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A novel non-truncating in-frame deletion in the CST3 gene causes adult-onset leukoencephalopathy, expanding the known genetic and clinical spectrum of the disease. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

September 27, 2025Journal of the Neurological Sciences1 citationsOpen Access

Two Japanese families with adult-onset leukoencephalopathy caused by pathogenic variants in CST3

KOKenta OrimoThe University of Tokyo TMTakashi MatsukawaThe University of Tokyo KSKazutaka ShiomiUniversity of Miyazaki

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Abstract

CST3 (NM₀00099. 4) encodes cystatin C, whose C-terminal truncating variants in this gene have recently been reported to cause adult-onset leukoencephalopathy, characterized by headaches, transient neurological symptoms, and distinct imaging findings. We present four patients from two Japanese families, including one with a novel variant (c. 358-2₃95del). Three patients from one family developed chronic headaches around the age of 20, whereas the patient from the other family remained asymptomatic until his fifties. mRNA analysis of the patient with c. 358-2₃95del revealed a splicing alteration leading to an in-frame deletion (p. Lys120Gln133del), representing the first CST3 variant that does not result in a truncated protein. These findings broaden our understanding of the clinical and genetic spectra of CST3-related leukoencephalopathy (114 words).

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