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

Abstract

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.

Keywords: CMT4C; Charcot–Marie–Tooth disease; SH3TC2 gene; SH3TC2 protein; Schwann cell; demyelinating polyneuropathy; myelin.

FIGURE 1

Deep phenotyping of 103 patients with SH3TC2 gene‐related demyelinating polyneuropathy (CMT4C). (A) Symptoms & signs observed in different parts of the body. (B) Symptoms & signs observed in head & neck.

FIGURE 2

Age at symptom onset & ambulation status in 103 patients with SH3TC2 gene‐related peripheral neuropathy. (A) Age distribution at symptom onset. (B) Ambulation status in relation to age.

FIGURE 3

SH3TC2 variants reported in this study. Schematic representation of SH3TC2 cDNA. Stop variants are shown in red, frameshift variants in orange, missense variants in blue, intronic variants in grey, and other variants in purple. The 22 new variants identified in our study are shown in the upper part of the figure, and the 34 previously described variants are shown in the lower part of the figure.

FIGURE 4

Allelic and genotype distribution of SH3TC2 gene variants in our series of 103 patients. (A) Allelic proportion of the different variation types: The proportion of the different variation types is represented as follows: Nonsense variants (in red), frameshift variants (in orange), missense variants (in blue), splice site variants (in grey), and deletions (in purple). (B) Distribution of SH3TC2 genotypes categorised by truncation status. The outer ring categorises patients based on the presence of 1 or 2 truncated variants, or the absence of truncating variants. The inner chart illustrates the proportions of patients carrying different allelic combinations: 2‐truncated variants (in red) include homozygous stop, compound heterozygous stop + stop, homozygous frameshift, compound heterozygous stop + frameshift, frameshift + frameshift, and stop + deletion; 1‐truncated variants (in orange) include stop + missense, frameshift + missense, stop + splice, frameshift + splice, and deletion + missense; Non‐truncated variants (in blue) include homozygous missense, compound heterozygous missense, missense + splice, and homozygous splice.

FIGURE 5

Distribution of (A) CMTES and (B) CMTNS scores in relation to truncating SH3TC2 gene variants. Each dot represents an individual patient. The groups are categorised as follows: 2‐truncated variants (T2) (in red), 1‐truncated variants (T1) (in orange), and 0‐truncated variants (T0) (in blue). Data are represented as ± standard error of the mean. Pairwise Mann–Whitney tests were used for CMTES, and ANOVA was used for CMTNS. In this analysis, patients in the 2‐truncated‐variants group were more severely affected than patients in the 1‐truncated and 0‐truncated groups. p values: P < 0.05 (*), non‐significant (ns).