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Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Synonym: CMT4

, MD.

Author Information and Affiliations

Initial Posting: ; Last Revision: April 14, 2016.

Estimated reading time: 38 minutes



Clinical characteristics.

Charcot-Marie-Tooth neuropathy type 4 (CMT4) is a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity.


The diagnosis of CMT4 subtypes is based on clinical findings, neurophysiologic studies, and molecular genetic testing. Detection of biallelic pathogenic variants in one of the following 11 genes establishes the diagnosis: GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), HK1 (CMT4G), FGD4 (CMT4H), and FIG4 (CMT4J).


Treatment of manifestations: Treatment by a team including a neurologist, physiatrist, orthopedic surgeon, physical and occupational therapists; special shoes and/or ankle/foot orthoses to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility; exercise as tolerated; symptomatic treatment of pain, depression, sleep apnea, restless leg syndrome.

Prevention of secondary complications: Daily heel cord stretching to prevent Achilles' tendon shortening.

Surveillance: Monitoring gait and condition of feet to determine need for bracing, special shoes, surgery.

Agents/circumstances to avoid: Obesity (which makes ambulation more difficult); medications (e.g., vincristine, isoniazid, nitrofurantoin) known to cause nerve damage.

Other: Career and employment counseling.

Genetic counseling.

The CMT4 subtypes are inherited in an autosomal recessive manner. Parents of an affected individual are obligate carriers of the CMT4-related pathogenic variant present in their family. At conception, each sib of an affected individual 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in an affected family member are known.

GeneReview Scope

Charcot-Marie-Tooth Neuropathy Type 4: Included Phenotypes
  • CMT4A
  • CMT4B1
  • CMT4B2
  • CMT4B3
  • CMT4C
  • CMT4D
  • CMT4E
  • CMT4F
  • CMT4G
  • CMT4H
  • CMT4J

For synonyms and outdated names see Nomenclature.


Suggestive Findings

Charcot-Marie-Tooth neuropathy type 4 (CMT4) should be suspected in individuals with the following clinical findings, nerve conduction velocities, and family history.

Clinical findings

  • Progressive weakness of the distal muscles in the feet and/or hands
  • High-arched feet
  • Weak ankle dorsiflexion
  • Atrophic distal muscles
  • Depressed or absent tendon reflexes
  • Distal sensory loss

Nerve conduction velocities (NCVs) that are usually slow (<40 m/s)

Family history consistent with autosomal recessive inheritance (i.e., parents not affected unless multigenerational consanguinity exists)

Establishing the Diagnosis

The diagnosis of CMT4 is established in a proband with progressive motor and sensory neuropathy, slow nerve conduction velocities, and biallelic pathogenic variants in one of the 11 genes known to be associated with the CMT4 phenotype (Table 1).

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Serial single-gene testing can be considered based on the order in which pathogenic variants most commonly occur or by ethnicity if founder variants have been identified (Table 1).
  • A multigene panel that includes some (or all) of the 11 genes listed in Table 1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and the sensitivity of multigene panels vary by laboratory and over time.
  • More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes some or all of the genes associated with CMT4) fails to confirm a diagnosis in an individual with features of CMT4 [Schabhüttl et al 2014]. For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetics of CMT4

CMT SubtypeGene 1, 2Comment (% = proportion of all CMT4)
CMT4A GDAP1 1%-5% 3, 4, 5, 6
CMT4B1 MTMR2 1% 6
CMT4B2 SBF2 4% 6
CMT4B3 SBF1 See footnote 7
CMT4C SH3TC2 1%-12% 3, 4, 6, 8, 9
Founder variant in Spanish Gypsies [Claramunt et al 2007]
CMT4D NDRG1 Founder variant in the Bulgarian Gypsies originating from the community of Lom on the Danube 10
CMT4E EGR2 1% 6
CMT4F PRX 5% 6
CMT4G HK1 Founder variant in the Balkan (Russe) Gypsies 11
CMT4H FGD4 3% 6
CMT4J FIG4 See footnote 13

See Molecular Genetics for information on allelic variants detected in this gene.


Genetic abnormalities identified in 3312 of 17,880 individuals referred to a commercial genetic testing laboratory [DiVincenzo et al 2014] (USA)


197 individuals tested for CMT [Manganelli et al 2014] (Italy)


96 cases (axonal) [Saporta et al 2011] (USA)


Genetic abnormalities identified in 35 of 77 individuals tested [Baets et al 2011] (UK)


1206 individuals tested for CMT [Rudnik-Schöneborn et al 2016] (Germany)


449 cases (demyelinating) [Saporta et al 2011] (USA)


Clinical Characteristics

Clinical Description

The clinical findings of a peripheral neuropathy, slow NCV, mode of inheritance, and biallelic pathogenic variants in a specific gene have been the basis for classification for the majority of CMT subtypes.

Individuals with CMT4 usually have the clinical characteristics of the CMT phenotype, including distal muscle weakness and atrophy, sensory loss, and, often, pes cavus foot deformity. (See CMT Overview for more details.) Both axonal and demyelinating neuropathies are included in CMT4.

The autosomal recessive neuropathies tend to have an earlier onset (early childhood) and more severe progression than the autosomal dominant varieties. Except in the case of consanguinity, they also appear only in sibs or as simplex cases.

CMT4A was first identified in families in Tunisia. Typically, delayed motor development is noted in the second year of life. Distal muscle weakness and atrophy of feet progress to involve the proximal muscles by the end of the first decade. Hand atrophy may occur later. It is common for affected individuals to become wheelchair dependent, often by age 30 years [Claramunt et al 2005].

Some families with CMT4A have features of a demyelinating neuropathy, whereas others have features of axonal neuropathy [Nelis et al 2002b, Claramunt et al 2005, Kabzińska et al 2006b]. NCVs range from very slow to normal (from 18 to >50 m/s) [Ammar et al 2003, Senderek et al 2003a].

Mild sensory loss, absent tendon reflexes, skeletal deformities, and scoliosis can be observed. Vocal cord paresis may occur [Sevilla et al 2003, Stojkovic et al 2004, Sevilla et al 2008].

Nerve biopsy reveals hypomyelination with onion bulbs composed of basal laminae [Nelis et al 2002b, Kabzińska et al 2005, Kabzińska et al 2006b].

Cerebrospinal fluid protein concentration is normal.

Manifesting heterozygotes. Some individuals with a heterozygous GDAP1 pathogenic variant can have mild signs and symptoms of neuropathy compatible with autosomal dominant inheritance [Zimoń et al 2011, Kabzińska et al 2014].

CMT4B1 was first described in an Italian family by Quattrone et al [1996]. Five families of Italian and Saudi Arabian ancestry have been reported [Bolino et al 2000, Houlden 2001]. Nelis et al [2002a] and Parman et al [2004] reported two additional families showing variability in age of onset and severity. Progressive distal and proximal weakness of the lower limbs is noted in early childhood (mean onset age 34 months). Pes cavus foot deformity is common and a few individuals develop facial weakness. Nouioua et al [2011] reported associated vocal cord paresis, chest deformities, and claw hands.

Adults who are affected are seriously handicapped and frequently require wheelchairs by age 20 years. Duration of illness ranges from age 27 to 39 years and death occurs in the fourth or fifth decade. Intellect is normal.

Two families were reported by Parman et al [2004].

In a family with an MTMR2 pathogenic variant and a 17p11.2 duplication, the phenotype was severe early childhood-onset demyelinating neuropathy [Verny et al 2004].

Auditory evoked potentials are abnormal.

NCVs are very slow (15-17 m/s) and often undetectable.

Sural nerve biopsy reveals irregular redundant loops of focally folded myelin.

CMT4B2 was identified in a Turkish family with a severe sensorimotor neuropathy with slow nerve conduction and focally folded myelin [Othmane et al 1999]. Azzedine et al [2003] identified two families from Tunisia and Morocco who also had early-onset glaucoma. Additional families have been reported [Conforti et al 2004, Chen et al 2014] including one with juvenile glaucoma [Hirano et al 2004].

A Japanese family with neuropathy and nerve pathology showing irregular redundant loops and folding of the myelin sheath has been associated with juvenile onset of glaucoma [Kiwaki et al 2000]. A pathogenic variant in SBF2 was subsequently identified in this family [Hirano et al 2004].

CMT4B3 was identified in a single Korean family with demyelinating phenotype and focally folded myelin sheaths on nerve biopsy [Nakhro et al 2013]. Bohlega et al [2011] reported a consanguineous Saudi family with sensory motor neuropathy with marked hand weakness, microcephaly, and cognitive impairment.

CMT4C was initially reported in consanguineous Algerian families, and subsequently in families from other countries of North Africa and western Europe [Gabreëls-Festen et al 1999, Senderek et al 2003b, Parman et al 2004]. Onset is in childhood or adolescence, often associated with pes cavus foot deformity and a mild walking disability with a progressive, often severe scoliosis after a 15-year disease duration. Houlden et al [2009b] noted considerable clinical variability, ranging from severe childhood onset to mild scoliosis and foot deformity.

Severe kyphoscoliosis and cranial nerve involvement were found in ten cases reported by Ferrarini et al [2011].

Affected individuals have motor and sensory neuropathy in the lower limbs and slow median NCV (mean is 24 m/s).

Nerve biopsy shows an increase of basal membranes around demyelinated and unmyelinated axons, relatively few classic onion bulbs, and large cytoplasmic extensions of the Schwann cells [Gabreëls-Festen et al 1999].

Manifesting heterozygotes. Lupski et al [2010] have suggested that persons heterozygous for either the SH3TC2 pathogenic variant p.Arg954Ter or p.Tyr169His may be at risk for a mild late-onset neuropathy.

CMT4D has been reported in Bulgarian Gypsies by Kalaydjieva et al [1998] originating from the community of Lom on the Danube caused by a founder NDRG1 pathogenic variant (p.Arg148Ter). Progressive sensory motor neuropathy with slow NCVs is present and foot deformity is common [Guergueltcheva et al 2006, Claramunt et al 2007, Ricard et al 2013, Okamoto et al 2014].

CMT4D has the distinguishing clinical characteristic of sensorineural deafness, with onset usually in the third decade. Tongue atrophy has also been described.

A non-Gypsy family with CNS white matter lesions has been reported [Echaniz-Laguna et al 2007].

Nerve biopsy shows a hypertrophic onion bulb change.

CMT4E is a congenital hypomyelinating neuropathy (CHN) with early-onset slow NCVs and a Déjérine-Sottas syndrome-like presentation (see Nomenclature) [Boerkoel et al 2001a, Chung et al 2005]. Respiratory dysfunction and cranial nerve abnormalities may occur [Szigeti et al 2007].

Funalot et al [2012] have reported a child with severe CHN.

CMT4F is the designation for a severe demyelinating neuropathy with slow NCVs reported in three families [Delague et al 2000, Boerkoel et al 2001b, Guilbot et al 2001, Kijima et al 2004, Parman et al 2004].

Takashima et al [2002] described sibs in whom the phenotype was initially a marked sensory neuropathy with prominent demyelinating features.

A child had delayed motor milestones and marked weakness. Additional families are described by Kabzińska et al [2006a] and Otagiri et al [2006].

A more benign phenotype with later age of onset (7-12 years) but with marked spine deformities was reported by Nouioua et al [2011]. Tokunaga et al [2012] have also reported later onset and more benign course (including vocal cord paresis in one individual).

Prominent sensory loss occurred in one family [Auer-Grumbach et al 2008]. Sensory loss was also emphasized by Marchesi et al [2010].

Sural nerve pathology showed demyelination, onion bulbs, and focal myelin thickening.

CMT4G is a severe disabling form of peripheral neuropathy with prominent sensory loss and moderately reduced motor NCVs in Balkan (Russe) Gypsies linked to 10q22 [Guergueltcheva et al 2006, Hantke et al 2009]. CMT4G is less severe than CMT4D.

CMT4H was reported by De Sandre-Giovannoli et al [2005] as a severe demyelinating neuropathy linked to 12p11.2- p13.1. Associated findings are severe scoliosis, loss of myelinated nerve fibers, and outfoldings of the myelin sheath [Stendel et al 2007]. The early onset and prominent kyphoscoliosis have been confirmed in a Tunisian family reported by Boubaker et al [2013].

Two sibs in Ireland remained ambulatory into middle age [Houlden et al 2009a].

An Algerian and a Lebanese affected individual had marked slowing of nerve conductions [Baudot et al 2012].

CMT4J is a syndrome of severe childhood-onset demyelinating neuropathy [Chow et al 2007]. An individual with rapidly progressive paralysis without sensory symptoms was reported [Zhang et al 2008]. Nicholson et al [2011] have emphasized the highly variable onset age and severity, proximal and distal weakness that may be asymmetric, and frequent progression to severe amyotrophy.

Menezes et al [2014] reported a two generation family with a variety of compound heterozygous FIG4 pathogenic variants that masqueraded as “autosomal dominant” inheritance.

Genotype-Phenotype Correlations

In general, no specific consistent genotype-phenotype correlations are known.


Severe neuropathy with slow NCVs and onset in early childhood is often called the Déjérine-Sottas syndrome (DSS). This is a descriptive clinical term that does not refer to a specific disease because it is caused by pathogenic variants in multiple genes [Plante-Bordeneuve & Said 2002] (see CMT Overview).


The overall prevalence of hereditary neuropathies is estimated to be approximately 30:100,000 population. More than half of these cases are CMT type 1 (15:100,000).

The autosomal recessive forms of CMT are quite rare and often limited to specific ethnic groups (e.g., in North Africa), where they may be relatively common.

CMT4A is the most common cause of autosomal recessive CMT as noted in several studies [Bouhouche et al 2007, Auer-Grumbach et al 2008, Moroni et al 2009, Moroni et al 2012]. Two founder pathogenic variants have been identified GDAP1: p.Gln163Ter in Spain [Claramunt et al 2005] and p.Met116Arg in Italy [Di Maria et al 2004].

Three founder pathogenic variants are found in CMT4 in subgroups of the European Gypsy population [Gabrikova et al 2013, Sevilla et al 2013]:

Differential Diagnosis

See CMT Overview for a discussion of approach to diagnosis of other autosomal recessive disorders with peripheral neuropathy. Guidelines for genetic testing of individuals suspected of having a neuromuscular condition, such as CMT, have been published by Burgunder et al [2011] and Murphy et al [2012].

Baets et al [2011] reviewed the genetic spectrum of hereditary neuropathies presenting in the first year of life. The most common disorders are the CMT4 subtypes CMT4B2 (SBF2), CMT4C (SH3TC2), CMT4F (PRX), and CMT4H (FGD4).

CMT1E. Autosomal recessive inheritance of severe neuropathy has also been reported with homozygosity for single nucleotide variants in PMP22, in which heterozygous pathogenic variants typically cause the CMT1 phenotype. Parman et al [1999] and Numakura et al [2000] reported pathogenic variants in codon 157 (p.Arg157Gly) of PMP22 (NM_000304.2). The family reported by Parman et al [1999] included three sibs homozygous for the pathogenic variant and heterozygous, consanguineous, unaffected parents.

CMT2B1 is inherited in an autosomal recessive manner. In Algerian families, an autosomal recessive childhood- or adult-onset axonal neuropathy with progressively severe muscle weakness and wasting has been attributed to a unique homozygous pathogenic variant (p.Arg298Cys) in LMNA (NM_005572.3) which encodes the lamin A/C nuclear envelope proteins [De Sandre-Giovannoli et al 2002, Tazir et al 2004, Bouhouche et al 2007]. LMNA is mutated in several other genetic diseases, including Hutchinson-Gilford progeria syndrome.

CMT2B2. Leal et al [2001] reported an axonal neuropathy of late onset (mean age 34 years) in a Costa Rican family linked to 19q13.3. Berghoff et al [2004] further characterized this family and Rautenstrauss et al [2005] preliminarily reported a pathogenic variant in MED25. Some authors refer to this as CMT2B2 because it is an axonal neuropathy (although inherited in an autosomal recessive manner rather than an autosomal dominant manner).

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum, an autosomal recessive severe sensorimotor neuropathy with intellectual disability and agenesis of the corpus callosum has been reported in individuals from Quebec. It is caused by pathogenic variants in SLC12A6 (former names: ACCPN, KCC3), the gene encoding the K-Cl cotransporter [Howard et al 2002].

Other unclassified autosomal recessive neuropathies

  • COX6A1. Tamiya et al [2014] reported two consanguineous Japanese families with childhood onset slowly progressive axonal neuropathy with a 5-bp deletion in COX6A1, a component of mitochondrial complex IV.
  • HINT1. Loss-of-function pathogenic variants cause a motor (greater than sensory) axonal neuropathy with neuromyotonia (spontaneous high-frequency motor unit potentials on EMG) and myokymia [Zimoń et al 2012]. Hahn et al [1991] described the clinical details of this disorder including muscle cramping, twitching, distal weakness, and increased perspiration.
  • MME. Higuchi et al [2016] reported ten families from Japan with late onset (4th-6th decade) of axonal neuropathy associated with weakness, muscle atrophy, and sensory loss in the lower limbs. Homozygous and compound heterozygous missense and nonsense variants were identified in MME. Although MME encodes neprilysin (NEP) which is known to degrade beta amyloid, no evidence of dementia or Aβ accumulation was found [Higuchi et al 2016].
  • SIGMAR1. Li et al [2015] reported a consanguineous Chinese family with a childhood-onset distal motor neuropathy associated with distal muscle weakness and atrophy, pes cavus, and claw hands segregating an alternative splicing event in SIGMAR1 resulting in a truncated protein.
  • SURF1. Three individuals from consanguineous families with childhood-onset demyelinating motor/sensory neuropathy associated with nystagmus, lactic acidosis, hyperintense lesions in the putamen on T1-weighted MRI, and later development of cerebellar ataxia had complex IV deficiency in muscle fibers associated with biallelic (i.e., homozygous or compound heterozygous) SURF1 pathogenic variants [Echaniz-Laguna et al 2013]. Mutation of SURF1 has also been associated with Leigh syndrome.
  • TRIM2. The compound heterozygous pathogenic variants (p.Glu227Val and p.Lys567Argfs7Ter) were reported in a female with childhood-onset axonal and demyelinating neuropathy with low weight and small muscle mass [Ylikallio et al 2013]. Nerve biopsy showed enlarged myelinated fibers with increased density of neurofilaments. Vocal cord paralysis has been reported with a homozygous TRIM2 missense pathogenic variant [Pehlivan et al 2015].
  • VRK1. Gonzaga-Jauregui et al [2013] reported two families with early childhood onset progressive complex axonal motor sensory neuropathy with microcephaly and normal cognition with homozygous VRK1 nonsense pathogenic variants n.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4 (CMT4), the following evaluations are recommended:

  • Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
  • NCV to help determine whether the disease is axonal, demyelinating, or mixed
  • Detailed family history
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The affected individual is often managed by a multidisciplinary team that includes a neurologist, physiatrist, orthopedic surgeon, and physical and occupational therapists [Pareyson & Marchesi 2009, Reilly & Shy 2009, Rossor et al 2015].

Treatment is symptomatic and may include the following:

  • Special shoes, including those with good ankle support
  • Ankle/foot orthoses to correct foot drop and aid walking
  • Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000, Ward et al 2008]
  • Forearm crutches or canes for gait stability; fewer than 5% of affected individuals need wheelchairs.
  • Exercise within the individual's capability to remain physically active

Prevention of Secondary Complications

Daily heel cord stretching exercises are helpful in preventing Achilles' tendon shortening.


Children's feet should be watched at regular intervals to provide for properly fitting shoes and avoid sores and skin breakdown.

It is appropriate to monitor gait and condition of feet to determine need for bracing, special shoes, and/or surgery.

Agents/Circumstances to Avoid

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

Medications which are toxic or potentially toxic to persons with CMT comprise a range of risk from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No specific pregnancy management recommendations have been published. However, weight gain during pregnancy may produce additional gait disability.

Therapies Under Investigation

Ekins et al [2015] and Mathis et al [2015] have reviewed prior and ongoing treatment trials for CMT.

Search Clinical Trials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.


Career and employment may be influenced by the persistent weakness of hands and/or feet.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

All of the Charcot-Marie-Tooth neuropathy type 4 (CMT4) subtypes discussed in this GeneReview (CMT4A, 4B1, 4B2, 4B3, 4C, 4D, 4E, 4F, 4G, 4H, and 4J) are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • Parents of an affected individual are obligate heterozygotes and therefore carriers of one of the CMT4 subtype-related pathogenic variants present in the proband.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing CMT.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a 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 of one of the CMT4 subtype-related pathogenic variants present in the proband is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with CMT4 are obligate heterozygotes (carriers) for one of the CMT4 subtype-related pathogenic variants present in the proband.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, 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, are carriers, or are at risk of being carriers.

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 and Preimplantation Genetic Testing

Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CMT4 are possible.

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.


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
    Email: info@cmtausa.org
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Fax: 03 2651002
    Email: gisele.smeyers@ua.ac.be
  • 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
    Email: info@hnf-cure.org
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
    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
    Email: info@treat-nmd.eu
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    Evry cedex 91002
    Phone: +33 01 69 47 28 28
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    3743 JN Baarn
    Phone: 31 35 5480481
    Fax: 31 35 5480499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.org
  • RDCRN Patient Contact Registry: Inherited Neuropathies Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Charcot-Marie-Tooth Neuropathy Type 4: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 4 (View All in OMIM)


For a detailed summary of gene and protein information for the following genes, see Table A, Gene.


Gene structure. The gene comprises six exons, 13.9 kb, and an open reading frame of 1,077 nucleotides.

Pathogenic variants. Nonsense, missense, and frameshift variants

Table 3.

Selected GDAP1 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.347T>Gp.Met116Arg NM_018972​.2
c.358C>T 1p.Arg120Trp

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.


Associated with autosomal dominant inheritance; see Genetically Related Disorders.

Normal gene product. Ganglioside-induced differentiation-associated protein 1 [Baxter et al 2002]. The protein is highly expressed in neuronal mitochondria [Pedrola et al 2005].

Abnormal gene product. It is speculated that pathogenic variants may prevent the correct catalyzing S conjugation of reduced GCH, resulting in progressive attrition of both axons and Schwann cells. Pathogenic variants in GDAP1 cause abnormalities of mitochondrial dynamics [Cassereau et al 2011, Noack et al 2012].


Gene structure. The gene comprises 18 exons with an ORF of 1,932 nucleotides.

Pathogenic variants. Missense, nonsense, and splicing variants and small deletions

Table 4.

Selected MTMR2 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.826G>Tp.Glu276Ter NM_016156​.5

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Myotubularin-related protein 2 (MTMR2), a 643-amino acid protein, dephosphorylates phosphatidylinositol 3-phosphate. MTMR2 may interact with SBF2/MTMR13, the protein involved in CMT4B2 [Bolis et al 2007].

Abnormal gene product. Reduced phosphatase activity could cause malfunction of neural membrane recycling or trafficking [Berger et al 2002]. A mouse model with the equivalent of the human p.Glu276Ter pathogenic variant has been produced [Bonneick et al 2005] with myelin infoldings and outfoldings but no electrophysiologic changes. Cotter et al [2010] and Vaccari et al [2011]. show evidence that MTMR2 and FIG4 interact in both Schwann cells and neurons and that imbalance of PtdIns(3,5)P(2) is the basis of altered myelin growth.


Gene structure. SBF2 (also called MTMR13; myotubularin-related 13 gene) has at least 40 exons spanning approximately 600 kb.

Pathogenic variants. One family with CMT4B2 has a homozygous in-frame deletion of SBF2 exons 11 and 12 [Senderek et al 2003c]. Two nonsense variants in exons 23 and 27 have been reported [Azzedine et al 2003]. An Italian family had a pathogenic variant in the splice donor site of intron 32 [Conforti et al 2004].

Normal gene product. SBF2 is an 1849-amino acid member of the pseudophosphatase branch of myotubularins with striking homology to MTMR2, the gene that is mutated in CMT4B1.

Abnormal gene product. The pathogenic variant associated with SBF2 is predicted to disrupt an N-terminal domain of SBF2 that is highly conserved and may be important in sequestering proteins in the cytoplasmic compartment. A mouse model has reduced nerve conductions and myelin outfoldings/infoldings [Robinson et al 2008].


Gene structure. SBF1 comprises 41 exons (NM_002972.2).

Pathogenic variants. Nakhro et al [2013] found the heterozygous missense variants (c.1249A>G;p.Met417Val and c.4768A>G;p.Thr1590Ala) in a family with autosomal recessive demyelinating CMT.

Normal gene product. SET binding factor 1 is a member of the myotublarin family without known enzymatic function. SBF1 protein (1893 amino acids) and its mRNA have 59% overall sequence identity to SBF2.

Abnormal gene product. Mutation results in abnormal peripheral nerve/Schwann cell dysfunction by unknown mechanisms, possibly through interaction with myotubularin related protein 2 (MTMR2).


Gene structure. 62 kb of genomic sequence with 18 exons. Alternative splicing events may occur at exon 6 and between exons 8 and 9 with retention of intron 10.

Pathogenic variants. Eight protein-truncating pathogenic variants and three missense variants (homozygous or compound heterozygous) [Senderek et al 2003b]; p.Arg954Ter is a common pathogenic variant [Houlden et al 2009b].

Table 5.

Selected SH3TC2 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.505T>Cp.Tyr169His NM_024577​.3
c.3325C>Tp.Arg1109Ter 1

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.


A founder variant in Spanish Gypsies [Claramunt et al 2007]

Normal gene product. The ORF predicts a protein of 1,288 amino acids with no known function.

Abnormal gene product. Pathogenic variants may disrupt the formation of protein complexes. SH3TC2 pathogenic variants disrupt an interaction with Rab11 in myelin formation [Stendel et al 2010].


Gene structure. 60 kb of genomic DNA containing 16 exons, including an untranslated first exon

Pathogenic variants. A premature termination codon at position 148 (p.Arg148Ter) [Kalaydjieva et al 2000]

Table 6.

Selected NDRG1 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.442C>Tp.Arg148Ter NM_001135242​.1

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. It is proposed that the protein NDRG1 is involved in growth arrest and cell differentiation during development. It is highly expressed in peripheral nerves and Schwann cells.

Abnormal gene product. Abnormal protein NDRG1 may have abnormal interaction with PMP22 preventing development and maintenance of peripheral nerve/Schwann cell function and integrity.


Gene structure. EGR2 spans 4.3 kb and has two coding exons.

Pathogenic variants. Homozygosity for p.Ile268Asn has been observed.

Table 7.

Selected EGR2 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.803T>Ap.Ile268Asn NM_000399​.3

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Early growth response protein 2. Zinc finger transcription factor. Ortholog of murine Krox-2. Induces expression of several proteins involved in myelin sheath formation and maintenance.

Abnormal gene product. Krox-2 null mice show a block of Schwann cell differentiation. Conduction block occurs in a mouse model with the p.Ile268Asn pathogenic variant in EGR2 [Baloh et al 2009].


Gene structure. Boerkoel et al [2001b] found two PRX transcripts of 4853 and 5502 bp, excluding the polyA tails. The shorter mRNA is transcribed from seven exons and the deduced coding sequence extends from exon 4 through exon 7. The longer transcript arises by retention of intron 6, which introduces a stop codon and results in a truncated protein with an intron-encoded carboxyl terminus of 21 amino acids.

Pathogenic variants. Nonsense and frameshift pathogenic variants. The pathogenic variant p.Arg1070Ter is a mutation hot spot [Otagiri et al 2006].

Table 8.

Selected PRX Pathogenic Variants

DNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Reference Sequences

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions

Normal gene product. L and S periaxin, cytoskeletal proteins that may regulate Schwann cell shape and bind dystroglycan dystrophin-related protein-2. Found in the paranodal region of mature myelin sheaths. As myelin matures, periaxin moves from the adaxonal to the abaxonal membrane [Saifi et al 2003].

Abnormal gene product. Mice disrupted for Prx develop PNS compact myelin that degenerates as animals age [Gillespie et al 2000].


Gene structure. HK1 transcript variant NM_033498.2 has 21 exons including two noncoding exons. The gene spans 75-100kb. Alternative splicing results in five different transcript variants, some of which are tissue-specific. For details, see Table A, Gene. Note that HK1 is one of four different genes (with HK2, HK3, and HK4) encoding different forms of hexokinase.

Pathogenic variants. c.-249-3838G>C in an alternative untranslated exon of HK1 [Gabrikova et al 2013, Sevilla et al 2013] is a founder variant in the Balkan (Russe) Gypsies [Rogers et al 2000, Thomas et al 2001, Sevilla et al 2013].

Table 9.

HK1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequence
c.-249-3838G>C 2, 3
(g.9712G>C) 4
None 2 NM_033498​.2

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


Variant occurs in a novel alternative untranslated exon in HK1 [Sevilla et al 2013].


See rs397514654 for additional HGVS names and reference sequences for this variant.


Published designation of variant [Gabrikova et al 2013, Sevilla et al 2013]

Normal gene product. Hexokinase catalyzes the first step in glucose metabolism, using ATP for the phosphorylation of glucose to glucose-6-phosphate. Mitochondrially associated HK1 plays a role in growth factor- and Akt-mediated cell survival.

Abnormal gene product. Pathogenic variants in the HK1 coding sequence lead to enzyme deficiency and nonspherocytic hemolytic anemia. The consequence of the c.-249-3838G>C change in the untranslated exon associated with neuropathy is unknown.


Gene structure. FGD4 has 17 exons and a transcript of 2931 nucleotides [Delague et al 2007].

Pathogenic variants. Homozygous missense variants (p.Met298Arg and p.Met298Thr) [Delague et al 2007] as well as nonsense and frameshift variants are reported [Stendel et al 2007]. Missense, frameshift, and nonsense pathogenic variants and deletion of exon 2 have been reported [Delague et al 2007, Nicholson et al 2011].

Table 10.

Selected FGD4 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.823C>Tp.Arg275Ter NM_139241​.2
c.1698G>H 1p.Met566Ile

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.


H indicates sequence ambiguity; could be A, C, or T nucleotide.

Normal gene product. FGD4 encodes FYVE, RhoGEF and PH domain-containing protein 4 (frabin), a 766 amino-acid protein nucleotide exchange factor mediating actin cytoskeletal changes.

Abnormal gene product. Rat spiral motoneurons with Fgd4 pathogenic variants have reduced microspike formation [Delague et al 2007].


Gene structure. FIG4 has 23 coding exons.

Pathogenic variants. In four families, the p.Ile41Thr missense pathogenic variant in exon 2 occurs in the compound heterozygous state with several other protein truncating variants in affected persons [Chow et al 2007].

Table 11.

Selected FIG4 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.122T>Cp.Ile41Thr NM_014845​.5

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Phosphatidylinositol 3, 5 biphosphate (PtdIns (3,5) P2)

Abnormal gene product. Mice with a pathogenic variant in Fig4 (pale tremor mouse) have a complex phenotype that includes peripheral neuropathy and neurodegeneration in autonomic ganglia, cerebral cortex, and deep cerebellar nuclei, skin, and spleen [Chow et al 2007, Winters et al 2011]. Cotter et al [2010] and Vaccari et al [2011] show evidence that MTMR2 and FIG4 interact in both Schwann cells and neurons and that imbalance of PtdIns(3,5)P(2) is the basis of altered myelin growth. The common p.Ile41Thr pathogenic variant produces an unstable protein and a level of 10% of normal may be sufficient for nerve survival [Lenk et al 2011].


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  • Zimoń M, Baets J, Almeida-Souza L, De Vriendt E, Nikodinovic J, Parman Y, Battalo Gcaron Lu E, Matur Z, Guergueltcheva V, Tournev I, Auer-Grumbach M, De Rijk P, Petersen BS, Müller T, Fransen E, Van Damme P, Löscher WN, Barišić N, Mitrovic Z, Previtali SC, Topalo Gcaron Lu H, Bernert G, Beleza-Meireles A, Todorovic S, Savic-Pavicevic D, Ishpekova B, Lechner S, Peeters K, Ooms T, Hahn AF, Züchner S, Timmerman V, Van Dijck P, Rasic VM, Janecke AR, De Jonghe P, Jordanova A. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet. 2012;44:1080–3. [PubMed: 22961002]
  • Zimoń M, Baets J, Fabrizi GM, Jaakkola E, Kabzińska D, Pilch J, Schindler AB, Cornblath DR, Fischbeck KH, Auer-Grumbach M, Guelly C, Huber N, De Vriendt E, Timmerman V, Suter U, Hausmanowa-Petrusewicz I, Niemann A, Kochański A, De Jonghe P, Jordanova A. Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology. 2011;77:540–8. [PMC free article: PMC3272385] [PubMed: 21753178]

Suggested Reading

  • Bernard R, De Sandre-Giovannoli A, Delague V, Levy N. Molecular genetics of autosomal-recessive axonal Charcot-Marie-Tooth neuropathies. Neuromolecular Med. 2006;8:87–106. [PubMed: 16775369]
  • Vallat JM, Tazir M, Magdelaine C, Sturtz F, Grid D. Autosomal-recessive Charcot-Marie-Tooth diseases. J Neuropathol Exp Neurol. 2005;64:363–70. [PubMed: 15892292]

Chapter Notes

Revision History

  • 5 July 2018 (ma) Chapter retired: covered in Charcot-Marie-Tooth Hereditary Neuropathy Overview
  • 14 April 2016 (tb) Revision: MME and related reference added
  • 20 August 2015 (me) Comprehensive update posted live
  • 17 April 2014 (tb) Revision: edits to TRIM2
  • 20 February 2014 (tb) Revision: Ylikallio et al 2013 reference added describing one person with an unclassified recessive neuropathy
  • 26 September 2013 (tb) Revision: to Differential Diagnosis -- information on SURF1 deficiency [Echaniz-Laguna et al 2103]
  • 8 August 2013 (tb) Revision: addition of add FIG4 deletion/duplication analysis and CMT4B3 (SBF1)
  • 11 October 2012 (tb) Revision: hereditary neuropathy with neuromyotonia (caused by mutations in HINT1) included as a type of CMT4
  • 13 September 2012 (me) Comprehensive update posted live
  • 27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
  • 22 April 2010 (me) Comprehensive update posted live
  • 30 April 2009 (cd) Revision: sequence analysis available clinically for CMT4H
  • 12 June 2008 (cd) Revision: sequence analysis of entire NDRG1 coding region available clinically
  • 6 September 2007 (me) Comprehensive update posted live
  • 15 April 2005 (me) Comprehensive update posted live
  • 19 December 2003 (tb) Author revisions
  • 24 October 2003 (cd,tb) Revision: change in test availability
  • 21 August 2003 (cd,tb) Revision: change in gene name
  • 29 May 2003 (tb) Author revisions
  • 4 April 2003 (me) Comprehensive update posted live
  • 8 November 2001 (tb) Author revisions
  • 27 June 2001 (tb) Author revisions
  • 22 June 2001 (tb) Author revisions
  • 11 April 2001 (tb) Author revisions
  • 25 September 2000 (tb) Author revisions
  • 25 August 2000 (me) Comprehensive update posted live
  • 15 June 2000 (tb) Author revisions
  • 15 May 2000 (tb) Author revisions
  • 14 January 2000 (tb) Author revisions
  • 24 September 1999 (tb) Author revisions
  • 31 August 1999 (tb) Author revisions
  • 18 June 1999 (tb) Author revisions
  • 8 April 1999 (tb) Author revisions
  • 24 September 1998 (tb) Review posted live
  • April 1996 (tb) Original submission
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