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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Charcot-Marie-Tooth Neuropathy Type 4

Synonym: CMT4
, MD
Seattle VA Medical Center
Departments of Neurology and Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Revision: April 17, 2014.

Summary

Disease 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.

Diagnosis/testing. The diagnosis of CMT4 subtypes is based on clinical, pathologic, and genetic criteria. The genes associated with ten CMT4 subtypes have been identified: GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), FGD4 (CMT4H), and FIG4 (CMT4J).

Management. 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 (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 gene mutation 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 disease-causing mutations in an affected family member are known.

GeneReview Scope

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

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

Charcot-Marie-Tooth neuropathy type 4 (CMT4) is diagnosed in individuals with the following:

Molecular Genetic Testing

Genes

Evidence for locus heterogeneity

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in CMT4

Locus Name Gene 1Proportion of CMT4 Attributed to Mutations in This Gene 2Test Method Mutations Detected 3
CMT4AGDAP1~25%Sequence analysis 4Sequence variants
CMT4B1MTMR2RareSequence analysis 4Sequence variants
CMT4B2SBF2RareSequence analysis 4Sequence variants
CMT4B3SBF1RareSequence analysis 4Sequence variants
CMT4CSH3TC2 RareSequence analysis 4Sequence variants
Sequence analysis of select exons 4, 5Sequence variants in selected exons
Deletion/duplication analysis 6None reported 7
CMT4DNDRG1RareTargeted mutation analysisp.Arg148Ter
Sequence analysis of select exons 4, 5Sequence variants in select exons
Sequence analysis 4Sequence variants
CMT4EEGR2RareSequence analysis 4Sequence variants
CMT4FPRXRareSequence analysis 4Sequence variants
CMT4HFGD4RareSequence analysis 4Sequence variants
CMT4JFIG4RareSequence analysis 4Sequence variants
Deletion/duplication analysis 6Exonic or whole-gene deletions 8

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. Proportion of affected individuals with a mutation(s) as classified by CMT4 subtype; each subtype is identified based on detection of a mutation in the relevant gene; hence, the mutation detection frequency is 100%.

3. See Molecular Genetics for information on allelic variants.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Typically exon 7; selected exons may vary by laboratory.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. No deletions or duplications involving SH3TC2 have been reported to cause Charcot-Marie-Tooth neuropathy type 4C.

8. Nicholson et al [2011] reported missense, frameshift, and nonsense mutations as well as a deletion of exon 2 in FIG4.

Testing Strategy

To confirm/establishthe diagnosis in a proband. In families in which an autosomal recessive neuropathy is suspected, it is reasonable to test first for mutations in GDAP1 (CMT4A) because it is most common; CMT4E (EGR2) is perhaps the next most common. All others are rare (see Differential Diagnosis).

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

The subtypes of Charcot-Marie-Tooth neuropathy type 4 (CMT4) are based on clinical characteristics, ethnic background, neuropathologic findings, and associated gene or chromosomal locus. 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.) Some subtypes have specific clinical characteristics such as the sensorineural deafness associated with CMT4D. 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]. At least one mutation in GDAP1 (p.Arg120Trp) has been associated with autosomal dominant inheritance [Claramunt et al 2005, Zimoń et al 2011].

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].

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].

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, Kabzinska et al 2006b]. NCVs range from very slow to normal (from 18 to >50 m/s) [Ammar et al 2003, Senderek et al 2003a].

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

Cerebrospinal fluid protein concentration is normal.

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 with two different frameshift mutations in MTMR2 were reported by Parman 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] 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 mutation 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].

CMT4C was initially reported in consanguineous Algerian families, and subsequently in families from other countries of North Africa and western Europe [Gabreels-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. A founder mutation (p.Arg1109Ter) in SH3TC2 has been identified in Spanish Gypsies [Claramunt et al 2007].

Severe kyphoscoliosis and cranial nerve involvement were found in ten cases reported by Ferrarini et al [2011]; p.Arg954Ter was the most common mutation in SH3TC2.

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 [Gabreels-Festen et al 1999].

Five different SH3TC2 mutations in Turkish families were reported by Deymeer et al [2011].

The p.Arg1109Ter mutation is reported as a founder mutation in Spanish Gypsies [Claramunt et al 2007].

Lupski et al [2010] have suggested that heterozygous carriers of an SH3TC2 mutation (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 mutation (p.Arg148Ter) in NDRG1. Progressive sensory motor neuropathy with slow NCVs is present and foot deformity is common [Guergueltcheva et al 2006, Claramunt et al 2007].

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 homozygous for an EGR2 deletion including the myelin-specific enhanced region.

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 homozygous for the PRX mutation p.Cys715Ter in whom the phenotype was initially a marked sensory neuropathy with prominent demyelinating features.

A child with a different homozygous mutation (p.Leu83CysfsTer14) had delayed motor milestones and marked weakness. Additional families are described by Kabzinska 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 case) associated with two different mutations in PRX (p.Asp651Asn and p.Arg1070Ter).

Prominent sensory loss occurred in a family with the p.Ala700ProfsTer18 mutation [Auer-Grumbach et al 2008]. Sensory loss was also emphasized with four novel mutations reported by Marchesi et al [2010].

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

CMT4G is a severe neuropathy with prominent sensory loss found in Balkan (Russe) Gypsies [Guergueltcheva et al 2006].

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].

Two siblings in Ireland with the FGD4 p.Arg275Ter mutation remained ambulatory into middle age [Houlden et al 2009a]. A truncating mutation that creates a novel splice acceptor site (c.1762-2A>G) has been reported in an Italian patient [Fabrizi et al 2009].

Homozygous mutations in an Algerian (p.Arg442His) and a Lebanese (p.Met566Ile) patient were associated with marked slowing of nerve conductions [Baudot et al 2012].

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

Genotype-Phenotype Correlations

In general, no specific consistent correlations are known. However, the combination of mutation in GDAP1 and MFN2 causes a severe neuropathy [Cassereau et al 2011a, Vital et al 2012].

CMT4A. Genotype/phenotype correlations are reviewed by Cassereau et al [2011b]. Truncating mutations of GDAP1 produce a more severe phenotype.

CMT4B1. In a family with an MTMR2 mutation and a 17p11.2 duplication, the phenotype was severe early childhood-onset demyelinating neuropathy [Verny et al 2004].

Nomenclature

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 mutations in multiple genes [Plante-Bordeneuve & Said 2002] (see CMT Overview).

Prevalence

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.

Founder effects are observed for the GDAP1 mutations p.Gln163Ter in Spain [Claramunt et al 2005] and p.Met116Arg in Italy [Di Maria et al 2004].

Differential Diagnosis

See CMT Overview for a discussion of approach to diagnosis of other autosomal recessive disorders with peripheral neuropathy.

Baets et al [2011] reviewed the genetic spectrum of hereditary neuropathies presenting in the first year of life. The most common recessive mutations were in SH3TC2, PRX, SBF2, and FGD4.

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].

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

CMT2B1 is inherited in an autosomal recessive 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 from Quebec. It is caused by mutations in SLC12A6 (former names: ACCPN, KCC3), the gene encoding the K-Cl cotransporter [Howard et al 2002].

Other unclassified autosomal recessive neuropathies

  • A hereditary axonal neuropathy described in a large consanguineous Moroccan family begins in the second decade and is associated with areflexia, distal and/or proximal muscle weakness and atrophy, and pes cavus. The disease has been linked to chromosome 1q21 [Bouhouche et al 1999].
  • Thomas et al [1999] described a motor and sensory neuropathy with acrodystrophy causing severe distal sensory loss leading to prominent mutilating changes.
  • 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 mutation (p.Arg298Cys) in LMNA (NM_005572.3) that encodes the lamin A/C nuclear envelope proteins [De Sandre-Giovannoli et al 2002, Tazir et al 2004]. The same gene is mutated in several other genetic diseases, including CMT2B1 and Hutchinson-Gilford progeria syndrome.
  • Echaniz-Laguna et al [2013] reported three subjects from consanguineous families with childhood-onset demyelinating motor/sensory neuropathy associated with nystagmus, lactic acidosis, hyperintense lesions in the putamen on T1 MRI, and deficiency of COX activity in muscle fibers associated with homozygous or compound heterozygous mutation in SURF1. There was a later development of cerebellar ataxia. Mutations in SURF1 have also been associated with Leigh syndrome.
  • Compound heterozygous mutations (p.Glu227Val and p.Lys567Argfs7Ter) in TRIM2 have been reported in a single female with childhood-onset axonal and demyelinating neuropathy with low weight and small muscle mass [Ylikallio et al 2013]. TRIM2 is an E3 ubiquitin ligase; nerve biopsy showed enlarged myelinated fibers with increased density of neurofilaments.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease 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
  • Medical genetics consultation

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 [Carter et al 1995, Pareyson & Marchesi 2009, Reilly & Shy 2009].

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 [Carter et al 1995]
  • 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.

Surveillance

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 risks including:

  • Definite high risk. Vinca alkaloids (Vincristine)
    • This category should be avoided by all persons with CMT, including those who are asymptomatic.
  • Other potential risk levels. See Table 2. For more information click here (pdf).

Table 2. Medications Potentially Toxic to Persons with CMT

Moderate to Significant Risk 1
- Amiodarone (Cordarone)
- Bortezomib (Velcade)
- Cisplatin & Oxaliplatin
- Colchicine (extended use)
- Dapsone
- Didanosine (ddI, Videx)
- Dichloroacetate
- Disulfiram (Antabuse)
- Gold salts
- Leflunomide (Arava)
- Metronidazole/Misonidazole (extended use)
- Nitrofurantoin (Macrodantin, Furadantin, Macrobid)
- Nitrous oxide (inhalation abuse or Vitamin B12 deficiency)
- Perhexiline (not used in U.S.)
- Pyridoxine (mega dose of Vitamin B6)
- Stavudine (d4T, Zerit)
- Suramin
- Taxols (paclitaxel, docetaxel)
- Thalidomide
- Zalcitabine (ddC, Hivid)

Click here (pdf) for additional medications in lesser-risk categories.

The medications listed here present differing degrees of potential risk for worsening CMT neuropathy. Always consult your treating physician before taking or changing any medication.

1. Based on Weimer & Podwall [2006]. See also Graf et al [1996], Nishikawa et al [2008], and Porter et al [2009].

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

Carter et al [2008] and Young et al [2008] have reviewed prior and ongoing treatment trials for CMT.

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

Other

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, 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

All of the Charcot-Marie-Tooth neuropathy type 4 (CMT4) subtypes discussed in this GeneReview (CMT4A, 4B1, 4B2, 4B3, 4C, 4D, 4E, 4F, 4H, 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 are asymptomatic.

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.

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 Detection

Carrier testing is possible if the pathogenic variants have been identified in an affected family member.

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 or are 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variants have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

Resources

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
    13 allée de Grèce
    35140 Saint Aubin du Cormier
    France
    Phone: 820 077 540; 2 47 27 96 41
  • Charcot-Marie-Tooth Association (CMTA)
    2700 Chestnut Street
    Chester PA 19013-4867
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@charcot-marie-tooth.org
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Belgium
    Fax: 03 2651002
    Email: gisele.smeyers@ua.ac.be
  • Hereditary Neuropathy Foundation, Inc.
    1751 2nd Avenue
    Suite 103
    New York NY 10128
    Phone: 877-463-1287 (toll-free); 212-722-8396
    Email: info@hnf-cure.org
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • TREAT-NMD
    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 8605
    Fax: 44 0 191 241 8770
    Email: info@treat-nmd.eu
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    BP59
    Evry 91002
    France
    Phone: +33 01 69 47 28 28
    Fax: 01 69 47 77 12 16
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    JN Baarn 3743
    Netherlands
    Phone: 035 54 80 481
    Fax: 035 54 80 499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

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

129010EARLY GROWTH RESPONSE 2; EGR2
145900HYPERTROPHIC NEUROPATHY OF DEJERINE-SOTTAS
214400CHARCOT-MARIE-TOOTH DISEASE, TYPE 4A; CMT4A
601382CHARCOT-MARIE-TOOTH DISEASE, TYPE 4B1; CMT4B1
601455CHARCOT-MARIE-TOOTH DISEASE, TYPE 4D; CMT4D
601596CHARCOT-MARIE-TOOTH DISEASE, TYPE 4C; CMT4C
603557MYOTUBULARIN-RELATED PROTEIN 2; MTMR2
603560SET-BINDING FACTOR 1; SBF1
604563CHARCOT-MARIE-TOOTH DISEASE, TYPE 4B2; CMT4B2
605253NEUROPATHY, CONGENITAL HYPOMYELINATING OR AMYELINATING, AUTOSOMAL RECESSIVE; CHN
605262NMYC DOWNSTREAM-REGULATED GENE 1; NDRG1
605725PERIAXIN; PRX
606598GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1
607697SET-BINDING FACTOR 2; SBF2
608206SH3 DOMAIN AND TETRATRICOPEPTIDE REPEAT DOMAIN 2; SH3TC2
609311CHARCOT-MARIE-TOOTH DISEASE, TYPE 4H; CMT4H
609390FIG4, S. CEREVISIAE, HOMOLOG OF; FIG4
611104FYVE, RhoGEF, AND PH DOMAIN-CONTAINING PROTEIN 4; FGD4
611228CHARCOT-MARIE-TOOTH DISEASE, TYPE 4J; CMT4J
615284CHARCOT-MARIE-TOOTH DISEASE, TYPE 4B3; CMT4B3

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

GDAP1

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

Pathogenic allelic variants. Nonsense, missense, and frameshift mutations

Table 3. Selected GDAP1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.347T>Gp.Met116ArgNM_018972​.2
NP_061845​.2
c.487C>Tp.Gln163Ter
c.358C>T 1p.Arg120Trp

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

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

1. Associated with autosomal dominant inheritance; see Natural History.

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 mutations may prevent the correct catalyzing S conjugation of reduced GCH, resulting in progressive attrition of both axons and Schwann cells. Mutations in GDAP1 cause abnormalities of mitochondrial dynamics [Cassereau et al 2011c, Noack et al 2012].

MTMR2

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

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

Table 4. Selected MTMR2 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.826G>Tp.Glu276TerNM_016156​.5
NP_057240​.3

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

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.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 mutation 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.

SBF2 (MTMR13)

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

Pathogenic allelic variants. One family with CMT4B2 has a homozygous in-frame deletion of SBF2 exons 11 and 12 [Senderek et al 2003c]. Two nonsense mutations in exons 23 and 27 have been reported [Azzedine et al 2003]. An Italian family had a mutation 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 mutation 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].

SBF1 (MTMR5)

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

Pathogenic allelic variants. Nakhro et al [2013] found heterozygous missense variants in SBF1 (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).

SH3TC2

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

Table 5. Selected SH3TC2 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.505T>Cp.Tyr169HisNM_024577​.3
NP_078853​.2
c.2860C>Tp.Arg954Ter
c.3325C>Tp.Arg1109Ter 1

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

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

1. A founder mutation 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. Mutations may disrupt the formation of protein complexes. SH3TC2 mutations disrupt an interaction with Rab11 in myelin formation [Stendel et al 2010].

NDRG1

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

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

Table 6. Selected NDRG1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.442C>Tp.Arg148TerNM_001135242​.1
NP_001128714​.1

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

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

Normal gene product. Protein NDRG1 is proposed to be 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.

EGR2

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

Pathogenic allelic variants. Homozygosity for p.Ile268Asn causes a recessive neuropathy.

Table 7. Selected EGR2 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.803T>Ap.Ile268AsnNM_000399​.3
NP_000390​.2

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

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.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 mutation in EGR2 [Baloh et al 2009].

PRX

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

Table 8. Selected PRX Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.247delCp.Leu83CysfsTer14
(p.Arg82fsTer96)
NM_181882​.2
NP_870998​.2
c.1951G>Ap.Asp651Asn
c. delGp.Ala700ProfsTer18
(Ala700ProfsTer17)
c.2145T>Ap.Cys715Ter
c.3208C>Tp.Arg1070Ter

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

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

1. 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].

FGD4

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

Pathogenic allelic variants. Homozygous missense variants (p.Met298Arg and p.Met298Thr) [Delague et al 2007] as well as nonsense and frameshift mutations are reported [Stendel et al 2007].

Table 9. Selected FGD4 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.823C>Tp.Arg275TerNM_139241​.2
NP_640334​.2
c.893T>Gp.Met298Arg
c.1325G>Ap.Arg442His
c.893T>Cp.Met298Thr
c.1698G>H 1p.Met566Ile
c.1762-2A>G--

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

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

1. 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 mutations have reduced microspike formation [Delague et al 2007].

FIG4

Gene structure. FIG4 has 23 coding exons.

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

Table 10. Selected FIG4 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.122T>Cp.Ile41ThrNM_014845​.5
NP_055660​.1

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

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.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 mutation 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 mutation produces an unstable protein and a level of 10% of normal may be sufficient for nerve survival [Lenk et al 2011].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Suggested Reading

  1. 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]
  2. 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

  • 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 to live Web site
  • 15 April 2005 (me) Comprehensive update posted to live Web site
  • 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 to live Web site
  • 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 to live Web site
  • 15 June 2000 (tb) Author revisions
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  • 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 to live Web site
  • April 1996 (tb) Original submission
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