Clinical characteristics.

Charcot-Marie-Tooth neuropathy type 4C (CMT4C) is a demyelinating neuropathy characterized by early-onset severe spine deformities. The majority of affected children present with scoliosis or kyphoscoliosis between ages two and ten years, although earlier and later onset are observed. Slowly progressive neuropathy usually manifests in the first decade or adolescence, and occasionally earlier or later. Foot deformities (pes cavus, pes planus, or pes valgus) are common.

Diagnosis/testing.

Diagnosis is based on clinical findings, the results of motor nerve conduction velocity testing, and molecular genetic testing of SH3TC2, the only gene in which pathogenic variants are known to cause CMT4C. Because the diagnosis of CMT4C is defined by the presence of biallelic SH3TC2 pathogenic variants, all individuals with CMT4C have pathogenic variants in this gene.

Management.

Treatment of manifestations: Treatment of spinal deformities includes physiotherapy to preserve flexibility, bracing, and/or surgery, even at a young age. Treatment of foot deformities includes special shoes with good ankle support and/or ankle/foot orthoses (AFOs) to correct foot drop and aid walking, and in some cases surgery; associated pain and cramps may require medication.

Prevention of secondary complications: Daily heel cord stretching exercises and physical activity may help prevent contractures.

Surveillance: Monitor for onset and/or progression of scoliosis and changes in hand function and foot strength.

Agents/circumstances to avoid: Obesity; drugs and medications known to cause nerve damage (e.g., vincristine, isoniazid, taxol, cisplatin, nitrofurantoin).

Pregnancy management: Symptoms of CMT can worsen during pregnancy; some studies suggest that women with CMT require more interventions during delivery (possibly secondary to an increased incidence of abnormal fetal presentation) and may be at increased risk for postpartum bleeding.

Other: Career and employment may be influenced by hand and/or foot weakness.

Genetic counseling.

CMT4C is inherited in an autosomal recessive manner. 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 family members and prenatal testing for at-risk pregnancies are possible if both pathogenic variants have been identified in the family.

Suggestive Findings

Charcot-Marie-Tooth neuropathy type 4C (CMT4C) should be suspected in individuals with the following clinical manifestations, nerve conduction velocities, neuropathology, and family history:

Clinical manifestations

• Early and severe scoliosis, the presenting sign in most individuals [Kessali et al 1997, Gabreëls-Festen et al 1999, Azzedine et al 2006]
• Neuropathy that usually develops in the first decade or adolescence, but occasionally manifests as delay in onset of independent ambulation in early childhood
• Slowly progressive neuropathy, with some individuals becoming wheelchair dependent because of involvement of the proximal lower limbs

Motor nerve conduction velocities (MNCV) that are in the range observed in demyelinating disease:

• MNCV of the median nerve is typically 4-37 m/sec, with a mean of 22 m/sec.
• MNCV is not correlated with disease duration.
• In some cases, electroneuromyographic examination is incomplete or does not allow measurement of MNCVs because of the severity of the secondary axonal loss.

Neuropathology. Nerve biopsies show a combination of morphologic features unique among the demyelinating forms of CMT [Kessali et al 1997, Gabreëls-Festen et al 1999, Gooding et al 2005], including the following:

• Loss of myelinated fibers
• Relatively few and small classic onion bulbs, as observed in CMT1A (see CMT1)
• Basal membrane onion bulbs, consisting of concentric Schwann cell lamellae intermingled with single or double basal membranes or concentric basal membranes alone
• Schwann cells of unmyelinated axons, often with very thin processes and connecting links between axons

Family history consistent with autosomal recessive inheritance (includes simplex cases, i.e., a single occurrence in a family)

Establishing the Diagnosis

The diagnosis of CMT4C is established in a proband with early and severe scoliosis, slowly progressive neuropathy, slow nerve conduction velocities, and biallelic pathogenic variants in SH3TC2 (previously known as KIAA1985) [Senderek et al 2003] (see Table 1).

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

Serial single-gene testing can be considered based on the order in which pathogenic variants most commonly occur in individuals with the above suggestive findings:

• For simplex cases, exclusion of 17p11.2 duplication and pathogenic variants in PMP22 (CMT1A) (see CMT1), MPZ (CMT1B) (see CMT1), and GJB1, which encodes connexin 32 (CMTX1) (see CMTX)
• Sequence analysis of SH3TC2 followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found
• If molecular genetic testing does not identify biallelic SH3TC2 pathogenic variants, consideration of other demyelinating neuropathies. Of note, two (20%) of ten individuals with various neuropathies associated with pathogenic variants in EGR2 had scoliosis [Szigeti et al 2007] (see also Differential Diagnosis).

A multi-gene panel that includes SH3TC2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.

More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multi-gene panel) fails to confirm a diagnosis in an individual with features of CMT4C. For more information on comprehensive genomic testing click here.

Clinical Description

Charcot-Marie-Tooth neuropathy type 4C (CMT4C) is a demyelinating neuropathy characterized by early-onset severe scoliosis. Scoliosis as well as foot deformities were the presenting findings in most individuals with CMT4C.

Spine deformities (scoliosis or kyphoscoliosis) were observed between ages two and ten years in most cases [Kessali et al 1997, Gabreëls-Festen et al 1999], or more rarely, early in the second decade [Senderek et al 2003]. However, the disease may start at birth or much later: onset at age 37 years was reported in one individual [Colomer et al 2006].

Cumulative data indicate that scoliosis occurs in 73% of persons with CMT4C (Table 2). In some cases the spine deformities are moderate; in others they are disabling. The curvature progressed three to five degrees annually and required surgery in 7% to 39% of reported cases (Table 2) [Kessali et al 1997, Gabreëls-Festen et al 1999].

Foot deformities (pes cavus, pes planus, or pes valgus) were reported in 72% to 100% of affected individuals [Senderek et al 2003, Azzedine et al 2006, Colomer et al 2006]. Foot deformities were first observed between ages two and ten years, were moderately or severely disabling, and required surgery in 6% (1/18) to 11% (3/28) of cases (Table 2).

Other. No data are available on cramps and pain in individuals with CMT4C. In general, cramps and pain are common in all forms of CMT, occurring in 56 to 96% of affected individuals, according to different studies [Carter et al 1998, Abresch et al 2002, Tiffreau et al 2006, Padua et al 2008]. Cramps are usually present from the onset, whereas pain may develop as the disease progresses.

Hypoacousis (slightly diminished auditory sensitivity) was reported in 15/103 persons with CMT4C and deafness (significant reduction of auditory sensitivity) in 12/103 persons. The cumulative data from the literature showed that hypoacousis and deafness were each present in approximately 11.5% and 14.5% of individuals, respectively (Table 3). For more detailed discussion of hearing loss in general, see Deafness and Hereditary Hearing Loss Overview.

Nystagmus was reported in 2/18 persons with CMT4C [Senderek et al 2003].

Pupillary light reflexes, facial paresis, hypoventilation/respiratory insufficiency, lingual fasciculation, head tremor, sensory ataxia, and diabetes mellitus were also reported (Table 3). The cumulative data from the literature showed that respiratory problems occurred in approximately 18% and cranial nerve involvement in 45% of individuals with CMT4C (Table 3).

Pregnancy. See Management, Pregnancy Management.

Genotype-Phenotype Correlations

Significant intrafamilial variability in the disease course makes it difficult to identify genotype-phenotype correlations [Kessali et al 1997, Gabreëls-Festen et al 1999, Senderek et al 2003, Azzedine et al 2005a, Azzedine et al 2005b, Azzedine et al 2006].

• In 28 individuals with CMT4C, Azzedine et al [2006] found no correlation between the nature and the position of the pathogenic variant, disease duration, and the stage of disability. They also reported intrafamilial variability in age at onset, disease duration, and stage of disability.
• Colomer et al [2006] reported clinical variability in 14 affected individuals with the same pathogenic variant.

Prevalence

CMT4C (caused by biallelic pathogenic variants in SH3TC2) is a relatively frequent cause of the autosomal recessive demyelinating neuropathy CMT4. On the basis of the cumulative data, the prevalence of CMT4C among those with CMT4 is approximately 18% (53/299) [Senderek et al 2003, Azzedine et al 2006, Houlden et al 2009, Fischer et al 2012, Iguchi et al 2013].

Pathogenic variants in SH3TC2 have been found in individuals of diverse geographic origins (Algeria, Morocco, France, Belgium, England, the Netherlands, Germany, Austria, Italy, Bosnia, Czech, Greece, Turkey, Iran, Japan, and Canada) and diverse ethnic origins (gypsies from Spain and Turkey) [LeGuern et al 1996, Gabreëls-Festen et al 1999, Guilbot et al 1999, Senderek et al 2003, Azzedine et al 2005a, Azzedine et al 2005b, Azzedine et al 2006, Colomer et al 2006, Houlden et al 2009, Baets et al 2011, Fischer et al 2012].

• The pathogenic variant p.Arg954Ter is recurrent in several populations, including people who originated from the Mediterranean basin, Europe, and America [Azzedine et al 2005a, Azzedine et al 2005b]. This founder effect leads to a bias in the occurrence of the disease in those populations [Azzedine et al 2005a, Azzedine et al 2005b, Gosselin et al 2008].
• Five (20%) of 25 affected individuals of Turkish origin had biallelic SH3TC2 pathogenic variants [Parman et al 2004, Fischer et al 2012].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4C (CMT4C), the following evaluations are recommended:

• Examination by a child neurologist to evaluate for weakness and atrophy, gait stability, sensory loss, and other associated signs. It is important to distinguish between neuropathic pain and mechanical pain.
• Examination by a pediatric orthopedist to assess the amount and progression of spinal curvature and to determine the extent of foot deformities
• Examination by an otolaryngologist and/or ophthalmologist if problems with hearing or vision are present
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment is symptomatic. Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. See Grandis & Shy [2005] for a discussion of general treatment for CMT.

Treatment of spinal deformities

• Physiotherapy helps to preserve flexibility.
• If the curvature can be reduced with bracing, either a plaster or a thermo-molded plastic corset can be used.
• If bracing and physiotherapy together are not sufficient to correct the scoliosis, surgery can be performed at an early age, even before the end of linear growth (Table 2) [Kessali et al 1997, Gabreëls-Festen et al 1999]. Surgical intervention requires consensus among the family, child (if possible), and attending physicians.

Treatment of foot deformities

• Special shoes with good ankle support and/or ankle/foot orthoses (AFOs) to correct foot drop and aid walking
• Physiotherapy to preserve flexibility
• In approximately 9% of individuals, surgery to correct severe pes cavus deformity (Table 2) [Kessali et al 1997, Guyton & Mann 2000, Colomer et al 2006]

Treatment of pain and cramps

• Neuropathic pain can be treated with antiepileptic drugs (AEDs) (e.g., pregabalin, gabapentin).
• Mechanical pain can generally be managed with a combination of physiotherapy and orthopedic treatment.
• Cramps can be controlled with quinine. However, quinine is known to induce tinnitus and reversible high-tone hearing loss.

Other

• Some individuals require forearm crutches or canes for gait stability; some need wheelchairs.
• Exercise to help the individual remain physically active according to his/her abilities is encouraged.

Prevention of Secondary Complications

Daily heel cord stretching exercises help prevent Achilles' tendon shortening.

Physical activity (e.g., swimming, bicycling, stretching) adapted to the abilities of each individual by a physiotherapist is useful to prevent contractures.

Individuals with diabetes mellitus need excellent foot care to avoid foot ulceration and necrosis.

Surveillance

Scoliosis needs to be closely followed. Monitoring four times a year is recommended.

Hand function and foot strength should be evaluated by an orthopedist every six months starting from the date of diagnosis.

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 ranging from definite high risk to negligible risk. Click here for an up-to-date list.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from initiation of preventive measures. Evaluations can include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Consideration of motor nerve conduction velocities and nerve biopsy if the pathogenic variants in the family are not known.

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

Pregnancy Management

CMT appears to be an independent risk factor for complications during pregnancy and delivery.

• The symptoms of CMT can worsen during pregnancy; in particular: cramps, subjective sensitivity (e.g., paresthesias), difficulty walking, and fatigue.
• In rare cases, crises occurring during pregnancy do not subside post partum.
• A retrospective study in Norway between 1967 and 2002 comparing 108 births to mothers with CMT with 2.1 million births to mothers without CMT determined that mothers with CMT more frequently needed interventions during delivery [Hoff et al 2005]. Bleeding post partum was also more common in mothers with CMT.
• It has been postulated that fetal presentation tends to be abnormal because of the combination of CMT in the mother and fetus [Rayl et al 1996, Hoff et al 2005].

Therapies Under Investigation

See Grandis & Shy [2005].

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 persistent weakness of hands and/or feet.

Anesthesia. Relatively few studies reported in the literature address risks of anesthesia in patients with CMT. No complications were observed after anesthesia in a large cohort followed in specialized consultation, but the advice of the anesthesiologist should be followed.

• Although it had no adverse effects in 41 persons with CMT [Antognini 1992], use of succinylcholine for general anesthesia is usually contraindicated.
• Blockers of the neuromuscular junction should be used with caution.
• Local-regional anesthesia, especially epidural analgesia at child birth, has been used without problems in CMT. This use of anesthesia should be discussed on a case-by-case basis with the anesthesiologist.

Mode of Inheritance

Charcot-Marie-Tooth neuropathy type 4C (CMT4C) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one SH3TC2 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of a SH3TC2 pathogenic variant 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 CMT4C are obligate heterozygotes (carriers) for an SH3TC2 pathogenic variant.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of a SH3TC2 pathogenic variant

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SH3TC2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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 Diagnosis

Once the SH3TC2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CMT4C 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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Acknowledgments

This work was supported by the Association Française contre les Myopathies (AFM).

Author History

Hamid Azzedine, PhD (2008-present)
Luc Bontoux, MD; Centre Hospitalier Universitaire d'Angers (2008-2015)
Eric LeGuern, MD, PhD (2008-present)
Mustafa A Salih, MD, Dr Med Sci, FRCPCH, FAAN (2015-present)

Revision History

• 15 October 2015 (me) Comprehensive update posted live
• 6 July 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
• 31 March 2008 (me) Review posted to live Web site
• 10 February 2006 (ha) Original submission