Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy.

Background Autosomal recessive mutations in the SH3TC2 gene cause Charcot–Marie-Tooth type 4C (CMT4C) demyelinating peripheral neuropathy. Methods In this nationwide observational retrospective study involving 27 French University Hospitals, we analyzed the clinical, electrophysiological, and genetic features of 103 patients from 89 families with homozygous and compound heterozygous SH3TC2 gene mutations identified between 2003 and 2023. Results Mean age was 42 years (2–80), and 49% of patients were female. Mean age at disease onset was 14 years (0–52), 60% of patients started the disease before age 10 years, and 24% after age 20 years. Patients presented with distal motor weakness (93% of cases), sensory loss (86%), foot deformities (83%), scoliosis (73%), proximal limb weakness (40%), cranial nerve involvement (48%), hearing loss (37%), scoliosis-related respiratory insufficiency (14%), and genitourinary disorders (6%). Half the patients (48%) walked independently before age 50 years, in contrast with only 13% after age 50 years. After age 50 years, 23% of patients were wheelchair-bound. Nerve conduction studies showed sensorimotor abnormalities within the demyelinating range in all cases. We identified 56 different pathogenic variants in the SH3TC2 gene, including 22 previously undescribed. Patients with two SH3TC2 gene truncating variants had more severe symptoms than patients with one or zero truncating variants. Interpretation This study shows CMT4C is a severe childhood- and adult-onset demyelinating peripheral neuropathy often associated with scoliosis, hearing loss, and ambulation loss in a significant proportion of patients after age 50 years. Genotype–phenotype correlations suggest two truncating SH3TC2 gene variants cause a more severe phenotype.