Sex-Based Differences in Disease Burden and Phenotype in CADASIL: A Multicenter Study of 368 Korean Patients.

Background and Objectives: Previous studies have reported mixed findings regarding sex differences in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with some indicating earlier ischemic events in men, whereas others found no significant difference in stroke onset. However, evidence from Asian populations remains limited, where clinical manifestations and Methods: In this nationwide retrospective study, 577 patients were screened for CADASIL across 26 centers in South Korea. After excluding those with benign or uncertain variants or insufficient clinical or MRI data, 368 individuals with pathogenic NOTCH3 variants were included in the final analysis. Clinical features, vascular risk factors, and Results: The mean age of the patients at data collection was 61.7 ± 11.9 years, and 48.6% were male. Thirty-six distinct pathogenic variants were identified. The most frequent variant was R544C (40.8%) located at the EGFr 13/14 interdomain boundary (corresponding to exon 11). Other recurrent variants were R75P (17.9%), C542R (5.4%), and R587C (4.6%). Men exhibited a higher prevalence of ischemic stroke (70.9% vs 44.4%, Discussion: This nationwide study highlights distinct sex differences in CADASIL presentation within a Korean population. Male patients exhibited a higher prevalence and earlier onset of ischemic stroke not fully explained by conventional vascular risk factors. These findings underscore the importance of integrating sex, hormonal, and genetic-epigenetic factors into future research to guide precision phenotyping and sex-informed clinical management in CADASIL.