CONCLUSION

CMT-4C is an extremely rare autosomal recessive demyelinating motor sensory neuropathy. Thus far, a little more than 60 cases have been reported in the literature.^3–5 In addition to the classic features seen in all patients with CMT, such as distal muscle atrophy, weakness, cramping, areflexia, distal sensory impairment, and paresthesia, the disease is characterized by early-onset severe scoliosis between ages 2 and 10 years ^3–7 but can be seen rarely in the early second decade.¹³ The overall prevalence of scoliosis or kyphoscoliosis is between 36% to 96%.^3,4 The typical curvature progression is between 3 to 5 degrees per year.^6,7 Various foot deformities including pes cavus, pes vagus, and pes planus have been reported in 72% to 100% of affected individuals.^3–7 The typical age of onset is between 2 to 12 years of age. Auditory impairment in the form of hypoacousis or deafness has been associated with one third of patients with CMT-4C.^3–5 Cranial nerve, cervical nerve, and cerebellar involvement manifesting as nystagmus, abnormal papillary light reflexes, lingual fasciculation, facial paresis, and head tremor have also been described in a small number of patients.^3–5 Our patient presented with a constellation of symptoms consistent with a motor sensory neuropathy including diffuse hypotonia, absent DTRs, and gross motor developmental delay without regression.

Electrophysiologic studies uniformly show reduced motor nerve conduction velocity in the range of demyelinating neuropathies: 4 to 37 ms with a mean of 22 ms.⁵ The degree of velocity reduction is not directly proportional to the disease duration.³ The decrease in the motor nerve conduction velocity in both the upper and lower extremities at 11 ms to 18 ms is consistent with the demyelinating nature of CMT-4C. Nerve biopsy examination reveals axons with varying degrees of demyelination with increased basal membrane accompanied by multiple small onion bulbs that are extensions of Schwann cell processes.^5–7 Given the positive molecular genetic testing result, our patient was spared the surgical risk and discomfort of a nerve biopsy.

CMT-4C is caused by mutations of the SH3TC2 gene that maps to chromosome 5q32.^5,8 The protein product of the SH3TC gene contains tetratricopeptide repeat domains that are involved in numerous cellular processes via protein-protein interactions including mitosis, RNA synthesis, protein transport, and chaperon functions.⁹ On the other hand the SH3 domain of the gene product mediates interactions with enzymes, cytoskeleton components, and myosin exerting regulatory action in intercellular communication and signal transduction between cell surface and the nucleus.¹⁴ Thus far, 21 mutations of the SH3TC2 gene have been reported. ^3–5,10,11 The majority of the mutations are found in large families with history of consanguinity.^{3–8,12–14} Only two cases have been identified as sporadic.^5,6 The patients represent wide geographic locations including Algeria, Morocco, France, the Netherlands, Germany, Italy, Bosnia, Greece, Turkey, and Iran, as well as ethnic Roma from Spain and Turkey. The homozygous mutation p.Ser1077X (c.3230C>G) in our patient is a novel mutation that has never been previously reported. It is certainly the first case of CMT-4C reported in a patient of Chinese descent despite population genetic studies of other CMT subtypes.¹⁵ Given the patient’s adoption status, it is not known whether her birth parents are distantly related.

In summary, our 5-year-old female patient presented with clinical, electrophysiologic, and molecular genetic evidence supporting the diagnosis of CMT-4C. Her genetic mutation is a novel homozygous nonsense mutation of the SH3TC2 gene.