Clinical Diagnosis

Charcot-Marie-Tooth neuropathy type 4C (CMT4C) is characterized by the following:

• 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; some individuals become wheelchair dependent because of involvement of the proximal lower limbs

Electrophysiology. The motor nerve conduction velocity (MNCV) of the median nerve is in the range observed in demyelinating disease: 4-37 m/sec, with a mean of 22 m/sec. MNCV is not correlated with disease duration.

Testing

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

Molecular Genetic Testing

Gene. SH3TC2 (KIAA1985) [Senderek et al 2003] is the only gene in which mutation is known to cause CMT4C.

Clinical testing

• Sequence analysis. Because this disorder is defined by the presence of a mutation in the causative gene, the mutation detection rate is 100%.
  
  Note: Because sequence analysis only detects sequence variants in the coding region of the gene, mutations such as exonic, multiexonic, and whole-gene deletions or gross genomic rearrangements would not be detected by this method.

Table 1. Summary of Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 4C

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
SH3TC2	Sequence analysis	Sequence variants	100% 2	Clinical

Test Availability refers to availability in the GeneTests^TM Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests^TM 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. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Because sequence analysis only detects sequence variants in the coding region of the gene, mutations such as exonic, multiexonic, and whole-gene deletions or gross genomic rearrangements would not be detected by this method.

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

Testing Strategy

To establish the diagnosis in a proband, the following findings are necessary:

• Clinical findings suggestive of CMT4C

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

• MNCVs in the demyelinating range
  
  Note: In some cases, electroneuromyographic examination is incomplete or does not allow measurement of MNCVs because of the severity of the secondary axonal loss.

• For simplex cases, exclusion of 17p11.2 duplication and mutations in PMP22 (CMT1A) (see CMT1), MPZ (CMT1B) (see CMT1), and GJB1, which encodes connexin 32 (CMTX1) (see CMTX)

• Molecular genetic testing of SH3TC2

• If molecular genetic testing does not reveal two SH3TC2 mutations:

  • Another demyelinating neuropathy should be considered. Of note, two of ten (20%) individuals with various neuropathies associated with mutations in EGR2 had scoliosis [Szigeti et al 2007] (see also Differential Diagnosis);
    
    OR

  • A nerve biopsy may be needed to determine the nature of the neuropathy.
    
    Note: Nerve biopsy is of great diagnostic value in those with a demyelinating process.

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

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

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews^TM chapters any clinical uses of testing available from laboratories listed in the GeneTests^TM 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

No other phenotypes are known to be associated with mutations in SH3TC2.

Natural History

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 72% of persons with CMT4C (Table 2). Scoliosis or kyphoscoliosis was found in:

• 96% of affected individuals (27/28) in the largest series reported to date [Azzedine et al 2006];

• 47% (11/18) of individuals studied by Senderek et al [2003];

• 36% (5/14) of individuals studied by Colomer et al [2006].

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 80% of affected individuals, according to a recent study from the French CMT association [O Dubourg, personal communication]. Cramps are usually present from the onset, whereas pain may develop as the disease progresses.

Hypoacousis (slightly diminished auditory sensitivity) was reported in 7/46 persons with CMT4C [Senderek et al 2003, Azzedine et al 2006] and deafness (significant reduction of auditory sensitivity) in 7/46 persons [Senderek et al 2003, Colomer et al 2006]. The cumulative data from the literature showed that hypoacousis and deafness were each present in 15% of individuals (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 20% of individuals with CMT4C. The other findings occur in 2% to 6% of individuals with CMT4C (Table 3).

Pregnancy. 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.

• Exceptionally, 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].

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 2005].

• In 28 individuals with CMT4C, Azzedine et al [2006] showed the lack of correlation between the nature and the position of the mutation, 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 who had the same mutation.

Prevalence

CMT4C (caused by mutations in SH3TC2) is a relatively frequent cause of the autosomal recessive demyelinating neuropathy CMT4. On the basis of the cumulative data presented in Table 4, the prevalence of CMT4C among those with CMT4 is approximately 17%.

Only one out of 19 (5%) Turkish families had an SH3TC2 mutation [Parman et al 2004].

Mutations in SH3TC2 have been found in individuals of diverse geographic origins (Algeria, Morocco, France, the Netherlands, Germany, Italy, Bosnia, Greece, Turkey, and Iran) 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 2005, Azzedine et al 2006, Colomer et al 2006].

Evaluations Following Initial Diagnosis

To establish the extent of disease 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

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.

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 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 5. For more information, click here (pdf).

Testing of Relatives at Risk

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

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.

• For general anesthesia, succinylcholine is usually contraindicated; however, it had no adverse effects in 41 persons with CMT [Antognini 1992].

• 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.

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.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) 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 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 is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with CMT4C are obligate heterozygotes (carriers) for an SH3TC2 disease-causing mutation.

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 for at-risk family members is available once the disease-causing mutations have been identified 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, 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 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. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

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

Requests for prenatal testing for conditions which (like CMT4C) do not affect intellect or life span are not common. 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.

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^TM chapters any clinical uses of testing available from laboratories listed in the GeneTests^TM 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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Acknowledgments

We would like to thank Dr Merle Ruberg for critical review of the manuscript and Drs M Tazir, A Gabreëls-Festen, M Lammens, N Birouk, and O Dubourg for referral of affected individuals. This work was supported by the Association Française contre les Myopathies (AFM); The National center for neurodegenerative diseases, Department of Neurology, Section Charcot, CHU Angers; the Assistance Publique des Hôpitaux de Paris (AP-HP); the Institut National de la Santé et de la Recherche Médicale (INSERM) and GIS-Maladies Rares. Hamid Azzedine and Eric LeGuern are members of the French GIS-maladies rares research network on autosomal recessive forms of CMT.

Revision History

• 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