2025 Volume 42 Issue 3 Pages 408-412
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a rare hereditary small vessel disease caused by more than 300 pathogenic variants in the NOTCH3 gene, including both cysteine–altering and cysteine–sparing variants. Common clinical manifestations of CADASIL include migraines, mood disorders, ischemic strokes, and dementia ; however, not all patients exhibit these symptoms. Notably, approximately 20–30% of CADASIL patients remain stroke–free by the age of 70. Carriers of the NOTCH3 p.R75P variant, a relatively common pathogenic variant in Japan, frequently experience symptomatic hemorrhagic strokes prior to ischemic strokes. Although CADASIL is currently regarded as a single disease, it may, in the future, be classified into distinct subtypes based on phenotypic variations.
Furthermore, environmental factors are likely to influence the disease's clinical heterogeneity. For instance, smoking and hypertension have been reported to increase the risk of ischemic stroke in CADASIL patients. Understanding the impact of these modifiable factors is essential for developing optimized treatment strategies.
To address the disease's clinical heterogeneity and advance research, we are establishing CADREA (CADASIL Registry in East Asia) in collaboration with researchers from South Korea and Taiwan. CADREA will be the world's largest CADASIL registry, integrating clinical, genetic, and neuroimaging data. This longitudinal registry will evaluate outcomes such as stroke and cognitive decline over six years, enabling in–depth analyses of disease modifiers and genotype–phenotype correlations in over 1,000 CADASIL patients.
This initiative aims to enhance our understanding of CADASIL, contribute to the development of tailored therapeutic strategies, and establish CADREA as a leading platform for global CADASIL research.
