Clinical Diagnosis

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

• Progressive motor and sensory neuropathy
• Nerve conduction velocities (NCVs) that are usually slow (<40 m/s)
• A family history consistent with autosomal recessive inheritance (i.e., parents not affected unless multigenerational consanguinity exists)

Molecular Genetic Testing

Genes

• CMT4A. GDAP1 [Palau et al 2001, Baxter et al 2002, Cuesta et al 2002]. About 25% of autosomal recessive CMT is attributable to mutations in GDAP1 [Zuchner & Vance 2010].
• CMT4B1. MTMR2 [Bolino et al 2000]
• CMT4B2. SBF2 (MTMR13) [Azzedine et al 2003, Senderek et al 2003c]
• CMT4C. SH3TC2 (KIAA1985) [Senderek et al 2003b]
• CMT4D. NDRG1 [Kalaydjieva et al 2000]
• CMT4E. EGR2 [Warner et al 1999, Boerkoel et al 2001a]
• CMT4F. PRX [Boerkoel et al 2001b]
• CMT4H. FGD4 [Delague et al 2007]
• CMT4J. FIG4 [Chow et al 2007]

Evidence for locus heterogeneity

• 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 mutation 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).
• An autosomal recessive neuropathy with mutations in LMNA has been referred to as CMT2B1 [Bouhouche et al 2007].
• Barhoumi et al [2001] reported a Tunisian family with severe CMT linked to 8q21.3. (Some classifications consider this CMT2H.)
• CMT4G. Rogers et al [2000] and Thomas et al [2001] reported a severe disabling form of peripheral neuropathy with prominent sensory loss and moderately reduced motor NCVs in Balkan (Russe) Gypsies linked to 10q22. The disease is less severe than CMT4D, occurring in the Lom Gypsies [Guergueltcheva et al 2006].
• Zimoń et al [2012] reported loss-of-function mutations in HINT1 causing an autosomal recessive motor (greater than sensory) axonal neuropathy with neuromyotonia (spontaneous high-frequency motor unit potentials on EMG). Hahn et al [1991] described the clinical details of this disease including muscle cramping, twitching, and distal weakness.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in CMT4

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Locus Name	Gene Symbol	Proportion of CMT4 Attributed to Mutations in This Gene 1	Test Method	Mutations Detected	Test Availability
CMT4A	GDAP1	~25%	Sequence analysis	Sequence variants 2	Clinical
CMT4B1	MTMR2	Rare	Sequence analysis	Sequence variants 2	Clinical
CMT4B2	SBF2	Rare	Sequence analysis	Sequence variants 2	Clinical
CMT4C	SH3TC2	Rare	Sequence analysis	Sequence variants 2	Clinical
			Sequence analysis of select exons 3	Sequence variants 2 in selected exons
			Deletion / duplication analysis 4	None reported 5
CMT4D	NDRG1	Rare	Targeted mutation analysis	p.Arg148X	Clinical
			Sequence analysis of select exons 3	Sequence variants 2 in select exons
			Sequence analysis	Sequence variants 2
CMT4E	EGR2	Rare	Sequence analysis	Sequence variants 2	Clinical
CMT4F	PRX	Rare	Sequence analysis	Sequence variants 2	Clinical
CMT4H	FGD4	Rare	Sequence analysis	Sequence variants 2	Clinical
CMT4J	FIG4	Rare	Sequence analysis	Sequence variants 2	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. 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%.

2. 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.

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

4. 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. See CMA.

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

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

GDAP1. Mutations in GDAP1 have occasionally been associated with autosomal dominant inheritance (CMT2K) [Claramunt et al 2005].

MTMR2. CMT4B1 is the only phenotype associated with mutations in MTMR2.

SBF2. CMT4B2 is the only phenotype associated with mutations in SBF2.

SH3TC2. CMT4C is the only phenotype associated with mutations in SH3TC2 (KIAA1985).

NDRG1. CMT4D is the only phenotype associated with mutations in NDRG1.

EGR2 . Mutations in EGR2 are associated with CMT4E and autosomal dominant CMT1D [Warner et al 1999, Boerkoel et al 2001a].

PRX. CMT4F is the only phenotype associated with PRX.

FGD4. CMT4H is the only phenotype associated with FGD4.

FIG4. CMT4J is the only phenotype associated with FIG4.

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].

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.Arg1109X) 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.Arg954X 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.Arg1109X 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.Arg954X 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.Arg148X) 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.Cys715X in whom the phenotype was initially a marked sensory neuropathy with prominent demyelinating features.

A child with a different homozygous mutation (p.Leu83CysfsX14) 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.Arg1070X).

Prominent sensory loss occurred in a family with the p.Ala700ProfsX18 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.Arg275X 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.Gln163X in Spain [Claramunt et al 2005] and p.Met116Arg in Italy [Di Maria et al 2004].

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).

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.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

All of the Charcot-Marie-Tooth neuropathy type 4 (CMT4) subtypes discussed in this GeneReview (CMT4A, 4B1, 4B2, 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 the CMT4 subtype-related gene mutation 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 for the CMT4 subtype-related gene mutation present in the proband is 2/3.

Offspring of a proband. The offspring of an individual with CMT4 are obligate heterozygotes (carriers) of the CMT4 subtype-related mutation 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 disease-causing mutations 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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for some types of CMT4 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation if both disease-causing alleles have been identified in the family.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

If no laboratory offering prenatal testing for a subtype of CMT4 is listed in the GeneTests™ Laboratory Directory, prenatal testing may be available for families in which a disease-causing mutation has been identified through a laboratory offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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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]

Revision History

• 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
• 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 to live Web site
• April 1996 (tb) Original submission