enough nerves are studied [43]. Depending on the clinical presentation, it may make sense to perform these studies prior to sending out genetic testing.

The treatment of HNPP is conservative and primarily consists of strategies to avoid mild trauma and compression at vulnerable sites. This may entail special accommodations at school or work.

CMT1B — CMT1B, originally known as peroneal muscular atrophy, is most often caused by single nucleotide variants in the myelin protein zero (MPZ) gene on chromosome 1q22, which cause overexpression of the major myelin structural protein [44,45]. MPZ is one of the four genes that cause the vast majority of cases of CMT. There appear to be three distinctive phenotypic subgroups of pathogenic MPZ variants [46-48]:

An early-onset, severe demyelinating neuropathy with very slow nerve conduction velocities (<10 m/second)

A late-onset axonal neuropathy with slightly reduced or normal nerve conduction velocities, classified as CMT2I (see 'Additional CMT2 subtypes' below)

A dominant intermediate form of CMT, DI-CMTD [49,50]

Normal peripheral nerve myelination depends upon strict dosage of MPZ, and overexpression may be deleterious [51,52]. Transgenic mice containing extra copies of the MPZ gene manifest a dose-dependent, dysmyelinating neuropathy [51]. In six individuals with CMT1 from one family, comparative genome hybridization analysis revealed an increased gene dosage, estimated to be five copies, of the entire MPZ gene and flanking genes [53]. Pathogenic variants of MPZ gene introns that disrupt normal protein splicing have also been identified in a small number of families with CMT1B [54].

MPZ is normally expressed on the cell membrane of Schwann cells and plays a major role in myelin membrane adhesion [55,56]. In one family with CMT1B, in vitro fluorescence analysis demonstrated that mutant MPZ was localized in the endoplasmic reticulum and Golgi apparatus rather than on the cell membrane [57]. In addition, the adhesiveness of cells expressing mutant MPZ was diminished compared with controls.

Additional CMT1 subtypes

CMT1C is caused by pathogenic variants in the lipopolysaccharide-induced tumor necrosis factor-alpha factor (LITAF) gene, also known as SIMPLE, which is located at chromosome 16p.13.1-p12.3 [58,59]. LITAF is widely expressed and encodes a protein that may play a role in protein degradation pathways. The clustering of pathogenic variants associated with CMT1C suggests that a domain of LITAF may be important in peripheral nerve function. In contrast with other known genes that cause CMT1, the level of expression of the LITAF transcript did not change during development or in response to lung injury, suggesting a potential new mechanism of peripheral nerve perturbation resulting in demyelinating neuropathy.

CMT1D is caused by pathogenic variants in the early growth response 2 (EGR2) gene on chromosome 10q21.1-q22.1 [60].

CMT1E is characterized by a classic CMT phenotype and sensorineural hearing loss [61]. The cause is single nucleotide variants in the PMP22 gene [62].

CMT1F is caused by pathogenic variants in the neurofilament light (NEFL) gene on chromosome 8p21 [63]. Pathogenic variants in the same gene can cause an axonal form classified as CMT2E. (See 'CMT2' below.)

The Roussy-Levy syndrome, first described in 1926, is a CMT1 phenotype with manifestations that include postural tremor, gait ataxia, distal muscle atrophy, pes cavus, areflexia, and mild distal sensory loss [64,65]. Genetic testing of members of the original family identified a heterozygous missense variant for the extracellular domain of the MPZ gene, indicating CMT1B disease [64]. However, testing in another large family with the same phenotype found a partial duplication at chromosome 17p11.2, indicating that it is also allelic with CMT1A [65].

CMT2 — CMT2 is characterized by primarily axonal damage and an autosomal dominant mode of inheritance. A systematic review of epidemiologic studies found that CMT2 accounts for 12 to 36 percent of all CMT cases [10].

The axonal injury is reflected in diminished motor amplitudes on nerve conduction studies, with signs of chronic reinnervation on needle electromyography (EMG). Sural nerve biopsy shows axonal degeneration without hypertrophic features; demyelination with onion bulb formation does not occur or is minimal [66]. These features distinguish CMT2 from CMT1 [66].

The classic clinical manifestations of CMT2 include distal weakness, atrophy, sensory loss, decreased deep tendon reflexes, and variable foot deformity [67]. The onset of symptoms usually is in the second or third decade of life, a bit later than in CMT1. The clinical course is similar to that of CMT1, but sensory symptoms, with loss of vibration and proprioception, may be more prominent, and peripheral nerves are not palpably enlarged. Distal trophic ulcerations in the feet may occur.

An early-onset form of CMT2 becomes clinically apparent before the child reaches five years of age. Weakness progresses rapidly, with loss of strength below the knees by the second decade. Sensory symptoms are present but overshadowed by the motor weakness. Ambulation often is lost by the time the child reaches mid-teens.

Possible late-onset forms of CMT2 presenting from 35 to 85 years of age (median age 57) have been described in six families [68]. The electrophysiologic findings were primarily those of axonal involvement. The late-onset forms are likely to be genetically heterogeneous. Autosomal dominant inheritance was demonstrated in two of the families, while inheritance patterns were unclear in the remaining four families.

Genetics of CMT2 — Autosomal dominant pathogenic variants are responsible for most cases of CMT2, though autosomal recessive inheritance can occur [69-71]. However, the genetic basis of CMT2 is incompletely described. A retrospective study from a neuropathy clinic published in 2012, at the dawn of the next generation sequencing era, reported that, of 115 patients with CMT2, pathogenic variants were identified in only 25 percent [72].

There are many different subtypes of CMT2, as discussed in the sections that follow.

CMT2A — CMT2A is the most common CMT2 phenotype and accounts for approximately 20 percent of axonal CMT cases and 5 percent of all CMT [47]. The gene most commonly implicated in CMT2A is mitochondrial fusion protein mitofusin 2 (MFN2) [67,73-76]. The inheritance mode is autosomal dominant in most cases. However, some studies suggest that some MFN2 pathogenic variants cause a form of early-onset CMT with apparent autosomal recessive inheritance [77,78].

An early report identified a pathogenic variant in the kinesin family member 1B gene (KIF1B) in a single Japanese family [79], but this pathogenic variant has not been confirmed in other CMT2A families and may represent a benign rare polymorphism [80].

Additional CMT2 subtypes — Other CMT2 subtypes are rare and difficult to diagnose [47]:

CMT2B is characterized by predominant sensory involvement; it maps to chromosome 3q21.3 and is associated with pathogenic variants in RAS-associated protein 7 (RAB7) [81,82].

CMT2C is characterized by distal muscle weakness, vocal cord paralysis, mild sensory impairment, and axonal neuropathy [83,84]. It maps to chromosome 12q24.1 and is associated with pathogenic variants in the TRPV4 gene [85,86]. TRPV4 pathogenic variants also cause congenital distal spinal muscular atrophy and scapuloperoneal spinal muscular atrophy.

CMT2D is characterized by predominant hand weakness and atrophy with a locus on chromosome 7p15 [87]. Associated pathogenic variants have been identified in the glycyl tRNA synthetase (GARS) gene [88].

CMT2E is caused by pathogenic variants in the NEFL gene linked to chromosome 8p [89-91]. In several families with CMT2E, electrophysiological studies showed features consistent with a mixed axonal and demyelinating neuropathy, while pathological studies revealed an axonopathy with giant axons, accumulation of disorganized neurofilaments, and significant secondary demyelination [92]. Other pathogenic variants in the NEFL gene cause a predominantly demyelinating neuropathy classified as CMT1F. (See 'CMT1' above.)

CMT2F is characterized by a classic CMT phenotype with a locus on chromosome 7q11.23 [93] and is associated with missense variants in the heat shock 27kDa protein 1 (HSPB1) gene [94].

CMT2I is a clinically distinct late-onset CMT phenotype associated with pathogenic variants in the MPZ gene and characterized by axonal polyneuropathy, prominent sensory involvement, pupillary abnormalities, and hearing loss [46,95-98].

CMT2K is a form of axonal CMT with autosomal dominant or recessive inheritance caused by pathogenic variants in the GDAP1 gene [99-101]. Pathogenic variants in GDAP1 have also been identified in patients with CMT4A, a demyelinating form. (See 'CMT4' below.)

CMT2L is characterized by a classic CMT phenotype and maps to chromosome 12q24.23 [102] and is associated with pathogenic variants in the heat shock protein 8 (HSPB8) gene [103].

CMT2M is caused by pathogenic variants in the DNM2 gene [104,105]. DNM2 has also been associated with an autosomal dominant form of intermediate CMT, known as DI-CMTB [106,107].

CMT2P is characterized by a classic axonal CMT phenotype. Originally designated CMT2G and mapped to chromosome 12q12-q13 [108], the disease locus was later reassigned to 9q33.3-q34.1 and the cause was related to pathogenic variants in the leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1) gene [109].

CMT2S is caused by truncating and missense variants in the IGHMBP2 gene and is characterized by slowly progressive weakness, muscle atrophy, and sensory loss without significant respiratory compromise [110,111]. Pathogenic variants in IGHMBP2 are also the cause of spinal muscular atrophy with respiratory distress type 1 (SMARD1). (See "Spinal muscular atrophy", section on 'Spinal muscular atrophy with respiratory distress type 1'.)

CMT2T is caused by MME gene pathogenic variants, which were identified in 10 unrelated patients from Japan with late-onset autosomal recessive CMT2 [112]. The late-onset axonal phenotype for biallelic pathogenic variants was confirmed in a cohort from Spain [113].

CMT2 caused by a mitochondrially encoded ATP synthase 6 (MT-ATP6) gene pathogenic variant, which does not yet have a subtype letter designation, is characterized by onset in the first to second decade, variable severity, an initial pure motor neuropathy that evolves to a motor-predominant axonal neuropathy in the third to fourth decades, and early proximal leg weakness regardless of the presence of distal weakness [114]. Rapid clinical deterioration may occur in the setting of a febrile infectious illness. In a cohort of 270 patients with a clinical phenotype consistent with CMT2, a pathogenic variant in the MT-ATP6 gene was identified in 1 percent.

CMT2DD is caused by dominant pathogenic variants in ATP1A1 that are associated with dysfunction of the sodium-potassium pump, leading to distal extremity weakness with preserved proximal strength, vibratory sensory loss, axonal loss on electrophysiologic studies, and variable age of onset from childhood to adulthood [115].

X-LINKED CMT — There are X-linked dominant and X-linked recessive forms of CMT involving different loci [71]. Together, the X-linked forms account for approximately 10 to 15 percent of all CMT cases.

CMTX1 — CMTX1, the X-linked dominant form of CMT, is the second most common form of CMT after CMT1A, accounting for 7 to 12 percent of all CMT cases [13,71,116,117]. It is the most common X-linked form of CMT, accounting for approximately 50 percent of X-linked cases [118]. (See 'CMT1' above.)

CMTX1 is caused by pathogenic variants in the gap junction protein beta 1 (GJB1) gene, also known as the connexin 32 gene, on chromosome Xq13.1 [20-22,66]. The gene is expressed in myelinating Schwann cells but not incorporated into the myelin sheath [119]. Most GJB1 pathogenic variants are thought to cause disability by a loss of function of the gap junction protein connexin 32 [120].

The symptoms of CMTX1 are more prominent and begin earlier in males [121], who generally present in infancy or later in childhood with gait problems (eg, toe walking, flat footed walking, falls, difficulty running); some present in infancy with foot deformities (pes planus or pes cavus) [122]. Less common features include tremor, hand weakness, and sensorineural deafness. However, all patients remain ambulatory. Reflexes are lost at the ankles in all cases, whereas patellar reflexes are retained in approximately one-half of females. The neuropathy may be asymmetric and therefore mimic an acquired immune-mediated neuropathy [47].

Children and young adults with CMTX1 can experience transient central nervous system manifestations, including limb weakness (eg, hemiparesis, quadriparesis, or monoparesis), dysarthria, dysphagia, ataxia, or combinations of deficits [123-126]. At presentation with these stroke-like episodes, brain magnetic resonance imaging (MRI) typically shows reversible lesions on diffusion-weighted, T2, and fluid-attenuated inversion recovery (FLAIR) sequences in the deep white matter, predominantly in the posterior brain regions or splenium of the corpus callosum. In some cases, the nature of the transient attacks and the MRI appearance of associated brain lesions are reminiscent of acute disseminated encephalomyelitis. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Neuroimaging'.)

Other reports have described patients with X-linked CMT, mainly CMTX1, who developed clinical features and central nervous system demyelination compatible with a diagnosis of multiple sclerosis [127]. (See "Evaluation and diagnosis of multiple sclerosis in adults" and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis".)

The pathophysiology typically of CMTX1 includes features of both demyelination and axon loss, and this is reflected in neurophysiologic studies. Nerve conduction velocities are moderately slowed but not to the same degree as in autosomal dominant CMT1 [128]. Demyelination and axonal loss is observed histologically, but onion bulb formation is minimal.

Additional CMTX subtypes

CMTX2 is the X-linked recessive form that maps to Xp22 [129,130]. In the one described family, carrier females were unaffected. In males, the phenotype was notable for infantile onset, atrophy and weakness of lower leg muscles, areflexia, and pes cavus. Intellectual disability was present in some. Electrophysiologic studies demonstrated both demyelination and axonal involvement. No causative gene has been identified [131].

CMTX3 is also X-linked recessive and is caused by a 78 kb insertion at chromosome Xq27.1 that originates from chromosome 8 [118,129,130,132]. In two described families, the phenotype was notable for juvenile onset, distal atrophy with weakness, and normal intelligence, with both demyelination and axonal features by electrophysiologic studies [129,130]. In a third family, disease severity was variable between affected males, with widely ranging nerve conduction velocities [118]. Symptoms began in the legs during the first decade of life, and arm involvement followed approximately 10 years later in two-thirds of patients. Pain and paresthesia were frequently the first sensory symptoms. Pyramidal signs, tremor, and hearing loss were not observed. Female carriers were usually asymptomatic. A series of 11 families demonstrated early onset including foot deformity during infancy, severe hand weakness, and rapid progression during childhood, with primarily demyelinating features on electrophysiological testing [133].

Cowchock syndrome (CMTX4; CMT with deafness and intellectual disability) is a rare form of infantile-onset axonal X-linked CMT [134]. Affected males demonstrated severe muscle weakness associated with deafness and intellectual disability. Females demonstrated only minor abnormalities involving sensory nerve conduction, electromyography, and hearing. The disorder is caused by pathogenic variants in the apoptosis inducing factor mitochondria-associated 1 (AIFM1) gene on chromosome Xq26 [135].

CMTX5 is an X-linked recessive disorder with deafness and optic neuropathy that has been reported in a Korean family [136]; the disease is caused by pathogenic variants in the phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene [137].

CMTX6 is an X-linked dominant disorder described in a family from Australia and characterized by an axonal-predominant motor and sensory form of CMT with childhood onset and gradual disease progression in affected males [138]. Carrier females were either mildly symptomatic or asymptomatic. The cause is pathogenic variants in the pyruvate dehydrogenase kinase 3 (PDK3) gene.

CMT3 — Two disorders, Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy, are classified as CMT3. These are severe, early-onset peripheral neuropathies that are thought to be caused by an inability of the Schwann cells to produce normal myelin, resulting in thin, poorly formed myelin. On histologic examination, patients with Dejerine-Sottas syndrome have thin myelin sheaths and large onion bulb formation, whereas those with congenital hypomyelinating neuropathy show essentially absent myelin without evidence of inflammation, myelin breakdown, or onion bulbs.

Historically, Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy were considered to be distinct clinical and histologic entities. However, their genetic etiologies overlap considerably and the distinction between the two diseases is becoming blurred.

Dejerine-Sottas syndrome — Dejerine-Sottas syndrome is a severe demyelinating neuropathy that presents in early infancy with hypotonia. The phenotype is characterized by delayed motor development, prominent sensory loss, distal followed by proximal weakness, absent reflexes, ataxia, and profound slowing of nerve conduction velocities to ≤10 m/second. Scoliosis appears early and progresses with time, and contractures develop. Progression is slow, often with ambulation maintained through adult life [139]. Although Dejerine-Sottas syndrome can still be distinguished clinically from classic CMT and congenital hypomyelinating neuropathy, genetic overlap with these other phenotypes has blurred the boundaries among these subtypes of inherited neuropathies [140].

Autosomal recessive and several dominant heterozygous forms of Dejerine-Sottas syndrome have been described, affecting genes that are also involved in CMT1 and CMT4. They include pathogenic variants in the PMP22 gene (also found in CMT1A) [52,66,141,142], the MPZ gene (also found in CMT1B) [52,66], and the EGR2 gene (as perhaps occurs in CMT1C) [143,144]. In one series of nine patients, for example, four novel single-nucleotide variants occurred in PMP22 and two in MPZ; two cases were autosomal dominant [52]. Recessive inheritance involving the PRX gene (the cause of CMT4F) was described in three unrelated patients with Dejerine-Sottas neuropathy [145].

Congenital hypomyelinating neuropathy — Congenital hypomyelinating neuropathy presents at birth with profound hypotonia and contractures. Conduction velocities are either absent or extremely slow. Feeding difficulties and respiratory distress often lead to death in infancy [146]. However, several cases that exhibited spontaneous improvement in motor function with increasing age have been reported [147-149]; one patient completely recovered by four months [147].

Congenital hypomyelinating neuropathy is genetically heterogeneous. Most cases are thought to be caused by pathogenic variants in either PMP22 or MPZ [149-152]. Other pathogenic variants have been described in EGR2 [60] and MTMR2 [153]. Genetic transmission in most cases is autosomal dominant, but rare autosomal recessive cases have been reported.

CMT4 — CMT4 is a rapidly expanding heterogeneous group of autosomal recessive demyelinating motor sensory neuropathies. These autosomal recessive forms of CMT are rare, clinically more severe, and less likely to result from pathogenic variants in structural myelin proteins than the autosomal dominant forms. Individuals with CMT4 have a typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and foot deformities (ie, pes cavus) [154]. Conduction velocities are typically slow (<40 m/second) on nerve conduction studies.

Several subtypes of CMT4 disease are described based upon electrophysiologic, pathologic, and genetic criteria.

CMT4A was identified in Tunisian consanguineous families. It presents in early childhood with distal weakness and mild sensory loss [155]. The neuropathy is rapidly progressive. Patients often are incapacitated by the fourth decade. Hypomyelination, loss of myelinated fibers, and basal laminal onion bulbs are present. Conduction velocities are moderately reduced. The disease has been mapped to chromosome 8q13-q21.1. Pathogenic variants have been identified in the GDAP1 gene [156,157]. GDAP1 appears to be predominately expressed in neurons but not in Schwann cells and localized in mitochondrial membranes [158]. This finding suggests that mitochondrial abnormalities may cause CMT4A [158]. Of note, there have been several reports of patients with recessive GDAP1 pathogenic variants who have features of both demyelination and axonal loss, suggesting that some of these patients have mixed physiology [159,160].

CMT4B is divided into several subtypes:

CMT4B1 was first described in a consanguineous Italian family [161,162]. The disease presented in patients at age 2 to 4 with distal and proximal weakness with moderate sensory loss and frequent involvement of cranial nerves [163]. Histologic features included loss of myelin fibers, segmental demyelination and remyelination, and numerous onion bulbs; focally folded myelin sheaths were present in peripheral nerves. Conduction velocity was slow. The causative MTMR2 gene is on chromosome 11q22-23 [164]. CMT4B1 disease is more severe than CMT4B2 due to earlier onset and more frequent motor milestones delay, wheelchair use, and respiratory involvement [165].

CMT4B2 shares the same morphological features on nerve biopsy as CMT4B1 but is generally less severe and differs in age of onset and clinical presentation [165]. The causative SBF2 gene is on chromosome 11p15 [166,167]. The age of onset ranged from 4 to 13 years old [166-170]. Distal weakness was prominent on presentation, with proximal weakness developing only after several years. Motor nerve conduction velocities were similarly slowed. Early-onset glaucoma was a feature in some families [167,169,170]. An Italian family was also been reported with CMT4B2 [171,172].

CMT4B3, described in a Korean family, has a similar though less severe phenotype compared with CMT4B1 and CMT4B2 [173]. It is caused by compound heterozygous pathogenic variants in the SBF1 gene on chromosome 22q13.33. The SBF1 gene is structurally similar to the SBF2 gene associated with CMT4B2.

CMT4C was first described in Algerian families with severe spinal deformities and weakness in childhood and adolescence [174-176] and was later reported in various ethnic backgrounds, including European, African American, Native American, Chinese, Indian, Japanese, Korean, and Norwegian populations [177-182]. Scoliosis is a variable but sometimes severe manifestation that may require operative correction at an early age. Loss of myelinated fibers and some classic onion bulbs are present on nerve pathology. Motor nerve conduction velocity is slowed. CMT4C appears to account for approximately 20 percent of cases of autosomal recessive demyelinating CMT and is associated with pathogenic variants in the SH3TC2 gene on chromosome 5q32 [183,184].

CMT4D is also known as hereditary motor and sensory neuropathy-Lom (HMSNL) and is one of the more common autosomal recessive forms. It occurs in divergent Romani groups descended from a small founder population [185]. CMT4D is an early-onset neuropathy that presents with muscle weakness and wasting, skeletal deformities, sensory loss, and severe reduction in nerve conduction velocities. Neural deafness develops during the second or third decade of life. Slow motor nerve conduction velocity occurs and onion bulbs are present in peripheral nerves. The founder pathogenic variant involves the NDRG1 gene on chromosome 8q24.3 [186]. NDRG1 is ubiquitously expressed, with particularly high levels in Schwann cells, and may play a role in growth arrest and cell differentiation.

CMT4E corresponds to a congenital hypomyelinating neuropathy caused by a homozygous missense variant in the early growth response 2 gene (EGR2) on chromosome 10q21-22 [60]. Distal weakness is present at birth. Myelin sheaths are thin or absent and onion bulbs are present.

CMT4F was found in a large consanguineous Lebanese family [187]. Onset is in early childhood, with distal muscle weakness and severe sensory loss. Nerve conduction studies revealed the total absence of any sensory or motor evoked response in the upper and lower limbs. Nerve pathology showed severe depletion of myelinated fibers and multiple small onion bulbs. The defective gene (PRX) encodes periaxin, a protein of myelinating Schwann cells [145,187].

CMT4G, originally termed "hereditary motor and sensory neuropathy – Russe" and described in Romany families, is characterized by childhood onset of leg weakness followed later by arm weakness [188,189]. Accompanying manifestations include distal sensory loss with areflexia, pes cavus. The disorder is caused by pathogenic variants in the hexokinase 1 (HK1) gene [190].

CMT4H was described in Lebanese and Algerian families as a severe form of CMT with onset in the first two years of life [191]. Major features include unsteady gait, loss of reflexes, scoliosis, and severe demyelinating neuropathy [191]. It is caused by pathogenic variants in the FGD4 gene on chromosome 12p11.2 [192,193].

CMT4J was first identified in four unrelated patients as a severe form of childhood-onset CMT [194]. Nerve pathology from one patient showed axonal loss and evidence of demyelination and remyelination. In a subsequent report, two siblings with adult-onset CMT4J developed a progressive asymmetric paralysis that clinically resembled motor neuron disease [195]. Neurophysiologic testing showed severe and widespread denervation, while nerve pathology from one sibling revealed severe loss of myelinated nerve fibers [195]. In these families, CMT4J was caused by pathogenic variants in the FIG4 gene on chromosome 6q21 [194].

In addition to these designated CMT4 subtypes, a study of two families with genetically undefined CMT4 identified SURF1 gene variants as the probable cause [196]. Additional features such as lactic acidosis, brain magnetic resonance imaging abnormalities, and cerebellar ataxia developed in affected individuals consistent with the role of this gene as an assembly factor of the mitochondrial respiratory chain complex IV.

A novel form of autosomal recessive CMT has been associated with pathogenic variants in MCM3AP. Four families were found to have primarily axonal neuropathies while another family was found to have primarily demyelinating neuropathies, with seven of nine affected individuals having mild-to-moderate intellectual disability [197].

HMSN/CMT 5, 6, AND 7 — Hereditary motor sensory neuropathy (HMSN) types 5, 6, and 7 were used in the 1975 Dyck classification, but these disorders are referred to more commonly by the associated symptoms:

HMSN 5 refers to patients with autosomal dominant spastic paraparesis with sensory neuropathy.

HMSN 6 refers to patients with dominant or recessive optic atrophy and motor sensory neuropathy.

HMSN 7 refers to patients with retinitis pigmentosa and motor sensory neuropathy.

INTERMEDIATE CMT — Intermediate CMT is an uncommon CMT variant characterized by mixed axonal-demyelinating physiology. Several X-linked forms of CMT are well-known to have these features. There has been controversy among experts regarding the existence and classification of this form of CMT [198,199], especially for the autosomal subtypes, and thus whenever possible these entities are grouped in with the more traditional categories of CMT described above. Genes unique to intermediate CMT are noted below.

This intermediate group is further distinguished from CMT1 by the absence of clinically observed nerve hypertrophy [200]. Nerve conduction studies (NCS) generally reveal median nerve motor conduction velocities of 25 to 45 m/second, although values may vary between different laboratories.

Dominant intermediate CMT type A (DI-CMTA) has been linked to a locus on chromosome 10q24.1-q25.1, but the causative gene has yet to be identified [201].

Dominant intermediate CMT type C (DI-CMTC) is caused by pathogenic variants in the tyrosyl-tRNA synthetase (YARS) gene [202,203].

Several types of intermediate CMT are inherited in an autosomal recessive manner, including those associated with pathogenic variants in GDAP1, KARS, and PLEKKHG5. See CMT4 section above for details on RI-CMTA (GDAP1). (See 'CMT4' above.)

Recessive intermediate CMT type B (RI-CMTB) is caused by pathogenic variants in the lysyl-tRNA synthetase (KARS) gene [204].

Recessive intermediate CMT type C (RI-CMTC) is caused by pathogenic variants in the pleckstrin homology and RhoGEF domain containing G5 (PLEKHG5) gene [205,206].

EVALUATION AND DIAGNOSIS — A comprehensive history and physical examination remain the core of ascertainment of and evaluation for cases of CMT (see 'When to suspect CMT' below). Genetic testing is key to confirming the diagnosis after electrodiagnostic testing. In a patient with a family history of confirmed CMT, bypassing electrodiagnostic testing in favor of immediate genetic testing may be appropriate, especially when a relative has a known pathogenic variant. However, inheritance patterns can be obscured because of the highly variable expression of CMT, such that oligosymptomatic relatives may escape detection [207]. In addition, sporadic CMT is common and may be caused by de novo pathogenic variants.

Despite the widespread availability of genetic testing, electrodiagnostic testing remains important in many cases. Premature genetic testing may result in inappropriate use of expensive resources on patients who turn out to have other diagnoses, such as idiopathic pes cavus.

Nerve biopsy is rarely performed today in the diagnostic evaluation of CMT. However, it may still play a role when the clinical presentation is atypical and/or the electromyography (EMG) findings are equivocal. In decades past, nerve biopsy was a key diagnostic tool for this evaluation.

Various imaging techniques are emerging as potential diagnostic modalities for neuromuscular diseases, including CMT. For example, nerve ultrasound can distinguish CMT1A from other subtypes [208]. (See "Diagnostic ultrasound in neuromuscular disease", section on 'Findings in neuropathy'.)

When to suspect CMT — Even in the absence of a clear family history of neuropathy, features that increase suspicion for an inherited neuropathy include [47]:

Slowly progressive symptoms

Foot deformities (pes cavus and hammertoes)

Lack of positive sensory symptoms despite clear sensory involvement

However, a key presenting feature, pes cavus, may also be present in isolation as an idiopathic, sometimes hereditary phenomenon. Therefore, it is important to examine a patient with pes cavus for other features of CMT before pursuing further diagnostic testing. A retrospective cohort study of children with pes cavus evaluated in a pediatric EMG laboratory found that the diagnosis of CMT correlated with the presence of one or more of the following [209]:

Weakness

Distal muscle atrophy

Gait abnormalities

Sensory deficits

Absent distal reflexes

Family history of pes cavus and CMT

Thus, patients with several of these abnormalities should be referred for EMG, followed by genetic testing as indicated.

Patients with isolated pes cavus and none of the other clinical features associated with CMT should be monitored for the development of those features but do not require EMG and genetic testing.

Electrodiagnostic studies — EMG is the next step in the evaluation once a thorough history and physical examination have led the physician to suspect the presence of CMT. When performed by trained and experienced neurophysiologists, EMG is an efficient and highly informative diagnostic study that can confirm or disprove the presence of a polyneuropathy compatible with the diagnosis of CMT and determine the likely physiology of the neuropathy. For most patients with no family history of CMT, it is important to perform EMG prior to genetic testing, as the absence of a neuropathy would indicate that genetic testing for CMT is unnecessary, while the physiology of a neuropathy detected on EMG will help guide the interpretation of subsequent genetic testing.

In some situations, immediate genetic testing (rather than EMG) may be warranted, such as when the patient has an affected family member who already has a known CMT pathogenic variant or if CMT1A seems likely based upon the clinical features or family history. CMT1A is the most common type of CMT, and the genetic test is very simple and quick.

An EMG test typically involves two components, nerve conduction studies (NCS) and the needle EMG study; the latter is also referred to as the needle examination. The NCS portion of the test can detect signs of demyelination (via slow conduction velocities, prolonged distal latencies, prolonged F response latencies, conduction block, and/or temporal dispersion) and axonal loss (via low amplitude nerve potentials). However, low amplitude nerve potentials may be compatible with several different types of neuromuscular disease. Thus, these findings if present must be correlated with neurogenic abnormalities on the needle EMG examination to confirm the presence of an axonal neuropathy. In some cases, there will be features of both demyelination and axonal loss, which has been described in certain subtypes of CMT. In others, the EMG may be normal, indicating that CMT is not present, or may be abnormal, indicating that the disease process is not CMT but something entirely different, such as a myopathy or disorder of the neuromuscular junction.

Genetic testing and counseling — Genetic testing is a key component of the diagnostic evaluation for CMT and is necessary for the confirmation of subtype-specific diagnoses.

Genetic counseling should be made available to all patients and families with a suspected hereditary neuropathy [47]. Information about genetic testing and its implications should be provided. Prenatal testing for pregnancies at increased risk is possible for some types of CMT if the pathogenic variant in the family is already known [210].

Genetic screening for asymptomatic relatives of a patient diagnosed with CMT is an option, but risk assessment depends on several factors, including accuracy of the diagnosis, determination of the mode of inheritance for the individual family, and identification of a specific pathogenic variant in an affected relative by molecular genetic testing [210].

Sanger and next-generation sequencing — A landmark study published in 2011 clarified the genetic distribution of CMT subtypes [7]. This study examined 787 patients with a clinical diagnosis of CMT between 1997 and 2009, among whom specific pathogenic variants were identified in 67 percent. The most commonly identified CMT subtypes were CMT1A (PMP22 duplication), CMTX1 (GJB1 pathogenic variant), hereditary neuropathy with liability to pressure palsies (PMP22 deletion), CMT1B (MPZ pathogenic variant), and CMT2A (MFN2 pathogenic variant). Together, these five subtypes accounted for 92 percent of genetically defined CMT cases. All other CMT subtypes and associated pathogenic variants each accounted for <1 percent of genetically defined CMT.

The take-home point of this study from the Sanger sequencing era was that genetic testing in most cases should focus only on PMP22, MPZ, GJB1, and MFN2, since these four genes were responsible for the vast majority of CMT cases. This prioritization of genes to be tested has become somewhat less relevant since 2011, as next-generation sequencing (NGS) test panels have reduced the cost dramatically.

In the era before NGS panels became widely available, broad genetic test panels based on the older Sanger sequencing technology were prohibitively expensive and included a large number of genes that were each associated with <1 percent of cases [211]. With the advent of NGS, it is now only marginally more expensive to test 100 or more genes as it is to test a handful on one of these panels. However, both EMG and knowledge regarding the distribution of pathogenic variants remain important for the interpretation of genetic test results. The dreaded variant of unknown significance appears in NGS reports as often, if not more often, than in the old Sanger sequencing panels, and the ability to provide a clinical interpretation for such genetic test reports is a critical skill among physicians that is not adequately appreciated. The most common pathogenic variant of all, the PMP22 duplication, is not detected reliably by short-read NGS technology, and thus it is important to know exactly what types of pathogenic variants will be identified with any genetic test that is ordered.

Focused genetic testing — We have used an algorithmic strategy of focused genetic testing for CMT directed by age at onset, electrodiagnostic findings, and inheritance pattern [7]. Over time, this algorithm has become less relevant for the selection of diagnostic testing with the now widespread availability of next-generation sequencing panels that can be supplemented with deletion/duplication testing, but it still provides useful information with respect to the interpretation of genetic test results, especially when one or more variants of unknown significance are reported in a potentially causative gene.

The algorithm is as follows:

For patients with slow upper extremity (ulnar) motor nerve conduction velocities (>15 to ≤35 m/second) and a classic CMT phenotype (ie, walking before age 15 months), test first for the PMP22 duplication (CMT1A). If negative and if no male-to-male transmission in the pedigree, test next for GJB1 (CMTX1) followed by MPZ (CMT1B), or test only for MPZ if there is male-to-male transmission. If these are negative, test for single-nucleotide variants in LITAF/SIMPLE (CMT1C), PMP22 (CMT1E), and EGR2 (CMT1D). If these are all negative and if there is no affected parent or child, test for recessive forms of CMT.

For patients with very slow motor nerve conduction velocities (≤15 m/second) and delayed walking (age 15 months or later), test for both the PMP22 duplication (CMT1A) and MPZ pathogenic variants (CMT1B). For patients who walked before age 15 months, test first for the PMP22 duplication, followed by the MPZ pathogenic variant. If PMP22 duplication and MPZ pathogenic variant testing are negative, test next for PMP22 sequencing (CMT1E). If that is negative, proceed to testing for single-nucleotide variants in LITAF/SIMPLE (CMT1C), PMP22, and EGR2 (CMT1D). If these all negative and if there is no affected parent or child, test for recessive forms of CMT.

For patients who have intermediate slowing of motor nerve conduction velocities (>35 to ≤45 m/second) with a classic CMT phenotype of childhood onset and no male-to-male transmission, test for GJB1 (CMTX1) followed if negative by MPZ (CMT1B); if there is male-to-male transmission, test only for MPZ. If these are all negative and there is no affected parent or child, test for recessive forms of CMT.

For patients with intermediate slowing of motor nerve conduction velocities (>35 to ≤45 m/second) and adult-onset CMT, test first for MPZ pathogenic variants (CMT1B). If negative and no male-to-male transmission, test next for GJB1 (CMTX1); if there is male-to-male transmission and no affected parent or child, test for recessive forms of CMT.

For patients with either normal upper extremity motor nerve conduction velocities (>45 m/second) or unobtainable motor nerve conduction velocities and compound muscle action potentials who have symptom onset in infancy or severe symptoms in childhood, first test for MFN2 (CMT2A). For patients with a classic phenotype or adult onset and no male-to-male transmission, first test for GJB1 (CMTX1) followed if negative by MPZ (CMT1B); if there is male-to-male transmission, test only for MPZ. If testing for GJB1 and/or MPZ is negative, test next for MFN2. Regardless of age of onset or severity, testing for other forms of CMT2 may be appropriate if testing for CMT2A, CMTX1, and CMT1B is negative. For patients with pure motor upper limb greater than lower limb onset, test next for GARS (CMT2D); for other presentations, test for both NEFL (CMT2E) and GDAP1 (CMT2K). If these are all negative and there is no affected parent or child, test for recessive forms of axonal CMT.

Hereditary neuropathy with liability to pressure palsies (HNPP) is distinguished from other forms of CMT by a distinct phenotype that includes focal episodes of weakness or sensory loss (see 'Hereditary neuropathy with liability to pressure palsy' above). Electrophysiologic studies show a distinctive sensorimotor neuropathy pattern that can help to establish the diagnosis [28,212]. A generalized sensory neuropathy with slowed conduction velocity and prolongation of distal motor latencies occurs, the latter often including findings suggestive of carpal tunnel syndrome. Motor conduction velocity is slowed only mildly, and F-wave latencies are prolonged. These changes are indicative of disproportionate slowing of distal nerve conduction. A superimposed but independent entrapment neuropathy with focal slowing at sites of compression with acute weakness also occurs. When these features are present, test for PMP22 deletion and single-nucleotide variants.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of CMT includes a long list of other length-dependent neuropathies with hereditary etiologies as well as acquired peripheral neuropathies of various causes [47,207,210].

Hereditary conditions

Idiopathic pes cavus may cause some foot pain and gait difficulties and raises suspicion for CMT. However, this condition does not involve a detectable neuropathy. Electromyography (EMG) can help to differentiate the two possible diagnoses for a patient who presents with pes cavus but little or no other associated symptoms or signs of CMT. Genetic testing is not indicated if the EMG does not show the presence of a neuropathy [209].

Familial amyloid polyneuropathy (FAP) represents a group of common autosomal dominant multisystemic disorders associated with polyneuropathy. Unlike CMT, FAP usually presents in later life with progressive pain and sensory loss.

Friedreich ataxia is an autosomal recessive disorder. Almost all patients present with limb and gait ataxia. Deep tendon reflexes eventually are lost in most patients. Additional manifestations can include optic atrophy, dysphagia, dysarthria, motor weakness, distal loss of position and vibration sense, reduced visual acuity, hearing loss, bladder dysfunction, kyphoscoliosis, cardiomyopathy, and diabetes mellitus. Atypical phenotypes include those with late-onset disease, preserved reflexes, lower limb spasticity, and/or absence of cardiomyopathy. (See "Friedreich ataxia".)

Refsum disease is an autosomal recessive disorder caused by pathogenic variants in either the PHYH gene, which accounts for approximately 90 percent of cases, or the PEX7 gene. Symptom onset varies from infancy to middle age. Initial clinical features typically include deteriorating vision due to retinitis pigmentosa and anosmia. Sensorineural hearing loss, ataxia, peripheral polyneuropathy, ichthyosis, and cardiac conduction defects develop later. The neuropathy resembles demyelinating CMT due to the presence of pes cavus, progressive course, and demyelinating features [207]; nerve conduction studies often show a slowed conduction velocity. Cerebrospinal fluid analysis shows an elevated protein concentration without an increase in cells. (See "Peroxisomal disorders", section on 'Refsum disease'.)

Krabbe disease is a rare autosomal recessive disorder caused by the deficiency of galactocerebrosidase. Most patients with Krabbe disease present with symptoms within the first six months of life; approximately 10 percent present later in life, including adulthood. A peripheral motor sensory neuropathy occurs in all patients, but the early-onset forms are dominated by symptoms related to central nervous system dysfunction, including irritability, developmental delay or regression, limb spasticity, axial hypotonia, absent reflexes, optic atrophy, and microcephaly. Seizures and tonic extensor spasms eventually appear. (See "Krabbe disease".)

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disease caused by pathogenic variants in the arylsulfatase A (ARSA) gene. Peripheral neuropathy occurs in all forms and may be a presenting feature, particularly in the late infantile form. The late-infantile form of MLD presents from age 6 months to 2 years; early signs include regression of motor skills, gait difficulty, ataxia, hypotonia, extensor plantar responses, optic atrophy, and peripheral neuropathy. The juvenile form of MLD presents between 3 and 16 years of age with gait disturbance, intellectual impairment, ataxia, upper motor neuron signs, and a peripheral neuropathy. Seizures may occur. (See "Metachromatic leukodystrophy".)

Ataxia-ocular apraxia type 1 (AOA1) is an autosomal recessive disorder caused by pathogenic variants in the APTX gene. It is characterized by cerebellar ataxia, oculomotor apraxia, cerebellar atrophy, and a severe axonal sensorimotor neuropathy that can resemble CMT. Additional manifestations include hypoalbuminemia and elevation of serum total cholesterol. (See "Ataxia-telangiectasia", section on 'Differential diagnosis'.)

Adrenomyeloneuropathy (AMN) is a form of adrenoleukodystrophy, an X-linked disorder caused by pathogenic variants in the ABCD1 gene. AMN typically presents in adult males between 20 and 40 years of age. The primary manifestation is spinal cord dysfunction with progressive spastic paraparesis, abnormal sphincter control, and sexual dysfunction. Gonadal dysfunction may precede motor abnormalities. The majority have adrenal insufficiency. AMN may also present as a progressive cerebellar disorder. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Myeloneuropathy'.)

Distal hereditary motor neuropathies (dHMN) are a group of rare, genetically heterogeneous disorders characterized by slowly progressive distal motor weakness and length-dependent neuropathy [47]. They are distinguished from CMT by the absence of sensory involvement.

Biallelic pathogenic variants in SORD cause an inherited predominantly motor neuropathy [213]. Affected individuals have been classified as having a dHMN or CMT2, depending on the individual case.

Hereditary sensory and autonomic neuropathies (HSAN) occur much less frequently than CMT. The major feature of these conditions is loss of large myelinated and unmyelinated fibers. HSAN type I, the most common form, is characterized by degeneration of dorsal root ganglion and motor neurons, leading to distal sensory loss and later distal muscle wasting and weakness and variable neural deafness. Bone necrosis and spontaneous distal amputation can occur. Symptoms often begin in early childhood but may be delayed until the third decade. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN1'.)

Brown-Vialetto-van Laere disease is an autosomal recessive condition characterized by sensorineural deafness, cranial neuropathies including bulbar palsy, and signs of motor neuron disease. The associated gene is SLC52A3, previously known as C20ORF54, which encodes a riboflavin transporter [214]. Some affected individuals improve with riboflavin therapy.

A biotin-deficient autosomal recessive syndrome has been associated with biallelic variants in SLC5A6 [215]. Patients may present with failure to thrive, developmental delay, and seizures. However, the phenotype in patients with milder symptoms includes a motor neuropathy that may respond to therapy with biotin, pantothenic acid, and lipoic acid.

The distal muscular dystrophies are a heterogeneous group of rare genetic myopathies (table 2) characterized by weakness that starts distally in the arms and/or legs and gradually progresses to affect proximal muscles. Almost all forms of distal myopathy can present as early as the second decade, although the onset is usually between 40 and 60 years of age.

Several mitochondrial disorders are associated with peripheral neuropathy:

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a multisystem disorder characterized by progressive, severe gastrointestinal dysmotility and cachexia, ptosis, ophthalmoplegia or ophthalmoparesis, symmetric polyneuropathy, and asymptomatic leukoencephalopathy. The age of onset, the order of symptom presentation, and the rate of disease progression are highly variable.

Neuropathy, ataxia, and retinitis pigmentosa (NARP) is characterized by a variable combination of developmental delay, sensory polyneuropathy, ataxia, pigmentary retinopathy, muscle weakness, epilepsy, and dementia. Late childhood or adult onset is most common.

Acquired conditions — Acquired peripheral neuropathy may be idiopathic or caused by systemic diseases (eg, diabetes mellitus, chronic HIV infection, hypothyroidism, vitamin deficiencies, neurosyphilis, and neuroborreliosis), inflammatory and immune-mediated mechanisms (eg, chronic inflammatory demyelinating polyneuropathy [CIDP], vasculitis, and occult neoplasm), and toxins (eg, alcohol, chemotherapy, and heavy metals).

Of these, the most important to recognize in the differential diagnosis of CMT are the immune-mediated neuropathies, particularly CIDP [207]. CIDP is a disorder of peripheral nerves and nerve roots with a number of variants. Both the cellular and humoral components of the immune system appear to be involved in the pathogenesis of CIDP and its variants. The classic form of CIDP is fairly symmetric and motor involvement is greater than sensory. Weakness is present in both proximal and distal muscles. Most patients have globally diminished or absent reflexes. The course may be progressive or relapsing-remitting. In some cases, CIDP may mimic CMT [207]. Nerve conduction studies in CIDP typically show nonuniform, nonhomogeneous slowing with partial or complete conduction blocks. This finding can help differentiate CIDP from CMT, since nerve conduction slowing in the demyelinating forms of CMT is typically diffuse and homogeneous. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis".)

MANAGEMENT — Management of CMT is currently supportive; however, such supportive therapy can dramatically improve a patient's quality of life. Specific disease-modifying therapy is not available. This is reviewed separately. (See "Charcot-Marie-Tooth disease: Management and prognosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Charcot-Marie-Tooth disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definition and shared features – Charcot-Marie-Tooth (CMT) disease is a spectrum of inherited disorders caused by pathogenic variants in genes that are expressed in peripheral nerve myelin and/or axons. Common features include both motor and sensory nerve manifestations with distal leg weakness, foot deformities (pes cavus, hammer toes), and sensory deficits (table 1). (See 'Overview' above.)

Evaluation and diagnosis – A comprehensive history and physical examination remain the core for diagnosis and evaluation of CMT. Genetic testing is key to confirming the diagnosis after electrodiagnostic testing. (See 'Evaluation and diagnosis' above and 'When to suspect CMT' above.)

Differential diagnosis – The differential diagnosis of CMT includes several length-dependent neuropathies with hereditary etiologies as well as acquired peripheral neuropathies of various causes. (See 'Differential diagnosis' above.)

Specific CMT disorders

CMT1 – CMT1 is a demyelinating disorder characterized by calf muscle atrophy, pes cavus foot deformity, hammer toes, and loss of reflexes. Affected patients typically present in the first or early second decade, but infants may be symptomatic. Sensory loss is gradual and mainly involves proprioception and vibration. Later changes include atrophy of the intrinsic hand and foot muscles. Palpable enlargement of the peripheral nerves may occur. Sural nerve biopsy shows "onion bulb" demyelination that affects primarily the large nerve fibers. (See 'CMT1' above.)

The most common type of CMT1, CMT1A, is most frequently caused by a duplication of the PMP22 gene. Hereditary neuropathy with liability to pressure palsy (HNPP), a recurrent, episodic demyelinating neuropathy, is an autosomal dominant disorder associated with PMP22 deletions and single-nucleotide variants that is allelic to CMT1A. CMT1B is most often caused by single-nucleotide variants in the myelin protein zero (MPZ) gene. (See 'Genetics of CMT1' above.)

CMT2 – CMT2, also called axonal CMT, is characterized by predominating sensory loss along with distal weakness, atrophy, decreased deep tendon reflexes, and variable foot deformity. The onset of symptoms usually is in the second or third decade of life. The genetic basis of CMT2 is heterogeneous, though MFN2 pathogenic variants appear to be the most common cause. (See 'CMT2' above.)

CMTX1 – CMTX1 is an X-linked dominant demyelinating and axonal disorder, characterized by gait impairment and foot deformities. Children and young adults with CMTX1 can experience transient stroke-like episodes. It is caused by pathogenic variants in the GJB1 or connexin 32 gene. (See 'X-linked CMT' above.)

CMT3 – Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy, classified as CMT3, are severe, early-onset peripheral neuropathies that present in infancy with hypotonia. They are caused by several genetic variants including PMP22, MPZ, and EGR2 genes that lead to thin, poorly formed myelin. (See 'CMT3' above.)

CMT4 – CMT4 is a heterogeneous group of rare autosomal recessive demyelinating motor sensory neuropathies. Individuals with CMT4 have a typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and foot deformities (eg, pes cavus). (See 'CMT4' above.)

Intermediate CMT – Intermediate CMT is an uncommon variant characterized by both axonal and demyelinating clinical and histologic features that are "intermediate" between CMT1 (primarily demyelinating) and CMT2 (primarily axonal). (See 'Intermediate CMT' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert P Cruse, DO, who contributed to earlier versions of this topic review.

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Topic 6220 Version 36.0

References

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