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Charcot-Marie-Tooth Hereditary Neuropathy Overview

Synonym: CMT
, MD
Seattle VA Medical Center
Departments of Neurology and Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Revision: May 7, 2015.


Clinical characteristics.

Charcot-Marie-Tooth (CMT) hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy. The affected individual typically has distal muscle weakness and atrophy often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet.


The genetic neuropathies need to be distinguished from the many causes of acquired (non-genetic) neuropathies. Clinical diagnosis is based on family history and characteristic findings on physical examination, EMG/NCV testing, and occasionally sural nerve biopsy. More than 40 different genes/loci are associated with CMT. Molecular genetic testing is possible for some types of CMT.

Genetic counseling.

CMT hereditary neuropathy syndrome can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing. Prenatal testing for pregnancies at increased risk is possible for some types of CMT if the pathogenic variant(s) in the family are known.


Treatment of manifestations: Management by a multidisciplinary team of neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists; special shoes and/or ankle/foot orthoses (AFOs) to correct foot drop and aid walking; gripping exercises for hand weakness; orthopedic surgery as needed for severe pes cavus deformity and hip dysplasia; acetaminophen or nonsteroidal anti-inflammatory agents for musculoskeletal pain; tricyclic antidepressants, carbamazepine or gabapentin for neuropathic pain.

Prevention of secondary complications: Daily heel cord stretching exercises.

Agents/circumstances to avoid: Drugs and medications such as vincristine, taxol, cisplatin, isoniazid, and nitrofurantoin that are known to cause nerve damage; obesity as it makes walking more difficult.


Clinical Manifestations

Charcot-Marie-Tooth (CMT) hereditary neuropathy (also called hereditary motor/sensory neuropathy [HMSN]) results from involvement of peripheral nerves that can affect the motor system and/or the sensory system. Individuals with CMT experience symmetric, slowly progressive distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands. Pes cavus foot deformity is common.

Although usually described as "painless," the neuropathy of CMT can be painful [Carter et al 1998].

Other findings can include hearing loss and hip dysplasia, which may be under-recognized manifestations of CMT [McGann & Gurd 2002].

Establishing the Diagnosis of CMT

Reviews on diagnosis include Pareyson & Marchesi [2009a], Pareyson & Marchesi [2009b], and Reilly & Shy [2009].

Progressive weakness of the distal muscles in the feet and/or hands is evident on medical history.

Individuals with typical CMT have high-arched feet, weak ankle dorsiflexion, thin distal muscles, depressed tendon reflexes, and distal sensory loss.

Electrophysiologic studies (electromyography [EMG] and nerve conduction velocity [NCV]), when carefully done, are almost always abnormal [Carter et al 2004, Pareyson et al 2006].

Sural nerve biopsy is not routinely performed, but is occasionally helpful in establishing the diagnosis of CMT hereditary neuropathy because relatively characteristic lesions are found in CMT1, leprosy, vasculitis, and amyloid neuropathy [Schröder 2006].

Differential Diagnosis of CMT

Causes of acquired peripheral neuropathy include alcoholism, vitamin B12 deficiency, thyroid disease, diabetes mellitus, HIV infection, vasculitis, leprosy, neurosyphilis, amyloid deposition associated with chronic inflammation, occult neoplasm, heavy metal intoxication, and inflammatory and immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP).

Blindness (with the exception of optic atrophy in CMT2A and CMTX5), seizures, dementia, and intellectual disability are not part of the CMT hereditary neuropathy phenotype and suggest a different diagnosis.

Autosomal dominant disorders with neuropathy

  • Familial brachial plexus neuropathy (hereditary neuralgic amyotrophy). Affected individuals have sudden onset of pain and weakness in the shoulder or upper arm associated with distal and/or proximal weakness and atrophy of the upper extremity. Associated sensory loss may occur. Onset frequently occurs in childhood but can occur at any age. Partial or full recovery is typical. The syndrome may recur in the same or opposite limb and occasionally in the lower extremity. In some families, associated clinical features include short stature, ocular hypotelorism, cleft palate, epicanthal folds, facial asymmetry, and partial syndactyly [Jeannet et al 2001]. Pathogenic variants in SEPT9 are causative [Kuhlenbäumer et al 2005].
  • Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by the acute onset of recurrent, painless, focal sensorimotor neuropathy in a single nerve [Kumar et al 2002]. Deletion of one copy of PMP22 is causative.
  • Amyloid neuropathies, including transthyretin-associated amyloidosis, result in progressive accumulation of amyloid protein in peripheral nerves [Lynch & Chance 1997].

Autosomal recessive disorders with neuropathy

Hereditary motor neuropathies (HMN) are associated with distal weakness without sensory loss [Irobi et al 2004, Auer-Grumbach et al 2005]. The key distinction between typical CMT and HMN is that the latter has no sensory loss.

CMT syndrome with spasticity. Some individuals with distal muscle atrophy and weakness may have signs of spasticity with brisk tendon reflexes and/or Babinski responses. This set of findings has been called HMSN V and sometimes overlaps with hereditary motor neuropathy (HMN).

One type is associated with pathogenic variants in BSCL2 (see BSCL2-Related Neurologic Disorders) and another with pathogenic variants in SPG20, the gene encoding spartin (see Troyer Syndrome).

See also Hereditary Spastic Paraplegia Overview.

Hereditary sensory neuropathies (HSN). Several autosomal dominant axonal neuropathies have primarily sensory symptoms (one family is described as having "burning feet syndrome" [Stögbauer et al 1999]), and are classified as hereditary sensory neuropathies (HSNs) [Auer-Grumbach et al 2003]. Distal weakness may also occur. The most common form is HSAN-1 resulting from pathogenic variants in SPTLC1. Rotthier et al [2012] have reviewed the clinical and genetic factors associated with six autosomal dominant and seven autosomal recessive types. Kornak et al [2014] have reported two autosomal dominant families with a missense mutation in ATL3, a paralogue of ATL1, which is associated with spastic paraplegia and another form of sensory neuropathy [Guelly et al 2011].

See also Hereditary Sensory Neuropathy Type I and Hereditary Sensory and Autonomic Neuropathy Type II.

Distal myopathies. See Table 1.

Table 1.

Distal Myopathies

NameMean Age at Onset (Years)Initial Muscle Group InvolvedInheritanceGene
Welander distal myopathy >40Distal upper limbs (finger and wrist extensors)Autosomal dominantTIA1
Udd distal myopathy >35Anterior compartment in legsTTN
Zaspopathy (Markesbery-Griggs late-onset distal myopathy) >40LDB3
Distal myotilinopathy >40Posterior > anterior in legsMYOT
Laing early-onset distal myopathy (MPD1) <20Anterior compartment in legs and neck flexorsMYH7
Nonaka early-adult-onset distal myopathy 15-20Anterior compartment in legsAutosomal recessiveGNE
Miyoshi early-adult-onset myopathy Posterior compartment in legsDYSF
Distal myopathy with vocal cord and pharyngeal signs (MPD2)35-60Asymmetric lower leg and hands, dysphoniaAutosomal dominantUnknown
Distal myopathy with pes cavus and areflexia 15-50Anterior and posterior lower leg; dysphonia and dysphagia
New Finnish distal myopathy (MPD3)>30Hands or anterior lower leg

Mitochondrial disorders associated with peripheral neuropathy

  • NARP (neuropathy, ataxia, and retinitis pigmentosa). A mitochondrial disorder caused by mutations in mitochondrial DNA (mtDNA)
  • MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) [Said et al 2005]

See also Mitochondrial Disorders Overview.


Charcot-Marie-Tooth (CMT) hereditary neuropathy is the most common genetic cause of neuropathy. Prevalence is about 1:3,300.

Approximately 20% of all individuals presenting to neuromuscular clinics with an unclassified chronic peripheral neuropathy have CMT1A.

The prevalence of genetic subtypes differs in Japan, where there are fewer cases of CMT1A (23% of CMT1) and more cases with an unknown genetic cause [Abe et al 2011].

In a large study of German individuals with a CMT1 phenotype (776), Gess et al [2013] found the following percentages: CMT1A (51%), CMTX1 (9%), and CMT1B (5%). Sixty-six percent of subjects with a CMT1 phenotype had a genetic diagnosis. Of those with a CMT2 phenotype, 11% had CMTX1, 8% had CMT2A, and 6% had the rare giant axonal neuropathy. Thirty-five percent of individuals with CMT2 had a genetic diagnosis.

Rossor et al [2013] show the prevalence of CMT subtypes relative to all CMT, CMT1, CMT2, or intermediate CMT; see Figure 1.

Figure 1.

Figure 1.

Genetic diagnoses in CMT and related disorders

Rossor et al [2013]; reprinted with permission


Single-Gene Causes

The classification used in this GeneReview is based on inheritance patterns and molecular genetics (see Table 2). However, classification is especially difficult when different pathogenic variants in a single gene are associated with both autosomal dominant and autosomal recessive inheritance, and/or both axonal and demyelinating neuropathy. Reviews of the diagnosis and natural history include Pareyson & Marchesi [2009a], Pareyson & Marchesi [2009b], and Reilly & Shy [2009].

Table 2.

Single-Gene Causes of CMT Hereditary Neuropathy

Disease Name 1 PathologyMode of InheritanceProportion of all CMT 2
CMT1 Abnormal myelin AD40%-50%
CMT2 AxonopathyAD10%-15%
Intermediate formCombination of myelinopathy and axonopathy in individualADRare
CMT4 Either myelinopathy or axonopathyARRare
CMTX Axonopathy with secondary myelin changesXLD10%-15%

See Charcot-Marie-Tooth Disease: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.


Each of the CMT subtypes (CMT1, CMT2, CMT4, and CMTX) is further subdivided primarily on molecular genetic findings [De Jonghe et al 1997, Keller & Chance 1999, Nelis et al 1999].


Saporta et al [2011]

Vance [2000] suggested a similar classification system that differs slightly, with CMT3 referring to axonal presentations that are autosomal recessive and CMT4 referring to demyelinating presentations that are autosomal recessive.

Other valid classification systems may emphasize electrophysiologic characteristics such as nerve conduction velocities or pathologic findings.

The molecular genetics of CMT has been reviewed by Carter et al [2004], Houlden & Reilly [2006], Kleopa & Scherer [2006], Nicholson [2006], Reilly & Shy [2009], and Pareyson & Marchesi [2009a], and the molecular pathogenesis has been reviewed by Bernard et al [2006] and Züchner & Vance [2006]. The various genetic subtypes and their associated genes are shown in Figure 2 [Pareyson & Marchesi 2009a]. Rossor et al [2013] have illustrated the molecular and anatomic relationships of all the genes and proteins reported thus far to cause various subtypes of CMT; see Figure 3.

Figure 2. . Different forms of Charcot-Marie-Tooth disease and associated genes

There are areas of overlap between different types of CMT.

Figure 2.

Different forms of Charcot-Marie-Tooth disease and associated genes

There are areas of overlap between different types of CMT. Red shading indicates the most commonly involved genes.

dHMN = distal hereditary motor neuropathy
DI (more...)

Figure 3.

Figure 3.

Known disease genes for CMT and related disorders, and their proposed pathomechanism

Rossor et al [2013]; reprinted with permission

Charcot Marie Tooth Type 1 (CMT1) is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity (typically 5-30 m/sec; normal: >40-45 m/sec). It is usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually become symptomatic between ages five and 25 years. Fewer than 5% of individuals become wheelchair dependent. Life span is not shortened.

The six subtypes of CMT1 are clinically indistinguishable and are designated solely on molecular findings [Saifi et al 2003] (Table 3).

Table 3.

CMT1: Molecular Genetics

Locus NameProportion of CMT1 (excluding CMTX) 1GeneProtein Product
CMT1A70%-80%PMP22Peripheral myelin protein 22
CMT1B10%-12%MPZMyelin P0 protein
CMT1C~1%LITAFLipopolysaccharide-induced tumor necrosis factor-alpha factor
CMT1DUnknownEGR2Early growth response protein 2
CMT1E~1%PMP22Peripheral myelin protein 22
(sequence changes)
CMT1F/2EUnknownNEFLNeurofilament light polypeptide

Charcot Marie Tooth Type 2 (CMT2) is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy. Nerve conduction velocities are usually within the normal range; however, occasionally they fall in the low-normal or mildly abnormal range (35-48 m/sec). Peripheral nerves are not enlarged or hypertrophic.

CMT2 shows extensive clinical overlap with CMT1; however, in general, individuals with CMT2 tend to be less disabled and have less sensory loss than individuals with CMT1. A threshold of 38 m/sec for median motor nerve conduction is often used clinically to distinguish CMT1 from CMT2.

CMTX1 may present with a relatively axonal form of CMT that may be confused with CMT2.

CMT2A2, the most common type of CMT2, is caused by mutation of MFN2 (reviewed in Chung et al [2006]). Known MFN2 pathogenic variants and related pathophysiology are reviewed in Cartoni & Martinou [2009].

CMT2B, caused by mutation of RAB7A, is associated with prominent sensory loss [Cogli et al 2009].

Table 4.

CMT2: Molecular Genetics

Locus NameProportion of CMT2 1Gene / Chromosomal Locus 2Protein Product
CMT2A1UnknownKIF1BKinesin-like protein KIF1B
CMT2BUnknownRAB7ARas-related protein Rab-7
CMT2B1UnknownLMNALamin A/C
CMT2B2UnknownMED25Mediator of RNA polymerase II transcription subunit 25
CMT2CUnknownTRPV4Transient receptor potential cation channel subfamily V member 4
CMT2D3%GARS Glycyl-tRNA synthetase
CMT2E/1F 4%NEFL Neurofilament light polypeptide
CMT2FUnknownHSPB1 Heat-shock protein beta-1
CMT2H/2K5%GDAP1Ganglioside-induced differentiation-associated protein-1
CMT2I/2JUnknownMPZMyelin P0 protein
CMT2LUnknownHSPB8Heat-shock protein beta-8
CMT2NUnknownAARSAlanyl-tRNA synthetase, cytoplasmic
CMT2OUnknownDYNC1H1Cytoplasmic dynein 1 heavy chain 1
CMT2PUnknownLRSAM1E3 ubiquitin-protein ligase LRSAM1
CMT2SUnknownIGHMBP2DNA-binding protein SMUBP-2
CMT2TUnknownDNAJB2DnaJ homolog subfamily B member 2
CMT2UUnknownMARSMethionine--tRNA ligase, cytoplasmic

Saporta et al [2011]


Chromosomal locus given only when gene is unknown

Autosomal Dominant Intermediate CMT

Autosomal dominant intermediate CMT (DI-CMT) (Table 5) is characterized by a relatively typical CMT phenotype with clinical and pathologic evidence of both abnormal myelin and axonopathy. Nerve conduction velocities (NCVs) overlap those observed in CMT1 and CMT2 [Nicholson & Myers 2006]. Motor NCVs usually range between 25 and 50 m/sec. In the two families reported by Soong et al [2013] median motor nerve conduction velocities (MNCV) ranged from clearly slow/demyelinating (16.5-28 m/s) to normal (44-45 m/s). The family members with slow MNCV would have been classified as having CMT1.

Table 5.

Autosomal Dominant Intermediate CMT: Molecular Genetics

Locus NameProportion of Intermediate CMT Gene / Chromosomal Locus 1Protein ProductReference
DI-CMTAUnknown10q24.1-q25.1UnknownVerhoeven et al [2001]
DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB)DNM2 Dynamin 2Kennerson et al [2001], Züchner et al [2005]
YARS-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTC)YARS Tyrosyl-tRNA synthetaseJordanova et al [2003], Jordanova et al [2006]
MPZ-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTD) MPZMyelin P0 protein
GNB4-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTF)GNB4Guanine nucleotide-binding protein subunit beta-4Soong et al [2013]

Chromosomal locus given only when gene is unknown

Charcot-Marie-Tooth type 4 (CMT4) is a group of progressive motor and sensory axonal and demyelinating neuropathies. It is distinguished from other forms of CMT by autosomal recessive inheritance (see Table 6). Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. The autosomal recessive forms of CMT are reviewed by Bernard et al [2006] and Kabzinska et al [2008].

Note: The term Dejerine-Sottas syndrome (DSS) was originally used to describe a severe demyelinating neuropathy of infancy and childhood associated with very slow NCVs, elevated CSF protein, marked clinical weakness, and hypertrophic nerves with onion bulb formation. Inheritance of DSS was assumed to be autosomal recessive. Subsequently, individuals with this clinical diagnosis have had various types of autosomal recessive CMT (CMT4) and have been heterozygous for point mutations in genes associated with CMT1 including: PMP22 (CMT1A), MPZ (CMT1B), and EGR2 (CMT1D) [Boerkoel et al 2001a, Boerkoel et al 2001b].

Although the term DSS is still sometimes used to indicate a clinical phenotype, it does not imply an inheritance pattern or a specific genetic defect [Parman et al 2004].

Table 6.

CMT 4: Molecular Genetics

Locus NameProportion of CMT4Gene Protein Product
CMT4AUnknownGDAP1Ganglioside-induced differentiation-associated protein 1
CMT4B1MTMR2Myotubularin-related protein 2
CMT4B2SBF2Myotubularin-related protein 13
CMT4CSH3TC2SH3 domain and tetratricopeptide repeats-containing protein 2
CMT4EEGR2Early growth response protein 2
CMT4HFGD4FYVE, RhoGEF and PH domain-containing protein 4
CMT4JFIG4Phosphatidylinositol 3, 5 biphosphate

X-Linked CMT

Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is characterized by a moderate to severe motor and sensory neuropathy in affected males and usually mild to no symptoms in carrier females. Sensorineural deafness and central nervous system symptoms also occur in some families (see Table 7).

Five other forms of hereditary neuropathy have been linked to the X chromosome. The genes associated with CMTX5 and CMTX6 have been identified. Associated findings are [Huttner et al 2006]:

Kennerson et al [2010] described two families with an X-linked distal motor neuropathy similar to CMT with missense mutations in ATP7A, the same gene involved in Menkes disease.

A retrospective review of X-linked CMT in childhood has been reported [Yiu et al 2011].

Table 7.

CMTX: Molecular Genetics

Disease NameProportion of X-Linked CMTGene / Chromosomal Locus 1Protein Product
CMTX190%GJB1Gap junction beta-1 protein (connexin 32)
CMTX4/Cowchock syndromeAIFM1Apoptosis-inducing factor 1
CMTX5PRPS1Ribose-phosphate pyrophosphokinase 1
CMTX6PDK3Pyruvate dehydrogenase kinase isoform 3

Chromosomal locus given when gene is unknown

Mitochondrial CMT

Mitochondrial abnormalities are known to sometimes be associated with peripheral neuropathy. Mutation of the nuclear gene MFN2 produces abnormal mitochondrial fusion/fission and resultant neuropathy (CMT2A). Mutations in the mitochondrial genome may also be associated with neuropathy, for example in NARP. Pitceathly et al [2012] have reported an axonal predominantly motor neuropathy associated with the MT-ATP6 variant m.9185T>C.

Evaluation Strategy

Establishing the specific cause of Charcot-Marie-Tooth (CMT) hereditary neuropathy for a given individual involves a medical history, physical examination, neurologic examination, and nerve conduction and EMG testing, as well as a detailed family history and the use of molecular genetic testing when available.

Family History

A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or through review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.

Individuals with CMT may have a negative family history for many reasons, including mild subclinical expression in other family members, autosomal recessive inheritance, or de novo (new) mutation of a dominant gene.

  • About one third of individuals with identifiable point mutations in PMP22, GJB1, or MPZ causing the CMT hereditary neuropathy phenotype have de novo mutations, and thus present as simplex cases (i.e., a single occurrence in a family) [Boerkoel et al 2002].
  • PMP22 duplications (which are much more common than point mutations) occur de novo in about 10%-20% of people with CMT1 [Blair et al 1996, Bort et al 1997].

Physical Examination

In individuals who have no family history of neuropathy, the first step is to exclude acquired causes of neuropathy by standard neurologic evaluation (see Differential Diagnosis of CMT).

Distal weakness, sensory loss, depressed tendon reflexes, and foot deformity are commonly (but not always) present.

In CMT1, the most common CMT subtype, NCVs are very slow and peripheral nerves may be palpably enlarged. This is not true of CMT2.

Molecular Genetic Testing

Testing is possible for pathogenic variants in numerous genes associated with similar phenotypes. Note: Failure to identify a pathogenic variant in a proband does not rule out a diagnosis of CMT since undetected variants in other genes may be causative.

One genetic testing strategy is serial single gene molecular genetic testing based on family history and neurophysiologic data [England et al 2009, Saporta et al 2011]. The relative frequencies of various CMT subtypes are shown in Figure 1.

Positive family history

  • In families with at least two-generation involvement, known male-to-male transmission, and very slow NCVs (<15 m/sec):
    • First, obtain testing for the PMP22 duplication (CMT1A).
    • If normal, follow with testing of MPZ (CMT1B) and point mutations in PMP22 (CMT1E).
    • If both are normal, test for LITAF (CMT1C) and EGR2 (CMT1D) [England et al 2009 (full text; see figure), Saporta et al 2011 (full text; see Figure 2)].
  • In families with at least two-generation involvement and slow NCVs (15-35 m/sec), but without male-to-male transmission, molecular genetic testing of PMP22 (CMT1A), GJB1 (CMTX), MPZ (CMT1B), and LITAF (CMT1C) should be performed sequentially [Saporta et al 2011 (full text; see Figure 1)]

    Note: In more than 90% of individuals with a CMT1 phenotype a pathogenic variant is found in one of three genes (PMP22, MPZ, GJB1) [Szigeti et al 2006, Saporta et al 2011].
  • In families with probable X-linked inheritance of the CMT phenotype, molecular genetic testing of GJB1 (CMTX) is appropriate to confirm the diagnosis.
  • In individuals with the CMT2 phenotype, MFN2 (CMT2A2) can be tested first followed by testing of MPZ (CMT2I/2J) and GJB1 (CMTX1). Other rarer causes include GDAP1 (CMT2H/2K), NEFL (CMT2E/1F), and EGR2 (CMT1D) [Saporta et al 2011 (full text; see Figure 4)].

Early childhood onset. Based on the Baets et al [2011] study of 77 unrelated subjects with onset of neuropathy in the first year of life, pathogenic variants in MPZ, PMP22, and EGR2 should be evaluated first as they were most frequent in those individuals with hypotonia and breathing difficulties. Testing of FGD4, PRX, MTMR2, SBF2, SH3TC2, and GDAP1 is indicated in individuals with early foot deformities and delay in motor milestones after an uneventful neonatal period.

Negative family history (i.e., a single occurrence in a family)

  • Molecular genetic testing of PMP22dup (CMT1A), MPZ (CMT1B), and GJB1 (CMTX) should be performed on males and females who have no family history of neuropathy because de novo duplications of the 17p11 region (causing CMT1A) are common and because females who have a GJB1 pathogenic variant (causing CMTX1) may be asymptomatic.
  • If no pathogenic variant is identified in any of these three genes testing for rarer subtypes can be considered [England et al 2009 (full text; see Figure)].
  • Early-onset severe CMT may be caused by mutation of PMP22 (CMT1A or 1E), GDAP1 (CMT4A), EGR2 (CMT4E), PRX (CMT4F), SH3TC2 (CMT4C), FDG4 (CMT4H), or MTMR2 (CMT4B1).

An alternative genetic testing strategy is use of a multi-gene panel that includes genes associated with CMT and other genes of interest (see Differential Diagnosis of CMT) [Rossor et al 2013]. Panels exist for dominantly and recessively inherited CMTs as well as demyelination and axonal forms. Larger (all-inclusive) panels may also be available. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

A reasonable testing approach is to first test for pathogenic variant(s) in the single most likely gene that best fits the phenotype (e.g., CMT1A or CMT2A). If such testing does not identify the pathogenic variant(s), then proceed to a genetic neuropathy panel followed by whole-exome sequencing if appropriate [Rossor et al 2015].

DiVincenzo et al [2014] have reported the results of genetic testing of more than 17,000 samples submitted to the largest commercial laboratory providing CMT testing in the USA. The cases were not screened for family history or phenotype, but represented individuals with peripheral neuropathy whose physicians suspected possible CMT. In 18% of those tested, a causative allelic variant was identified in a CMT-related gene. Importantly, 95% of the positive results involved one of four genes (PMP22, GJB1, MPZ, MFN2). The authors conclude that these four genes should be screened first before proceeding with further genetic testing.

Manganelli et al [2014], in a large Italian cohort with CMT, essentially confirm the findings of DiVincenzo et al [2014] except for finding a larger number of GDAP1 pathogenic variants (4%).

Test characteristics. See Clinical Utility Gene Card [Aretz et al 2010] for information on test characteristics including sensitivity and specificity.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Charcot-Marie-Tooth (CMT) hereditary neuropathy may be transmitted in an autosomal dominant, autosomal recessive, or X-linked manner depending on the genetic subtype in a family.

Risk to Family Members — Autosomal Dominant

Parents of a proband

  • Most individuals diagnosed as having autosomal dominant CMT have an affected parent, although occasionally the family history is negative.
  • Family history may appear to be negative because of failure to recognize CMT in family members, early death of the parent before the onset of symptoms, late onset in an affected parent, or reduced penetrance of the mutant allele in an asymptomatic parent.

Sibs of a proband

  • The risk to sibs depends on the genetic status of the proband's parents.
  • If one of the proband's parents has a mutant allele, the risk to the sibs of inheriting the mutant allele is 50%.

Offspring of a proband. Individuals with autosomal dominant CMT have a 50% chance of transmitting the mutant allele to each child.

Risk to Family Members — Autosomal Recessive

Parents of a proband

  • The parents are obligate heterozygotes and therefore carry a single copy of a pathogenic variant.
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes are asymptomatic.

Offspring of a proband. All of the offspring are obligate carriers.

Risk to Family Members — X-Linked

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the genetic status of the proband's mother.
  • A female who is a carrier has a 50% chance of transmitting the pathogenic variant with each pregnancy. Sons who inherit the pathogenic variant will be affected; daughters who inherit the variant may or may not be affected.
  • If the mother is not a carrier, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. All the daughters of an affected male inherit the pathogenic variant and may or may not have symptoms; none of his sons will be affected.

Other family members of proband. The proband's maternal aunts and their offspring may be at risk of being carriers.

Empiric Risks to Family Members

Empiric data regarding recurrence risk are not available for genetic counseling of individuals who represent simplex cases (i.e., single occurrences in a family) in which no pathogenic variant is identified.

Related Genetic Counseling Issues

Considerations in families with apparent de novo mutation. When neither parent of a proband with an autosomal or X-linked condition has the pathogenic variant or clinical evidence of the disorder, it is likely that mutation occurred de novo in the proband. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
  • Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. One study found that many individuals with CMT give themselves high disability ratings and 36% would choose not to have children [Pfeiffer et al 2001].

Testing of asymptomatic adult relatives who are at risk of developing CMT is possible after direct DNA testing has identified the specific pathogenic variant in an affected relative. Such testing should be performed in the context of formal genetic counseling.

Testing of asymptomatic at-risk children is discouraged. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk may be available from a laboratory offering testing for the gene of interest or custom testing.

Requests for prenatal diagnosis of (typically) adult-onset diseases are uncommon. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate [Bernard et al 2002].

Preimplantation genetic diagnosis (PGD) for some forms of CMT has been reported [Sharapova et al 2004, Lee et al 2013] and may be available for some families in which the pathogenic variant(s) have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association CMT France
    Phone: 820 077 540; 2 47 27 96 41
  • Charcot-Marie-Tooth Association (CMTA)
    PO Box 105
    Glenolden PA 19036
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Fax: 03 2651002
  • Hereditary Neuropathy Foundation, Inc.
    432 Park Avenue South
    4th Floor
    New York NY 10016
    Phone: 855-435-7268 (toll-free); 212-722-8396
    Fax: 917-591-2758
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
    Institute of Genetic Medicine
    University of Newcastle upon Tyne
    International Centre for Life
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Phone: 44 (0)191 241 8617
    Fax: 44 (0)191 241 8770
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    Evry cedex 91002
    Phone: +33 01 69 47 28 28
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    3743 JN Baarn
    Phone: 31 35 5480481
    Fax: 31 35 5480499
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
  • Muscular Dystrophy Campaign
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
  • RDCRN Patient Contact Registry: Inherited Neuropathies Consortium


Treatment of Manifestations

Reviews of treatment approaches to CMT are available [Carter et al 2008, Young et al 2008, Reilly & Shy 2009]. Reviews of the diagnosis, natural history and management are available [Pareyson & Marchesi 2009a, Pareyson & Marchesi 2009b].

Treatment is symptomatic. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Carter et al 2004, Grandis & Shy 2005]. Quality of life has been measured and compared among various groups of individuals with Charcot-Marie-Tooth (CMT) [Vinci et al 2005a, Burns et al 2010]. Persistent weakness of the hands and/or feet has important career and employment implications; anticipatory counseling is appropriate.

Special shoes, including those with good ankle support, may be needed. Affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking.

Some individuals require forearm crutches or canes for gait stability; fewer than 5% of individuals need wheelchairs.

Exercise is encouraged within the individual's capability and many individuals remain physically active.

Orthopedic surgery may be required to correct severe pes cavus deformity [Guyton & Mann 2000, Guyton 2006, Casasnovas et al 2008, Ward et al 2008]. Surgery is sometimes required for hip dysplasia [Chan et al 2006].

The cause of any pain should be identified as accurately as possible [Padua et al 2006].

  • Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [Carter et al 1998].
  • Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.

Modafinil has been used to treat fatigue [Carter et al 2006].

Prevention of Secondary Complications

Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable, as well as gripping exercises for hand weakness [Vinci et al 2005b].

Agents/Circumstances to Avoid

Obesity is to be avoided because it makes walking more difficult.

Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. Click here (pdf) for an up-to-date list.

Chemotherapy for cancer that includes vincristine may be especially damaging to peripheral nerves and severely worsen CMT [Graf et al 1996, Nishikawa et al 2008].

Therapies Under Investigation

Patel & Pleasure [2013] and Ekins et al [2015] have summarized the potential treatment approaches to CMT1.

Dyck et al [1982], Ginsberg et al [2004], and Carvalho et al [2005] have described a few individuals with CMT1 and sudden deterioration in whom treatment with steroids (prednisone) or IVIg has produced variable levels of improvement. Nerve biopsy has shown lymphocytic infiltration. One such family had a specific MPZ pathogenic variant (p.Ile99Thr) [Donaghy et al 2000]. A young child with CMT1A and an inflammatory neuropathy has been reported [Marques et al 2010].

Sahenk et al [2003] are studying the effects of neurotrophin-3 on individuals with CMT1A.

Passage et al [2004] reported benefit from ascorbic acid (vitamin C) in a mouse model of CMT1. However, a study of 277 persons with CMT1A found no significant effect of a daily 1.5-g dose of ascorbic acid after two years [Pareyson et al 2011]. Similar studies of smaller numbers of patients have also shown no benefit of such treatment [Micallef et al 2009, Verhamme et al 2009]. Lewis et al [2013] also found no positive treatment response to ascorbic acid vs. placebo in 110 subjects with CMT1A.

Sereda et al [2003] and Meyer zu Horste et al [2007] used a progesterone antagonist to improve neuropathy in a transgenic rat model of CMT1A.

Search for access to information on clinical studies for a wide range of diseases and conditions.


Night splints have not improved ankle range of motion [Refshauge et al 2006].


Published Guidelines/Consensus Statements

  1. Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 5-1-15. [PubMed: 23428972]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2012. Accessed 5-1-15.

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Suggested Reading

  1. Lupski JR, Garcia CA. Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 227. New York, NY: McGraw-Hill. Available online. 2015. Accessed 5-1-15.
  2. Nicholson G, Kennerson M, Brewer M, Gardern J, Shy M. Genotypes & sensory phenotypes in 2 new X-linked neruopathies (CMTX3 and dSMAX) and dominant CMT/HMN overlap syndromes. Adv Exp Med Biol. 2009;652:201–6. [PubMed: 20225027]
  3. Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K, Antoniadi T, Williams M, King C, Greenhalgh L, Newbury-Ecob R, Ellard S. Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet. 2011;89:308–12. [PMC free article: PMC3155164] [PubMed: 21820100]
  4. Weterman MA, Sorrentino V, Kasher PR, Jakobs ME, van Engelen BG, Fluiter K, de Wissel MB, Sizarov A, Nürnberg G, Nürnberg P, Zelcer N, Schelhaas HJ, Baas F. A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy. Hum Mol Genet. 2012;21:358–70. [PMC free article: PMC3276280] [PubMed: 22012984]

Chapter Notes

Revision History

  • 7 May 2015 (cd) Revision: heterozygous mutation of IGHMBP2 as causative of CMT2S, of DNAJB2 as causative of CMT2T, and of MARS as causative of CMT2U
  • 12 February 2015 (tb) Revision: additions to alternative genetic testing strategy
  • 6 March 2014 (tb) Revision: SPTLC1 and ATL3 added
  • 20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis; OMIM Phenotypic Series link added
  • 30 January 2014 (tb) Revision: edits to Evaluation Strategy
  • 14 November 2013 (tb) Revision: figures added to Prevalence and Single-Gene Causes [Rossor et al 2013]
  • 11 July 2013 (tb) Revision: TIA1 mutations causative of Welander distal myopathy; added information on: prevalence, ascorbic acid treatment
  • 28 March 2013 (tb) Revision: to include GNB4 mutations as causative of dominant intermediate Charcot-Marie-Tooth disease [Soong et al 2013]
  • 7 March 2013 (tb) Revision: to include mutations in AIFM1 as causative of CMTX4
  • 14 February 2013 (tb) Revision: to include mutation in PDK3 as causative of CMTX6
  • 27 September 2012 (tb) Revision: report of CMT resulting from mutation in a mitochondrial gene [Pitceathly et al 2012]
  • 9 February 2012 (tb) Revision: mutations in DYNC1H1 reported to be associated with CMT2O; mutation in LRSAM1 associated with CMT2P
  • 31 May 2011 (me) Comprehensive update posted live
  • 16 April 2009 (tb) Revision: sequence analysis available clinically for CMT4H; CMT4J added
  • 24 July 2008 (tb) Revision: gene (PRPS1) for CMTX5 identified
  • 31 August 2007 (me) Comprehensive update posted to live Web site
  • 19 June 2006 (cd) Revision: family history evaluation strategy
  • 3 February 2006 (tb) Revision: mutations in YARS cause DI-CMTC
  • 30 December 2005 (cd) Revision: testing for CMT2B clinically available
  • 20 December 2005 (tb) Revision: SEPT9 mutations identified in individuals with familial brachial plexus neuropathy; changes to Differential Diagnosis
  • 27 April 2005 (me) Comprehensive update posted to live Web site
  • 9 September 2004 (tb) Revision: test availability
  • 21 June 2004 (tb,cd) Revision: LITAF and MFN2 added
  • 11 May 2004 (me) Author revisions
  • 24 March 2004 (cd) Revision: CMT4A
  • 22 December 2003 (tb,bp) Revision
  • 23 October 2003 (cd) Revision: change in test availability
  • 12 August 2003 (tb) Revision: CMT4 molecular genetics
  • 29 May 2003 (td) Author revisions
  • 24 April 2003 (tb) Author revisions
  • 28 March 2003 (me) Comprehensive update posted to live Web site
  • 10 May 2002 (tb) Author revisions
  • 12 September 2001 (tb) Author revisions
  • 20 June 2001 (me) Comprehensive update posted to live Web site
  • 15 May 2000 (tb) Author revisions
  • 14 January 2000 (tb) Author revisions
  • 31 August 1999 (tb) Author revisions
  • 18 June 1999 (tb) Author revisions
  • 8 April 1999 (tb) Author revisions
  • 5 March 1999 (tb) Author revisions
  • 12 October 1998 (tb) Author revisions
  • 28 September 1998 (pb) Overview posted to live Web site
  • April 1996 (tb) Original submission
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