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
• 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 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 in individuals with the above suggestive findings:

• For simplex cases, exclusion of 17p11.2 duplication and pathogenic variants in PMP22 (CMT1A) (see CMT Overview), MPZ (CMT1B) (see CMT Overview), and GJB1, which encodes connexin 32 (CMT1X) (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 multigene panel that includes SH3TC2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

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 multigene panel) fails to confirm a diagnosis in an individual with features of CMT4C. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found 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).