A case of neuronal intranuclear inclusion disease presenting with leukoencephalopathy after the diagnosis of Charcot–Marie–Tooth disease type 4C

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.