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Updated: Jan 16, 2026

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

Kenta Orimo1, Takashi Matsukawa2, Kazutaka Shiomi3

  • 1Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Journal of the Neurological Sciences
|October 1, 2025
PubMed

Insights

Cystatin C (CST3) gene variants can cause adult-onset leukoencephalopathy. This study identifies a novel CST3 variant leading to an in-frame deletion, expanding the known genetic causes of this neurological disorder.

Area of Science:

  • Genetics
  • Neurology
  • Molecular Biology

Background:

  • Cystatin C (CST3) gene variants are linked to adult-onset leukoencephalopathy.
  • Clinical features include headaches, transient neurological symptoms, and specific imaging findings.

Purpose of the Study:

  • To investigate the clinical and genetic spectrum of CST3-related leukoencephalopathy.
  • To characterize a novel CST3 variant and its associated molecular mechanism.

Main Methods:

  • Clinical evaluation of four patients from two Japanese families.
  • Genetic analysis including sequencing and mRNA analysis.
  • Variant classification and functional impact assessment.

Main Results:

  • Identified four patients with CST3-related leukoencephalopathy.
  • Described a novel CST3 variant (c.358-2_395del) in one patient.
  • mRNA analysis revealed a splicing alteration causing an in-frame deletion (p.Lys120_Gln133del), the first non-truncating CST3 variant.

Conclusions:

  • The findings broaden the understanding of CST3-related leukoencephalopathy's clinical and genetic diversity.
  • This study highlights a novel non-truncating variant expanding the pathogenic mechanisms for this condition.

Keywords:
CST3Cystatin-CLeukodystrophyLeukoencephalopathyMCPMiddle cerebellar peduncle

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