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.

Diagnosis/testing.

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).

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 (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.

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.

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.

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 pathogenic variants 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.

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]:

• CMT4C (SH3TC2: p.Arg1109Ter) [Claramunt et al 2007]
• CMT4D (NDRG1: p.Arg148Ter) [Kalaydjieva et al 1998]
• CMT4G (HK1: c.-249-3838G>C) [Sevilla et al 2013]

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.

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 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.

Other

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

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.

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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]

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