A Patient With Charcot-Marie-Tooth Disease Type 4C (CMT4C) Presenting With Muscle Fasciculations and Motor Neuropathy.

We report an unusual patient who, at age 47 years, had presented with complaints of muscle fasciculations. After neurological examination and electromyogram testing, he was diagnosed with motor neuropathy. Over the next 10 years, in addition to fasciculations, he developed numbness in his feet without any other symptoms. His current neurological examination at age 57 years was normal, except for mildly decreased light touch in the anterior portion of both feet. The nerve conduction studies performed repeatedly showed sensorimotor polyneuropathy with demyelination features. Blood tests, including anti-ganglioside antibodies, were normal. Genetic testing revealed two rare variants in trans in the SH3 domain and tetratricopeptide repeats 2gene, c.3413 G>A p.(S1138N) and c.3269 C>G p.(A1090G). Protein modeling suggests that these are disease-producing mutations and likely the cause of the neuropathy of our patient. Our study expands the clinical and genetic spectrum of patients with Charcot-Marie-Tooth disease type 4C.

Genetic Landscape of SH3TC2 variants in Russian patients with Charcot-Marie-Tooth disease.

Introduction: Charcot-Marie-Tooth disease type 4C (CMT4C) OMIM#601596 stands out as one of the most prevalent forms of recessive motor sensory neuropathy worldwide. This disorder results from biallelic pathogenic variants in the SH3TC2 gene. Methods: Within a cohort comprising 700 unrelated Russian patients diagnosed with Charcot-Marie-Tooth disease, we conducted a gene panel analysis encompassing 21 genes associated with hereditary neuropathies. Among the cohort, 394 individuals exhibited demyelinating motor and sensory neuropathy. Results and discussion: Notably, 10 cases of CMT4C were identified within this cohort. The prevalence of CMT4C among Russian demyelinating CMT patients lacking the PMP22 duplication is estimated at 2.5%, significantly differing from observations in European populations. In total, 4 novel and 9 previously reported variants in the SH3TC2 gene were identified. No accumulation of a major variant was detected. Three previously reported variants, c.2860C>T p. (Arg954*), p. (Arg658Cys) and c.279G>A p. (Lys93Lys), recurrently detected in unrelated families. Nucleotide alteration p. (Arg954*) is present in most of our patients (30%).

Screening for SH3TC2 variants in Charcot-Marie-Tooth disease in a cohort of Chinese patients.

Mutations in the SH3TC2 gene cause Charcot-Marie-Tooth disease type 4C (CMT4C), characterized by inherited demyelinating peripheral neuropathy. CMT4C is a common form of CMT4/autosomal recessive (AR) CMT1. This study examined the SH3TC2 variants, investigated genotype-phenotype correlations and explored the frequency of CMT4C in Chinese patients. A total of 206 unrelated patients of Chinese Han descent clinically diagnosed with CMT were recruited. All patients underwent detailed history-taking, neurological examination, laboratory workups, and electrophysiological studies. Genetic analysis was performed via high-throughput target sequencing (NGS). Three patients, one male and two females, were found to carry five SH3TC2 mutations: patient 1 (c.3154C > T, p.R1054X; c.929G > A, p.G310E); Patient 2 (c.2872_2872del, p.S958fs; c.3710C > T, p.A1237V) and Patient 3 (c.2782C > T, p.Q928X; c.929G > A, p.G310E). The c.2872_2872del, c.3710C > T and c.2782C > T variants were not reported before. CMT4C caused by SH3TC2 mutation is a very common type of CMT4/AR CMT1. Three novel mutations, c.2872_2872del, c.3710C > T and c.2782C > T, were found in this study. Combination of clinical phenotype, nerve conduction studies, genetic analysis and bioinformatics analysis are of vital importance in patients suspected as CMT.

Dropped head syndrome as a manifestation of Charcot-Marie-Tooth disease type 4C.

Charcot Marie Tooth disease type 4C (CMT4C) is considered the most frequent autosomal recessive form of CMT worldwide, being described as an early-onset disorder with marked clinical heterogeneity. We report a CMT4C case associated with dropped head syndrome and predominant involvement of proximal muscles. An 11-year-old boy born to consanguineous parents presented with predominantly proximal muscle weakness with facial involvement, associated with dropped head and severe scoliosis. Symptoms started at the age of 3 years-old with frequent falls. Nerve conduction studies showed a sensorimotor demyelinating polyneuropathy. A comprehensive multigene next-generation sequencing panel for CMT revealed the homozygous pathogenic missense variant c.1969G > A (p.E657K) in SH3TC2 gene, confirming CMT4C diagnosis. The present report broadens the phenotype associated with CMT4C and raises the importance of considering early-onset inherited polyneuropathies in the differential diagnosis of patients with proximal muscle wasting associated with dropped head syndrome.

Clinical and Genetic Analysis of an Asian Indian Family with Charcot-Marie-Tooth Disease Type 4C.

Charcot-Marie-Tooth disease type 4C, an autosomal recessive genetic neuropathy, is caused by mutations in the SH3TC2 (SH3 domain and tetratricopeptide repeats 2) gene. Interestingly, although mutations in this gene have been observed in European gypsies, a population that originated in India, there are few publications describing Indian patients. We report our analysis of a 50-year-old woman of Asian Indian descent with onset of progressive distal weakness and sensory loss in childhood. A clinical examination revealed the presence of a neuropathy with pes cavus without spinal abnormalities. Electrophysiological testing confirmed a sensorimotor length-dependent neuropathy with demyelinating features. A genetic analysis revealed she carries 2 novel mutations, c.2488G>T variant (rs879254317) and c.731+5G>A variant (rs879254316), in the SH3TC2 gene. Further genetic testing demonstrated that her son is a carrier of the c.731+5G>A mutation. Our analysis confirms that this patient is a compound heterozygote inheriting these mutations, which are in trans, in an autosomal recessive pattern. Her son developed an episode of sciatic neuropathy with complete resolution. We hypothesize that in his case, haploinsufficiency caused by c.731+5G>A mutation may have predisposed him to the development of this focal neuropathy.