Mutational screening of the SH3TC2 gene in Greek patients with suspected demyelinating recessive Charcot‐Marie‐Tooth disease reveals a varied and unusual phenotypic spectrum

Abstract

Charcot‐Marie‐Tooth disease type 4 C (CMT4C) is an autosomal recessive form of demyelinating peripheral neuropathy caused by mutations in SH3TC2, characterized by early onset, spine deformities, and cranial nerve involvement. We screened SH3TC2 in 50 unrelated Greek patients with suspected demyelinating Charcot‐Marie‐Tooth disease and pedigree compatible with recessive inheritance. All patients had been previously screened for PMP22, GJB1, and MPZ mutations. We found five previously identified pathogenic mutations in SH3TC2 distributed among 13 patients in homozygosity or compound heterozygosity (p. Arg954Stop, Arg1109Stop, Gln892Stop, Ala878Asp, and Arg648Trp). Although most cases had early onset and spine deformities were almost omnipresent, a wide phenotypic spectrum was observed. Particularly notable were two siblings with Roussy‐Lévy syndrome and one patient with young‐onset trigeminal neuralgia. In conclusion, mutations in SH3TC2 are responsible for 26% of Greek patients with suspected CMT4, identifying CMT4C as the most common recessive demyelinating neuropathy in the Greek population, in accordance with other Mediterranean cohorts.

Characteristics of Clinical and Electrophysiological Pattern in a Large Cohort of Chinese Patients With Charcot-Marie-Tooth 4C

“…These mutations include nonsense, splice-site, and frameshift mutations, either in homozygous or compound heterozygous states, and they lead to the premature termination of protein synthesis or the production of nonfunctional proteins. Some missense mutations, such as E657K, R1109P, and R648W, have also been observed (1,2,11). In our study, 3 previously reported nonsense mutations (E553 * , R904 * , and R954 * ) (1, 10, 12), 4 novel splicing mutations (c.280…”

“…In a Southern Italy study, the prevalence of SH3TC2 in overall CMT population was 3.2%, but it raised at 11.6% in sporadic demyelinating CMT cohort (SH3TC2 represents the second prevalent gene in this selected population) (15). The R954 * mutation, which is located in exon 11, has been reported to be particularly prevalent in central Europe, the Mediterranean basin, and the USA (1,3,5,11,(15)(16)(17)(18). This mutation has been identified in more than half or nearly all of the patients in English, French, Greek, Norwegian and Czech cohorts (3,11,(16)(17)(18), whereas none of the patients in Japanese and Korean cohorts had reported the mutation (6, 7).…”

Implication of the SH3TC2 gene in Charcot-Marie-Tooth disease associated with deafness and/or scoliosis: Illustration with four new pathogenic variants

“…Cranial nerve involvement is another key point of CMT4C, as it is shown in our study with eight patients reporting HL and one patient with increased latencies of visual brainstem responses. Recently, Kontogeorgiou et al reported cranial nerve involvement in 31% of the cases [7], and Yger et al in a French cohort in 71% [4]. HL is the foremost observed condition [8].…”

A homozygous SH3TC2 mutation in a Korean patient with Charcot–Marie–Tooth disease type 4C

“…2,4 Furthermore, multiple phenotypes besides limb weakness or vibration-dominant sensory symptoms were identified; namely, deafness, diplopia, nystagmus, facial sensory loss, trigeminal neuralgia, cerebellar ataxia, and scoliosis. 1,2,4 To compare with reported typical patients, our patient presented with a mild phenotype. He did not show spine deformity, atrophy, or cranial nerve involvement, with CMTNS and distal weakness scores of 9 and 4, respectively.…”

“…Loss of functional SH3TC2 protein widens Ranvier nodes and thinning of myelin sheaths result in slow conduction velocity. 1 Law and tradition have prohibited consanguineous marriage in Korea. Therefore, the prevalence of autosomal recessive (AR) disease is relatively low and reported patients with CMT4C harbor compound heterozygote mutations in the SH3TC2.…”