We report a case of a 75-year-old woman who has had poor physical performance since childhood and developed bilateral lower limb muscle weakness at age 54. At 64, she was diagnosed with Charcot-Marie-Tooth disease type 4C (CMT4C) due to a homozygous p.Arg77Trp variant in the SH3TC2 gene. At 74, she developed memory impairment. At 75, brain MRI revealed extensive cerebral white matter lesions with T2-weighted hyperintensity and linear high intensity signal along the corticomedullary junction on diffusion-weighted imaging. Suspecting neuronal intranuclear inclusion disease (NIID), we performed a skin biopsy which demonstrated p62-positive intranuclear inclusions, and genetic testing identified the GGC repeat expansion in the NOTCH2NLC gene. The pathogenicity of the SH3TC2 variant identified in this patient remains uncertain, and her peripheral neuropathy was consistent with mild demyelination attributable to NIID. Therefore, we interpret the patient's symptoms as primarily driven by NIID. This case highlights the importance of long-term follow-up and additional assessment when variants of uncertain significance are identified in genetic testing.

Autosomal recessive mutations in the SH3TC2 gene cause Charcot-Marie-Tooth type 4C (CMT4C) demyelinating peripheral neuropathy. 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. 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. 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.

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive form of demyelinating neuropathy caused by the biallelic pathogenic mutations in the SH3TC2 gene and characterized by progressive scoliosis, muscular atrophy, distal weakness, and reduced nerve conduction velocity. Here, we report two novel SH3TC2 mutations (c.452dupT and c.731 + 1G > T) from a proband with typical clinical manifestations of CMT4C. Splicing assay reveals the SH3TC2 c.731 + 1G > T mutation leads to a 58-nucleotide (nt) deletion from the downstream of exon 6 causing a frameshift and resulting in an early termination of protein expression. Protein expression assay indicates SH3TC2 c.452dupT mutant is degraded by both the nonsense mediated decay (NMD) and the ubiquitin-proteasome pathway. Moreover, our intracellular immunofluorescence, co-immunoprecipitation, liquid chromatography mass spectrometry and molecular docking describe that SH3TC2 interacts with the transferrin receptor protein 1 (TFRC) encoding a cell surface receptor playing a crucial role in mediating iron homeostasis. Interestingly, both the two novel SH3TC2 mutations present in our CMT4C patients are defective in the association with TFRC. Our study reveals the pathogenesis of these two novel SH3TC2 mutations and indicates that the SH3TC2-TFRC interaction is relevant for peripheral nerve pathophysiology, thus provides a novel insight into the pathophysiology of CMT4C neuropathy.

Background: Primary ciliary dyskinesia (PCD) is a rare hereditary disorder caused by defective motile cilia, predominantly affecting the respiratory system. Conductive hearing loss (CHL) due to chronic otitis media with effusion (OME) is a typical feature of PCD, particularly in childhood. However, the underlying mechanisms contributing to sensorineural hearing loss (SNHL) in patients with PCD remain unclear. Methods: We present the case of a 52-year-old male with a clinical diagnosis of PCD, confirmed by the presence of situs inversus, chronic respiratory symptoms, and ultrastructural ciliary defects. Results: Despite a history of recurrent acute otitis media (AOM), the patient developed severe bilateral SNHL, a relatively uncommon and poorly understood manifestation of PCD. Genetic testing revealed a pathogenic SH3TC2 variant, a gene classically associated with Charcot-Marie-Tooth disease type 4C (CMT4C), raising the possibility of an alternative or contributory genetic etiology for the patient's auditory dysfunction. Conclusions: This case highlights the importance of comprehensive audiological and genetic evaluations in PCD patients, particularly those presenting with progressive or atypical HL. The presence of a pathogenic SH3TC2 mutation suggests a potential neuropathic component to the patient's HL, underscoring the need for further research into the intersection between ciliary dysfunction and genetic neuropathies. Early identification and intervention are critical to optimizing auditory outcomes and quality of life in affected individuals.

Charcot-Marie-Tooth type 4C (CMT4C) is a slowly progressive, autosomal recessive, sensorimotor polyneuropathy characterized by demyelination and distinct clinical features, including cranial nerve involvement. CMT4C is associated with pathogenic mutations in the SH3TC2 gene. A patient presenting with gait instability due to demyelinating polyneuropathy and refractory trigeminal neuralgia underwent comprehensive evaluation. Nerve conduction studies, magnetic resonance imaging (MRI) of the brain, cervical spine, and thoracic spine, lumbar puncture, and genetic test through next generation sequencing were performed. The genetic test found an Arg1109Stop mutation in the SH3TC2 gene, associated with demyelinating polyneuropathy and cranial neuropathy. Interestingly, brain MRI showed multiple, nonenhancing white matter hyperintensities. This is the first case of CMT4C associated with white matter lesions. Any patient with slowly progressive peripheral nervous system symptoms and disproportionally abnormal nerve conduction study findings should be tested for an inherited polyneuropathy and brain imaging for screening of possible central nervous system involvement should be performed. Further investigation is needed to elucidate the pathogenetic basis of CMT4C and a possible association with white matter lesions.