Expanding mutational and phenotypic spectrum of CST3-related leukoencephalopathy: a novel family and literature review.

CST3-related leukoencephalopathy is a recently recognized adult-onset neurodegenerative disorder caused by pathogenic CST3 variants with C-terminal truncations, frameshifts, or deletions. Owing to the limited number of reported cases, its clinical and radiological spectrum remains incompletely defined. Here, we report a Chinese family harboring a novel heterozygous nonsense variant of CST3 (c.327C > A; p.Cys109*), which represents the most 5’ pathogenic mutation identified to date. The proband, a 62-year-old woman, presented with recurrent encephalopathic episodes, progressive cognitive decline, tremor, urinary retention, and reduced serum cystatin C levels. Longitudinal MRI revealed extensive white matter lesions with persistent diffusion-weighted imaging (DWI) hyperintensities along the corticomedullary junction and the corpus callosum, which used to be viewed as a diagnostic marker of neuronal intranuclear inclusion disease. However, the possibility of neuronal intranuclear inclusion disease was excluded through comprehensive genetic and pathological evaluations. Notably, an asymptomatic young carrier already demonstrated white matter abnormalities with DWI hyperintensities, indicating that radiological changes can substantially precede clinical onset. Our findings expand the mutational and phenotypic spectrum of CST3-related leukoencephalopathy and highlight overlapping clinical and radiological features among adult-onset leukoencephalopathies presenting with corticomedullary junction DWI hyperintensities and episodic manifestations.