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

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 NOTCH3 variant distribution differ substantially from those in European cohorts. We investigated sex-specific variations in clinical phenotypes and brain MRI characteristics among Korean patients with CADASIL.

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 NOTCH3 variant positions classified by epidermal growth factor-like repeat (EGFr) domains were compared between sexes. Brain MRI findings-including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds, and atrophy-were evaluated. Sex differences in the onset of ischemic stroke and dementia were analyzed using Kaplan-Meier and Cox proportional hazards models.

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%, p < 0.001) and experienced their first event at an earlier age (median 53 vs 59 years, log-rank p < 0.001). On brain MRI, male sex was independently associated with a greater lacune burden (odds ratio 3.03, 95% CI 1.70-5.38, p < 0.001) while female sex tended to show higher WMH volume.

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.