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

INTRODUCTION — Charcot-Marie-Tooth (CMT) disease is a group of hereditary peripheral neuropathies characterized by progressive motor and sensory nerve dysfunction, including a characteristic atrophy of calf muscles in several subtypes. CMT is the most common hereditary peripheral neuropathy. It is caused by one of several pathogenic variants in genes whose protein products are expressed in myelin, gap junctions, and/or axonal structures within peripheral nerves.

The genetics, clinical features, and diagnosis of CMT will be reviewed here. CMT management and prognosis are discussed separately. (See "Charcot-Marie-Tooth disease: Management and prognosis".)

Other hereditary peripheral neuropathies and neuropathies associated with hereditary disorders are discussed separately.

●(See "Overview of hereditary neuropathies".)

●(See "Hereditary sensory and autonomic neuropathies".)

●(See "Neuropathies associated with hereditary disorders".)

PATHOGENESIS — CMT is caused by pathogenic variants in various genes implicated in the production or maintenance of proteins that contribute to the structure or function of peripheral nerves or myelin [1]. These variants lead to abnormalities in peripheral nerves or myelin, such as thin or misfolded myelin sheaths, alternating segments of demyelination and hypertrophic remyelination ("onion bulb" formation), or axonal loss [2]. The association of different pathogenic variants in the same gene with various clinical phenotypes suggests that CMT represents a spectrum of related phenotypes caused by underlying defects in peripheral nervous system myelination and axonal function. However, environmental and other factors may contribute to the neuropathogenesis of CMT, as abnormal protein levels may not always correlate with the severity of neuropathy, and clinical variability has been observed between patients with CMT in the same family [3-5].

Dysfunction in these nerve proteins can lead to axonal degeneration and peripheral nerve demyelination in any region of the body but typically appear first and most prominently in the largest and longest peripheral nerves that control motor and sensory function of the distal legs and hands [6]. Neuropathy in CMT is a progressive condition with symptoms that spread proximally, becoming more generalized over time [6]. In addition, chronic neuropathy leads to muscle atrophy and secondary skeletal deformities of the feet, ankles, vertebrae, and other joints.

CLASSIFICATION — CMT is divided into specific types labeled as CMT types 1 through 4, as well as an X-linked category (CMTX) based on a combination of clinical features, modes of inheritance, and patterns of nerve dysfunction (table 1). Within each category, a specific subtype associated with a particular gene is assigned a letter (eg, CMT1A, CMT1B) (table 2). The number of CMT subtypes continues to increase as new pathologic variants are discovered.

CMT-associated pathogenic variants may be inherited in an autosomal dominant, recessive, or X-linked manner. More than 100 pathogenic variants have been associated with CMT, including whole-gene duplications and deletions, as well as single nucleotide variants [7,8]. Duplication of the PMP22 gene causes CMT1A, the most common subtype (approximately 40 percent overall), and the vast majority of cases are attributed to pathogenic variants in just four genes:

●Peripheral myelin protein 22 (PMP22)

●Myelin protein zero (MPZ)

●Gap junction protein beta 1 (GJB1)

●Mitochondrial fusion protein mitofusin 2 (MFN2)

This genetic distribution identifying common variants in CMT was first described in a large cohort of 1024 CMT patients from the United States [9] and confirmed in a subsequent cohort of 1005 patients from Japan [10].

CMT1 — CMT1 is caused by pathologic variants in genes that are expressed in Schwann cells, the myelinating cells of the peripheral nervous system [8]. The most common types exhibit autosomal dominant inheritance and have been subdivided into types 1A, 1B, 1C, etc. However, autosomal recessive forms also occur [11].

CMT1 accounts for more than 50 percent of CMT cases [2].

●CMT1A – CMT1A is associated with a 1.5 Mb duplication in the PMP22 gene on chromosome 17p11.2-p1, leading to overexpression of PMP22 [7,12,13]. Patients with CMT1A typically present with characteristic clinical features of CMT, including distal weakness with atrophy and numbness. (See 'Clinical features' below.)

CMT1A accounts for approximately 70 to 80 percent of CMT1 cases [14,15].

●Hereditary neuropathy with liability to pressure palsy – Hereditary neuropathy with liability to pressure palsy (HNPP; tomaculous neuropathy) is an autosomal dominant recurrent demyelinating neuropathy genetically related to CMT, as it is associated with PMP22 deletions and single nucleotide variants allelic to CMT1A. 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 [16-19]. 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 [16,19-21].

The clinical presentation of HNPP is distinct from typical initial CMT features. Affected patients with HNPP typically present with isolated acute nerve palsies in areas frequently affected by compression or mild trauma. 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.

HNPP is discussed in greater detail separately. (See "Overview of hereditary neuropathies", section on 'Hereditary neuropathy with liability to pressure palsy'.)

●CMT1B – CMT1B, originally known as peroneal muscular atrophy, is most often caused by single nucleotide variants in the MPZ gene on chromosome 1q22, which cause overexpression of the protein product myelin protein zero, the major myelin structural protein [22,23]. CMT1B accounts for up to 5 percent of CMT1 cases [24].

Myelin protein zero is normally expressed on the cell membrane of Schwann cells and plays a major role in myelin membrane adhesion [25,26]. In one family with CMT1B, in vitro fluorescence analysis demonstrated that aberrant myelin protein zero localized in the endoplasmic reticulum and Golgi apparatus rather than on the cell membrane [27]. In addition, the adhesiveness of cells expressing variant protein was diminished compared with controls.

Normal peripheral nerve myelination depends upon strict dose of MPZ, and overexpression may be deleterious [28,29]. Transgenic mice containing extra copies of the MPZ gene manifest a dose-dependent, dysmyelinating neuropathy [28]. In six individuals with CMT1 from one family, comparative genome hybridization analysis revealed an increased gene dose, estimated to be five copies, of the entire MPZ gene and flanking genes [30]. Pathogenic variants of MPZ gene introns that disrupt normal protein splicing have also been identified in a small number of families with CMT1B [31].

●Additional CMT1 subtypes

•CMT1C is caused by pathogenic variants in the LITAF gene, also known as SIMPLE, which is located at chromosome 16p.13.1-p12.3 [32,33]. LITAF is widely expressed and encodes lipopolysaccharide-induced tumor necrosis factor-alpha factor, 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.

•CMT1D is caused by pathogenic variants in the EGR2 gene on chromosome 10q21.1-q22.1 that encodes the early growth response 2 protein [34].

•CMT1E is caused by single nucleotide variants in the PMP22 gene that alter the cellular distribution of the protein [13,35,36]. Patients with these single nucleotide variants in PMP22 usually have more prominent clinical manifestations than those with CMT1A who have duplications in that gene. In patients with CMT1E, PMP22 partially accumulates in the Schwann cells rather than being inserted in the myelin sheath [13].

•CMT1F is caused by pathogenic variants in the NEFL gene on chromosome 8p21, which encodes neurofilament light protein [37]. Other pathogenic variants in the same gene can also cause an axonal form classified as CMT2E. (See 'CMT2' below.)

•CMT1G is caused by a variant in PMP2, which encodes the peripheral myelin protein 2 [38].

•CMT1H is due to pathogenic variants in FBLN5 that cause dysfunction in the fibulin 5 protein and presents with late-onset sensory-predominating symptoms [39].

•CMT1I refers to the subtype caused by pathogenic variants in POLR3B, which encodes polymerase 3, ribonucleic acid subunit B [40]. Patients may present with ataxia and spasticity, along with a sensory-motor polyneuropathy [41].

•The Roussy-Lévy syndrome, first described in 1926, has a CMT1 phenotype with manifestations that include postural tremor, gait ataxia, distal muscle atrophy, pes cavus, areflexia, and mild distal sensory loss [42,43]. Genetic testing of members of the original family identified a heterozygous missense variant for the extracellular domain of the MPZ gene, indicating that this condition is a variant of CMT1B disease [42]. However, Roussy-Lévy syndrome may be a phenotypic variant of several CMT types. 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 [43].

CMT2 — CMT2 is characterized by primarily axonal damage to nerves and accounts for 12 to 36 percent of all CMT cases [44]. Autosomal dominant pathogenic variants are responsible for most cases of CMT2, though autosomal recessive inheritance can also occur [45-47].

There are many different subtypes of CMT2, but the genetic basis of CMT2 is incompletely described. A 2012 retrospective study of 115 patients with CMT2 found that pathogenic variants were identified in only 25 percent [24].

●CMT2A – CMT2A is the most common CMT2 phenotype, accounting for up to 20 percent of axonal CMT cases and approximately 5 percent among all CMT subtypes [48]. CMT2A is most commonly caused by pathogenic variants in MFN2 [49-53]. The inheritance mode is autosomal dominant in most cases. However, some MFN2 pathogenic variants have been reported to cause a form of early-onset CMT with apparent autosomal recessive inheritance [54,55].

One report also identified a pathogenic variant in the KIF1B gene in a single Japanese family [56], but this genetic association has not been confirmed and may represent a benign rare polymorphism [57].

●Additional CMT2 subtypes – Several other CMT2 subtypes that also feature an axonal neuropathy and their associated genes have also been identified. These subtypes are rare and can be difficult to diagnose because some features overlap with other subtypes [48]:

•CMT2B is characterized by predominant sensory involvement; it maps to chromosome 3q21.3 and is associated with pathogenic variants in RAB7, which encodes RAS-associated protein 7 [58,59].

•CMT2C is characterized by distal muscle weakness, vocal cord paralysis, mild sensory impairment, and axonal neuropathy [60,61]. It maps to chromosome 12q24.1 and is associated with pathogenic variants in TRPV4, which encodes transient receptor potential cation channel subfamily V member 4 [62,63].

•CMT2D is characterized by predominant hand weakness and atrophy with a locus on chromosome 7p15 [64]. Associated pathogenic variants have been identified in the GARS gene, which encodes glycyl tRNA synthetase [65].

•CMT2E is caused by pathogenic variants in the NEFL gene linked to chromosome 8p [66-68]. 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 [69]. 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 of progressive motor and sensory loss. CMF2F is associated with missense variants in the HSPB1 gene on chromosome 7q11.23, which encodes heat shock 27kDa protein family B member 1 [70,71].

•CMT2I is a clinically distinct late-onset CMT associated with pathogenic variants in the MPZ gene and, in contrast to the allelic CMT1B, is characterized by axonal polyneuropathy with prominent sensory involvement, along with pupillary abnormalities and hearing loss [72-76].

•CMT2K is a form of axonal CMT with autosomal dominant or recessive inheritance caused by pathogenic variants in the GDAP1 gene, which encodes ganglioside-induced differentiation-associated protein 1 [77-79]. Pathogenic variants in GDAP1 have also been identified in patients with CMT4A, a demyelinating form. (See 'CMT4' below.)

•CMT2L is associated with pathogenic variants in the HSPB8 gene on chromosome 12q24.23, which encodes heat shock protein 8 [80,81].

•CMT2M is caused by pathogenic variants in DNM2, which encodes dynamin 2 [82,83]. DNM2 has also been associated with an autosomal dominant form of intermediate CMT, known as CMTDIB [84,85]. (See 'Intermediate CMT' below.)

•CMT2N is due to a pathologic variant in AARS1, which maps to chromosome 16q22.1 and encodes alanyl-tRNA synthetase 1 [86].

•CMT2P was originally designated CMT2G and mapped to chromosome 12q12-q13 [87]; the disease locus was later reassigned to 9q33.3-q34.1, and the cause was related to pathogenic variants in the LRSAM1 gene, which encodes leucine-rich repeat and sterile alpha motif-containing 1 [88].

•CMT2S is caused by truncating and missense variants in the IGHMBP2 gene, encoding immunoglobulin mu deoxyribonucleic acid binding protein 2. CMT2S is characterized by slowly progressive weakness, muscle atrophy, and sensory loss [89,90].

•CMT2T is caused by pathogenic variants in the MME gene encoding membrane metalloendopeptidase, identified in 10 unrelated patients from Japan with late-onset autosomal recessive CMT2 [91]. The late-onset axonal phenotype for biallelic pathogenic variants was confirmed in a cohort from Spain [92].

•CMT2U is associated with autosomal dominant pathogenic variants in MARS1, which encodes methionyl-tRNA synthetase [93,94]. The phenotype reported to date is characterized by a late onset axonal polyneuropathy.

•CMT2V is associated with autosomal dominant pathogenic variants in NAGLU, which encodes alpha-N-acetylglucosaminidase [95].

•CMT2W is associated with autosomal dominant pathogenic variants in HARS1, which encodes histidyl-tRNA synthetase 1 [96,97].

•CMT2X is associated with autosomal recessive pathogenic variants in SPG11, which encodes spatacsin [98]. Onset of symptoms has been reported to range from childhood to early adulthood, with axonal polyneuropathy, foot deformities, and sometimes fasciculations. This gene has also been associated with hereditary spastic paraplegia. (See "Hereditary spastic paraplegia", section on 'Autosomal recessive HSP'.)

•CMT2Y is associated with autosomal dominant pathogenic variants in VCP, which encodes valosin-containing protein [99,100]. The phenotype includes distal weakness, sensory loss, and muscle atrophy. This disease is allelic with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia.

•CMT2Z is associated with autosomal dominant pathogenic variants in MORC2, which encodes a microrchidia (MORC) family CW-type zinc finger 2 protein [101,102]. Variants in MORC2 have also been associated with a distinct syndrome characterized by axonal neuropathy along with developmental delay, impaired growth, and dysmorphic facies, clinically similar to Cockayne syndrome [103,104]. (See "Neuropathies associated with hereditary disorders", section on 'Cockayne syndrome'.)

•CMT2DD is caused by dominant pathogenic variants in ATP2A1, which encodes ATP transporting subunit alpha 1. CMT2DD is associated with dysfunction of the sodium-potassium pump, leading to distal extremity weakness with preserved proximal strength, vibratory sensory loss, and axonal loss on electrophysiologic studies [105].

CMTX — There are X-linked dominant and X-linked recessive forms of CMT involving different loci [47]. 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 subtype of CMT after CMT1A, accounting for 7 to 12 percent of all CMT cases [6,15,47,106]. CMTX1 accounts for approximately 50 percent of X-linked cases [107].

CMTX1 is caused by pathogenic variants in the GJB1 gene, also known as the connexin 32 gene, on chromosome Xq13.1 [108-111]. The gene is expressed in myelinating Schwann cells but not incorporated into the myelin sheath [112]. Most GJB1 pathogenic variants are thought to cause disability by a loss of function of the gap junction protein connexin 32 [113].

●Additional CMTX subtypes

•CMTX2 is the X-linked recessive form that maps to chromosome Xp22 [114,115]. 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. The causative gene has not been identified [116].

•CMTX3 is an X-linked recessive subtype and is caused by a 78 kb insertion at chromosome Xq27.1 that originates from chromosome 8 [107,114,115,117]. 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 [114,115]. In a third family, disease severity was variable between affected males, with widely ranging nerve conduction velocities [107]. 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. 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 [118].

•CMTX4 (also called Cowchock syndrome or CMT with deafness and intellectual disability) is a rare form of infantile-onset, axonal X-linked CMT [119]. 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 AIFM1 gene on chromosome Xq26, encoding apoptosis inducing factor mitochondria-associated 1 [120].

•CMTX5 is an X-linked recessive disorder with deafness and optic neuropathy that has been reported in a Korean family [121]; the disease is caused by pathogenic variants in the PRPS1 gene, encoding phosphoribosyl pyrophosphate synthetase 1 [122].

•CMTX6 is an X-linked dominant disorder described in a family from Australia and characterized by an axonal-predominant motor and sensory neuropathy with childhood onset and gradual disease progression in affected males [123]. Carrier females were either mildly symptomatic or asymptomatic. The cause is pathogenic variants in the PDK3 gene, encoding pyruvate dehydrogenase kinase 3.

CMT3 — CMT3 includes uncommon, 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. Two disorders have been classified as CMT3:

●Dejerine-Sottas syndrome

●Congenital hypomyelinating neuropathy

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 – Autosomal recessive and several dominant heterozygous forms of Dejerine-Sottas syndrome have been described, affecting genes that are also involved in several subtypes of CMT1 and CMT4. They include pathogenic variants in the PMP22 gene (also found in CMT1A) [29,111,124,125], the MPZ gene (also found in CMT1B) [29,111], and the EGR2 gene (as also occurs in CMT1C) [126,127]. In one series of nine patients, for example, four novel single-nucleotide variants occurred in PMP22 (as also found in CMT1E) and two in MPZ (as found in CMT1B); two cases were autosomal dominant [29]. Recessive inheritance involving the PRX gene (the cause of CMT4F) was described in three unrelated patients with Dejerine-Sottas neuropathy [128].

●Congenital hypomyelinating neuropathy – Congenital hypomyelinating neuropathy is genetically heterogeneous. Most cases are thought to be caused by pathogenic variants in either PMP22 or MPZ [129-132]. Other pathogenic variants have been described in EGR2 [34] and MTMR2 [133]. Genetic transmission in most cases is autosomal dominant, but rare autosomal recessive cases have been reported.

CMT4 — CMT4 is an uncommon but rapidly expanding heterogeneous group of autosomal recessive demyelinating motor sensory neuropathies. Compared with many autosomal dominant subtypes, these autosomal recessive forms of CMT are rare, clinically more severe, and less likely to result from pathogenic variants in structural myelin proteins.

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 [134]. 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 [135,136]. GDAP1 appears to be predominately expressed in neurons but not in Schwann cells and localized in mitochondrial membranes [137]. This finding suggests that mitochondrial abnormalities may cause CMT4A [137]. 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 [138,139].

●CMT4B is divided into several subtypes:

•CMT4B1 was first described in a consanguineous Italian family [140,141]. 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 [142]. Histologic features included loss of myelin fibers, segmental demyelination and remyelination, and numerous onion bulbs; focally folded myelin sheaths were present in peripheral nerves. The associated MTMR2 gene is on chromosome 11q22-23, which encodes myotubularin related protein 2 [143].

•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 [144]. The associated SBF2 gene encodes SET binding factor 2 and is on chromosome 11p15 [145,146]. The age of onset ranged from 4 to 13 years old [145-149]. Distal weakness was prominent on presentation, with proximal weakness developing only after several years. An Italian family has also been reported with CMT4B2 [150,151].

•CMT4B3, described in a Korean family, has a similar though less severe phenotype compared with CMT4B1 and CMT4B2 [152]. It is caused by compound heterozygous pathogenic variants in the SBF1 gene on chromosome 22q13.33. The SBF1 gene encoding SET binding factor 1 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 [153-155] and was later reported in various ethnic backgrounds, including European, African American, Native American, Chinese, Indian, Japanese, Korean, and Norwegian populations [156-161]. Loss of myelinated fibers and some classic onion bulbs are present on nerve pathology. 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, encoding SH3 domain and tetratricopeptide repeats 2 [162,163].

●CMT4D is also known as hereditary motor and sensory neuropathy-Lom and is one of the more common autosomal recessive forms. It occurs in divergent Romany groups descended from a small founder population [164]. CMT4D is an early-onset neuropathy that presents with muscle weakness and wasting, skeletal deformities, and sensory loss. Onion bulbs are present in peripheral nerves. The founder pathogenic variant involves the NDRG1 gene on chromosome 8q24.3 [165]. 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 EGR2 on chromosome 10q21-22 [34]. 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 [166]. Onset is in early childhood, with distal muscle weakness and severe sensory loss. Nerve conduction studies (NCS) 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 associated PRX gene encodes periaxin, a protein of myelinating Schwann cells [128,166].

●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 [167,168]. Accompanying manifestations include distal sensory loss with areflexia and pes cavus. The disorder is caused by pathogenic variants in the HK1 gene, encoding hexokinase 1 [169].

●CMT4H was described in Lebanese and Algerian families as a severe form of CMT with onset in the first two years of life [170]. Major features include unsteady gait, loss of reflexes, scoliosis, and severe demyelinating neuropathy [170]. It is caused by pathogenic variants in the FGD4 gene on chromosome 12p11.2, encoding an F-actin binding protein (frabin) [171,172].

●CMT4J was first identified in four unrelated patients as a severe form of childhood-onset CMT [173]. 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 [174]. Neurophysiologic testing showed severe and widespread denervation, while nerve pathology from one sibling revealed severe loss of myelinated nerve fibers [174]. In these families, CMT4J was caused by pathogenic variants in the FIG4 gene on chromosome 6q21, encoding factor-induced gene 4 protein [173].

●CMT4K is associated with pathogenic variants in SURF1, which encodes surfeit 1 [175]. Additional features such as lactic acidosis, brain magnetic resonance imaging (MRI) 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, a gene that encodes minichromosome maintenance protein 3. 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 [176].

Intermediate CMT — Intermediate CMT is an uncommon form of CMT characterized by mixed axonal-demyelinating physiology. Several X-linked forms of CMT are well-known to have these mixed features. This intermediate group is further distinguished from CMT1 by the absence of clinically observed nerve hypertrophy [177]. NCS generally reveal median nerve motor conduction velocities of 25 to 45 m/second, although values may vary between different laboratories.

Genes unique to intermediate CMT are categorized by autosomal dominant or recessive inheritance (eg, CMTDI or CMTRI).

Autosomal dominant forms of intermediate CMT include:

●CMTDIA has been linked to a locus on chromosome 10q24.1-q25.1, but the causative gene has yet to be identified [178].

●CMTDIB due to variants in the DNM2 gene [179]

●CMTDIC due to variants in the YARS1 gene [180,181]

●CMTDID due to variants in the MPZ gene [182]

●CMTDIE due to variants in the INF2 gene [183]

●CMTDIF due to variants in the GNB4 gene [184]

●CMTDIG due to variants in the NEFL gene [185,186]

Autosomal recessive forms of intermediate CMT include:

●CMTRIA due to variants in the GDAP1 gene [187]

●CMTRIB due to variants in the KARS gene [188]

●CMTRIC due to variants in the PLEKHG5 gene [189,190]

●CMTRID due to variants in the COX5A1 gene [191]

There has been controversy among experts regarding the existence and classification of this form of CMT, especially for the autosomal subtypes [192,193]. Whenever possible, these entities are grouped in with the more traditional categories of CMT described above.

EPIDEMIOLOGY — The overall estimated prevalence of CMT is 40 per 100,000 [194], which varies from 10 to 82 per 100,000 in different reports [44]. There is no known ethnic predisposition [195]. CMT types 1 and 2 represent by far the largest proportion of patients, as documented in several studies, including ones from Russia [14] and France [196].

CLINICAL FEATURES — CMT is clinically heterogeneous; the age of onset, severity, specific features of neuropathy, and associated features vary by specific subtype. A distal-predominant motor and sensory neuropathy is a core feature across CMT types and subtypes.

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 in most CMT subtypes. Later in the course, foot deformities such as hammertoes ensue, along with hand weakness and atrophy.

Progressive weakness and numbness — Limb weakness and numbness or paresthesias are key features of the motor and sensory neuropathy of CMT disease.

●Classic phenotype – The characteristic neuropathic features associated with CMT1 (the most common type) include:

•Symptoms – History of distal lower extremity weakness with gait impairment. Walking is clumsy because of both muscle weakness and sensory loss. Patients may report a history of frequent sprained ankles or difficulty running and keeping up with peers. Ambulation may be significantly affected, but complete loss of ambulation is uncommon.

Disease exacerbation can occur in pregnancy, an effect that may be mediated by increased plasma progesterone [197]. In addition, individuals with CMT are susceptible to dramatic worsening of neuropathic symptoms in response to certain neurotoxic chemotherapeutic agents, such as vincristine. In some cases, such patients were previously undiagnosed with CMT [198].

•Signs – Examination may reveal bilateral weakness of the muscles of the foot, lower leg, and hand along with areflexia. Sensory loss progresses gradually and may be detected on physical examination via loss of proprioception and vibration. Palpable enlargement of the peripheral nerves may occur secondary to nerve hypertrophy. The clinical course is progressive over years, but some patients with severe or early-presenting subtypes may have a faster progression.

●Spectrum of phenotypic features – There can be considerable overlap between the characteristic motor and sensory neuropathic features of CMT1 with the neuropathic features of other several types of CMT disease. However, distinct clinical features may be used to help identify some subtypes (table 1):

•CMT2 – The clinical manifestations of CMT2 include distal weakness, atrophy, sensory loss, decreased deep tendon reflexes, and variable foot deformity [49]. The clinical course is similar to that of CMT1, but sensory symptoms, with loss of vibration and proprioception, may be more prominent. Unlike patients with CMT1, peripheral nerves are not palpably enlarged in those with CMT2.

An early-onset form of CMT2 becomes clinically apparent before the child reaches five years of age. Weakness progresses rapidly, with dramatic 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.

•CMTX1 – The symptoms of CMTX1 are more severe and begin earlier in males [199], who generally present in infancy or later in childhood with gait problems (eg, toe walking, flat footed walking, falls, difficulty running) [200]. However, patients have been reported to 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 [48]. (See "Immune-mediated neuropathies".)

•CMT3

-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, and ataxia. Scoliosis appears early and progresses with time, and contractures develop. Progression is slow, often with ambulation maintained through adult life [201].

-Congenital hypomyelinating neuropathy – Congenital hypomyelinating neuropathy presents at birth with profound hypotonia and contractures. Feeding difficulties and respiratory distress often lead to death in infancy [202]. However, several cases that exhibited spontaneous improvement in motor function with increasing age have been reported [129,203,204]; one patient completely recovered by four months [203].

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 [205].

•CMT4 – Individuals with CMT4 have a typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and foot deformities (ie, pes cavus) but may present earlier, in the first decade of life [206]. Some patients with CMT4 subtypes may also present with multiple cranial neuropathies [207].

CMT4B1 presents with frequent motor milestones delay, wheelchair use, and respiratory involvement [144].

Muscle atrophy and bony features — Distal lower extremity motor neuropathy that produces initial weakness eventually leads to calf muscle atrophy, causing the classic "stork leg deformity", which tends to become more prominent with disease progression.

Other lower extremity physical findings may include pes cavus (elevated longitudinal medial plantar arch), hammer toes (flexion deformity at the proximal interphalangeal joint), atrophy of the intrinsic foot muscles, and trophic ulcerations of the feet [6].

Late changes include atrophy of the intrinsic hand muscles and kyphosis or scoliosis.

Other neurologic features — In addition to the typical motor and sensory neuropathy and associated musculoskeletal and orthopedic abnormalities associated with the classic phenotype of CMT, patients with some subtypes may present with additional neurologic features related to CMT disease.

●Tremor – Postural tremor may be a feature of patients with several forms of CMT, including CMT1, CMT3, and CMTX [208-210].

●Sensorineural deafness – Sensorineural hearing loss has been reported in patients with CMT2, CMTX, and CMT4 [211-213].

●Glaucoma – Early-onset glaucoma was a feature in some families with CMT4B2 [146,148,149].

●Obstructive sleep apnea – Patients with CMT1A may have associated sleep apnea [214,215]. 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 [214].

●Transient neurologic episodes – 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 [216-219]. At presentation with these stroke-like episodes, brain MRI typically shows reversible lesions on diffusion-weighted, T2, and fluid-attenuated inversion recovery 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 or multiple sclerosis [220]. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Neuroimaging' and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis".)

Age of onset — The age of onset of CMT symptoms varies by subtype and across individuals.

Neuropathic symptoms frequently develop in childhood (first or second decade) for patients with CMT1 [221]. Onset in teen years or young adulthood is common among those with CMT2. Possible late-onset forms of CMT2 presenting from 35 to 85 years of age (median age 57) have been described in six families [222]. However, many patients with symptom onset during youth or young adulthood who have an indolent course may not present for evaluation until progressive symptoms become disabling or associated with muscle atrophy or bony changes (eg, hammer toes) during midlife.

Severe forms of CMT may be apparent in infancy, such as Dejerine-Sottas syndrome (CMT3), some subtypes of CMTX, and autosomal recessive forms of CMT4.

EVALUATION AND DIAGNOSIS — The diagnosis of CMT should be suspected in adults and children with symptoms of a progressive, distal-predominating, motor and sensory polyneuropathy. A family history of CMT increases the likelihood of a CMT diagnosis. Even in the absence of a clear family history of neuropathy, specific features increase suspicion for an inherited neuropathy like CMT including [48]:

●Slowly progressive symptoms

●Foot deformities (eg, pes cavus and hammertoes)

●Lack of positive sensory symptoms despite clear sensory involvement

The diagnostic evaluation of CMT includes a thorough medical and family history, complete neurologic examination, electrodiagnostic testing (EDX), and confirmatory genetic testing (algorithm 1).

●For most patients, we start with EDX to establish the presence of a polyneuropathy and categorize its type (demyelinating, axonal, or mixed) and severity, which can guide subsequent genetic test selection. EDX is followed by confirmatory genetic testing to identify the causative pathogenic variant(s).

●For selected patients with an established family history of confirmed CMT, we start with genetic testing for the known pathologic variant. If these results are negative, we then perform EDX testing and more comprehensive genetic testing.

Other testing such as nerve biopsy, nerve ultrasound, or nerve MRI may also be warranted for selected patients for additional diagnostic characterization, such as when clinical and electrodiagnostic findings are atypical or when genetic testing results are nonconfirmatory.

Comprehensive clinical evaluation — The evaluation of a patient with suspected CMT starts with a comprehensive history and physical examination that aims firstly to identify features of a motor and sensory neuropathy that are consistent with CMT and secondly to help identify distinct features associated with specific CMT subtypes (see 'Clinical features' above). This includes:

●The nature of symptoms (weakness versus numbness)

●The rate of progression of symptoms

●Family history of CMT (or suspected CMT if family members are undiagnosed)

Examination includes a complete neurologic examination as well as a general examination to identify musculoskeletal features (eg, calf atrophy, pes cavus) and other features associated with CMT subtypes (eg, tremor, hearing loss). (See 'Muscle atrophy and bony features' above and 'Other neurologic features' above.)

Electrodiagnostic studies — For most patients with no known family history of CMT, EDX is performed 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 EDX will help guide the interpretation of subsequent genetic testing. For selected patients with an affected family member who already has a known CMT pathogenic variant, immediate genetic testing for that variant (rather than EDX) may be warranted.

EDX typically involves two components, nerve conduction studies (NCS) and electromyography (EMG); EMG is also referred to as the needle examination. The NCS portion of the test can detect signs of demyelination (eg, slow conduction velocities, prolonged distal latencies, prolonged F response latencies, conduction block, and/or temporal dispersion) and axonal loss (eg, low amplitude nerve potentials). However, abnormal NCS findings may be found in many forms of neuromuscular disease and must be correlated with neurogenic abnormalities on the EMG to confirm the presence of an axonal neuropathy.

When performed by trained and experienced neurophysiologists, EDX can confirm or disprove the presence of a polyneuropathy compatible with the diagnosis of CMT and help guide further testing by determining the likely physiology of the neuropathy (eg, demyelinating or axonal). In some cases, EDX testing shows features of both demyelination and axonal loss, which is present in some subtypes of CMT. In others, testing may be normal, indicating that CMT is not present, or may show findings suggestive of a different condition, such as a myopathy or disorder of the neuromuscular junction.

Specific EDX findings associated with CMT types include:

●CMT1 – NCS show severe slowing of conduction velocity in both the motor and sensory nerves, typically with values approximately half of the lower limit of normal. The pattern of slowing is generally uniform (although some subtypes have been associated with nonuniform slowing), 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 [223]. EMG is typically normal. Frequently, little correlation exists between the electromyographic and clinical findings, as the latter are probably produced primarily by secondary axonal dysfunction [8,224,225].

There appear to be three distinctive EDX patterns among patients with MPZ variants and suspected CMT1B [48,76,226]:

•An early-onset, severe demyelinating neuropathy with very slow nerve conduction velocities (<10 m/second), consistent with CMT1B

•A late-onset axonal neuropathy with slightly reduced or normal nerve conduction velocities, classified as CMT2I

•A dominant intermediate form of CMT, CMTDID [182,227]

●CMT2 – The characteristic axonal findings in CMT2 are reflected in diminished motor amplitudes on NCS, with signs of chronic reinnervation on EMG. Evidence of demyelination is absent or is minimal, a finding that helps distinguish CMT2 from CMT1 [111].

●CMTX1 – 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 [228].

●CMT3 – Patients with congenital hypomyelinating neuropathy subtype have extremely slow or absent conduction velocities. Dejerine-Sottas disease typically consists of profound slowing of nerve conduction velocities to ≤15 m/second.

●CMT4 – Conduction velocities are typically slow (≤35 m/second) on NCS.

Genetic testing — We typically perform genetic testing for all patients with suspected CMT to confirm the diagnosis and to identify the specific subtype. Genetic testing is warranted even for patients without a clear family history of polyneuropathy or of CMT, because inheritance patterns can be obscured by the highly variable expression of CMT, and oligosymptomatic relatives may escape detection [229]. In addition, identifying risks of recessive forms of CMT can be difficult when information from a family pedigree is limited. Sporadic CMT is also common and may be associated with de novo pathogenic variants.

Approach to genetic testing — Selecting the appropriate gene tests for patients with CMT can be logistically challenging and costly due to the large and growing list of pathologic variants associated with different subtypes of CMT (table 2).

Our approach is as follows (algorithm 1):

●For patients with an established family history of confirmed CMT, we perform genetic testing for the known pathologic variant. In addition, some experts also perform initial genetic testing for PMP22 duplication for patients with classic clinical features and supportive family history for CMT1A (see 'Clinical features' above), as this genetic variant may account for up to 40 percent of CMT cases.

●In settings where next-generation sequencing (NGS) is available and affordable, we perform large panel testing for CMT-associated genes to identify and exclude a large number of known variants in one step. The interpretation of these results should be correlated with clinical and electrodiagnostic findings, as well as the inheritance pattern.

●In settings where large panel testing is unavailable or cost prohibitive, we use a strategy of focused genetic testing for CMT directed by age at onset, electrodiagnostic findings, and inheritance pattern [9].

Large panel testing — Since the advent and widespread availability of NGS, in many settings it has become only marginally more expensive to test 100 or more genes as it is to test a handful on one of these panels [230]. These panels can efficiently identify and exclude many variants associated with CMT.

However, both EDX and knowledge regarding the distribution of pathogenic variants remain important for the interpretation of genetic test results. Results that include one or more variant(s) of unknown significance appear in NGS reports as often, if not more often, than in the old sequencing panels. The ability to provide a clinical interpretation for such genetic test reports is a critical skill among clinicians that is not adequately appreciated. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Of note, 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 — In settings where NGS technology is not readily available/affordable, focused genetic testing may identify pathologic variants in most patients. This approach may also help avoid results that include multiple variants of unknown significance, as may be reported with large panel testing.

A landmark study published in 2011 clarified the genetic distribution of CMT subtypes and identified the genes most commonly responsible for the vast majority of CMT cases [9]. 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.

Incorporating motor upper extremity nerve conduction velocities on NCS testing can provide further guidance regarding the most likely candidate genes:

●Very slow velocities (≤15 m/second) – For patients with delayed walking (age 15 months or later), test for both the PMP22 duplication (CMT1A) and MPZ pathogenic variants (CMT1B). For those 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 for CMT1C, PMP22, and EGR2 for CMT1D. If these are all negative and if there is no affected parent or child, test for recessive forms of CMT.

●Slow velocities (>15 to ≤35 m/second) – For patients with a classic CMT phenotype (ie, walking before age 15 months), test first for the PMP22 duplication (CMT1A). If this is negative and if no male-to-male transmission exists 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.

●Mild slowing (>35 to ≤45 m/second) – For patients 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 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.

●Normal velocities (>45 m/second) or unobtainable velocities – For patients with either normal motor nerve conduction velocities 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 for CMT2E and GDAP1 for CMT2K. If these are all negative and there is no affected parent or child, test for recessive forms of axonal CMT.

Counseling and family screening — Genetic counseling should be made available to all patients and families with a suspected hereditary neuropathy [48]. Information about genetic testing and its implications should be provided. Prenatal testing is possible for some types of CMT if the pathogenic variant in the family is already known [231]. (See "Genetic counseling: Family history interpretation and risk assessment".)

Genetic screening for asymptomatic relatives of a patient diagnosed with CMT may also be performed, but risk assessment depends on several factors, including accuracy of the diagnosis, determination of the mode of inheritance for the individual family, and the likelihood of identifying a specific pathogenic variant in an affected relative by molecular genetic testing [231]. In addition, implications of both positive and negative results should be considered. These issues are discussed in greater detail separately. (See "Genetic testing".)

Other testing — We perform additional testing when clinical and electrodiagnostic findings are atypical or when confirmatory genetic testing is nondiagnostic. Some patients with clinical and electrodiagnostic features consistent with CMT may not have identifiable pathogenic variants on standard clinical genetic testing. Such patients may carry novel CMT variants yet to be discovered or variant types that are difficult to detect with current diagnostic technologies.

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

Sural nerve biopsy may be performed on patients with demyelinating forms of CMT to further characterize electrodiagnostic findings. Nerve biopsy may show demyelination that affects primarily the large nerve fibers (eg, CMT1) [232]. 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.

●Neuromuscular ultrasound – Various imaging techniques are emerging as potential diagnostic modalities for neuromuscular diseases, including CMT. For example, nerve ultrasound can distinguish CMT1A from other subtypes [233]. (See "Diagnostic ultrasound in neuromuscular disease", section on 'Findings in neuropathy'.)

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 [48,229,231].

Hereditary conditions

●Giant axonal neuropathy – Giant axonal neuropathy is an autosomal recessive hereditary neurodegenerative disorder characterized by a motor and sensory polyneuropathy and progressive cerebellar dysfunction. Patients often present in childhood with weakness and falls, similar to some patients with CMT. However, giant axonal neuropathy also features ataxia, dysmetria, nystagmus, and intellectual disability. Progressive muscle weakness often leads to severe disability in childhood and death in early adulthood. Electrodiagnostic testing (EDX) shows axonal loss, and nerve biopsy shows a characteristic axonal swelling. Genetic testing is confirmatory. (See "Overview of hereditary neuropathies", section on 'Giant axonal neuropathy'.)

●Familial amyloid polyneuropathy – Patients with familial amyloid polyneuropathy present with multisystemic symptoms such as cardiomyopathy and/or kidney impairment along with polyneuropathy. Inheritance is autosomal dominant. Unlike CMT, familial amyloid polyneuropathy usually presents in later life (eg, after 40 years old) with progressive pain and sensory loss. (See "Overview of amyloidosis", section on 'Neurologic abnormalities'.)

●Distal hereditary motor neuropathies – Distal hereditary motor neuropathies are a group of rare, genetically heterogeneous disorders characterized by slowly progressive distal motor weakness and length-dependent neuropathy [48]. They are distinguished from CMT by the absence of sensory involvement.

An inherited predominantly motor neuropathy may also occur with variants in sorbitol dehydrogenase (SORD) gene [234]. Affected individuals have been classified as having either a distal hereditary motor neuropathy or CMT2, depending on the individual case.

●Hereditary sensory and autonomic neuropathies – Hereditary sensory and autonomic neuropathies are a group of neuropathies categorized by sensory and/or autonomic nerve-predominating neuropathy. Clinical features can include numbness, orthostatic hypotension, and areflexia. Sensory loss can lead to musculoskeletal injuries, osteomyelitis, and infections. They occur much less frequently than do the primary hereditary motor sensory neuropathies. Symptoms often begin in early childhood but may be delayed until the third decade. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN1'.)

●Distal muscular dystrophies – Several muscular dystrophies are characterized by weakness that starts distally in the arms and/or legs and gradually progresses to affect proximal muscles. These conditions are a heterogeneous group of rare genetic myopathies (table 3). 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. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Distal muscular dystrophies'.)

●Friedreich ataxia – Patients with Friedreich ataxia typically present with limb and gait ataxia. Deep tendon reflexes are eventually 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. Inheritance is autosomal recessive, and testing for variants in the frataxin (FXN) gene is used for diagnostic confirmation. (See "Friedreich ataxia".)

●Refsum disease – Refsum disease is an autosomal recessive disorder that produces a polyneuropathy, ocular dysfunction, and other systemic symptoms. 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. Symptom onset varies from infancy to middle age. The neuropathy resembles demyelinating CMT due to the presence of pes cavus, progressive course, and demyelinating features [229]. Cerebrospinal fluid analysis shows an elevated protein concentration without an increase in cells. Refsum disease is caused by pathogenic variants in either the phytanoyl-CoA hydroxylase (PHYH) gene, which accounts for approximately 90 percent of cases, or the 7 PEX7 gene. (See "Peroxisomal disorders", section on 'Refsum disease'.)

●Krabbe 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 – Metachromatic leukodystrophy 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 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 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".)

●Adrenomyeloneuropathy – Adrenomyeloneuropathy (AMN) is a form of adrenoleukodystrophy, an X-linked disorder caused by pathogenic variants in the ABCD1 gene. The primary manifestation of AMN is spinal cord dysfunction with progressive spastic paraparesis, abnormal sphincter control, and sexual dysfunction. It typically presents in adult males between 20 and 40 years of age. 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'.)

●Ataxia-ocular apraxia type 1 – Ataxia-ocular apraxia type 1 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. It is an autosomal recessive disorder caused by pathogenic variants in the APTX gene that encodes aprataxin. (See "Ataxia-telangiectasia", section on 'Differential diagnosis'.)

●Hereditary syndromes related to vitamin metabolism

•The Brown-Vialetto-van Laere disease is an autosomal recessive condition that can mimic motor-predominating forms of CMT. It is characterized by sensorineural deafness, cranial neuropathies including bulbar palsy, and signs of motor neuron disease. The associated gene is the SLC52A3 gene, previously known as C20ORF54, which encodes a riboflavin transporter [235]. Some affected individuals improve with riboflavin therapy.

•A biotin-deficient autosomal recessive syndrome has been associated with biallelic variants in SLC5A6 [236]. 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.

●Some 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. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MNGIE'.)

•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. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'NARP'.)

●Idiopathic pes cavus – Pes cavus may also be present in isolation as an idiopathic condition that may occur as a hereditary phenomenon. It may cause some foot pain and gait difficulties and raises suspicion for CMT. However, this condition does not involve a detectable neuropathy or other signs and symptoms of CMT [237]. Therefore, it is important to examine a patient with pes cavus for other features of CMT before pursuing further diagnostic testing, such as genetic testing.

A retrospective cohort study of children with pes cavus evaluated in a pediatric EDX laboratory found that the diagnosis of CMT correlated with the presence of one or more of the following [238]:

•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 EDX testing, 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 [238].

Acquired conditions — Acquired peripheral neuropathy may also be idiopathic or caused by several conditions. These include:

●Systemic conditions

•Diabetes mellitus (See "Epidemiology and classification of diabetic neuropathy".)

•Human immunodeficiency virus (HIV) infection (See "HIV-associated distal symmetric polyneuropathy (HIV-DSPN)".)

•Syphilis (See "Neurosyphilis".)

•Neuroborreliosis (See "Nervous system Lyme disease".)

•Hypothyroidism (See "Neurologic manifestations of hypothyroidism", section on 'Peripheral neuropathy'.)

•Acquired vitamin deficiencies (See "Overview of water-soluble vitamins" and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

●Inflammatory and immune-mediated conditions

•Chronic inflammatory demyelinating polyneuropathy (CIDP) (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis".)

•Vasculitis (See "Clinical manifestations and diagnosis of vasculitic neuropathies".)

•Paraneoplastic neuropathies (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Peripheral nerve'.)

●Toxins (eg, alcohol, chemotherapy, and heavy metals) (table 4) (See "Overview of polyneuropathy", section on 'Toxic'.)

●Idiopathic polyneuropathy (See "Overview of polyneuropathy", section on 'Idiopathic'.)

Of these, the most important to recognize in the differential diagnosis of CMT are the immune-mediated neuropathies, particularly CIDP [229]. 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 [229]. Nerve conduction studies (NCS) 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".)

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 5^th to 6^th 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 10^th to 12^th 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 – Charcot-Marie-Tooth (CMT) disease is a group of hereditary peripheral neuropathies characterized by progressive motor and sensory nerve dysfunction, including a characteristic atrophy of calf muscles in several subtypes. CMT is the most common hereditary peripheral neuropathy. (See 'Introduction' above.)

●Pathophysiology – CMT is caused by one of several pathogenic variants in various genes implicated in the production or maintenance of proteins that contribute to the structure or function of peripheral nerves or myelin. A variety of pathogenic variants have been associated with CMT, including whole-gene duplications and deletions, as well as point pathogenic variants. Most cases are attributed to pathogenic variants in one of four genes: PMP22 that encodes peripheral myelin protein 22, MPZ that encodes myelin protein zero, GJB1 that encodes gap junction protein beta 1, or MFN2 that encodes mitochondrial fusion protein mitofusin 2. (See 'Pathogenesis' above and 'Classification' above.)

●Classification – CMT disease is categorized into specific types labeled as CMT types 1 through 4, as well as an X-linked category based on a combination of clinical features, modes of inheritance, and patterns of nerve dysfunction (table 1). Within each category, a specific subtype associated with a particular gene is assigned a letter (table 2). (See 'Classification' above.)

●Clinical features – CMT disease is clinically heterogeneous; the age of onset, severity, specific features of neuropathy, and associated features vary by specific subtype (table 1). A distal-predominating motor and sensory neuropathy is a core feature across CMT subtypes. (See 'Clinical features' above.)

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 in most CMT subtypes. Later in the course, foot deformities such as hammertoes ensue, along with hand weakness and atrophy.

●Diagnostic evaluation – The diagnostic evaluation of CMT includes a thorough medical and family history, complete neurologic examination, electrodiagnostic testing (EDX), and confirmatory genetic testing (algorithm 1). (See 'Evaluation and diagnosis' above.)

•For most patients, we start with EDX to establish the presence of a polyneuropathy and categorize its type (demyelinating, axonal, or mixed) and severity, which can guide subsequent genetic test selection. EDX is followed by confirmatory genetic testing to identify the causative pathogenic variant(s).

•For selected patients with an established family history of confirmed CMT, we start with genetic testing for the known pathologic variant. If these results are negative, we then perform EDX testing and more comprehensive genetic testing.

Other testing such as nerve biopsy, nerve ultrasound, or nerve MRI may also be warranted for selected patients for additional diagnostic characterization, such as when clinical and electrodiagnostic findings are atypical or when genetic testing results are nonconfirmatory.

●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. (See 'Differential diagnosis' above.)

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