ABCC6 pathogenic variants are associated with hemorrhagic phenotypes in Japanese patients with severe cerebral small vessel disease

ABCC6 pathogenic variants affect ischemic and hemorrhagic lesions in multiple organs and represent the third most common cause of hereditary cerebral small vessel diseases (CSVD) in Japan, yet their CSVD phenotypes remains unclear. We conducted a multicenter, cross-sectional study of 158 consecutive Japanese adults with severe CSVD. Genetic analysis was performed, and clinical and brain MRI findings were compared among ABCC6-related CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and genetically undetermined CSVD. Univariate and multivariate analyses assessed the association between ABCC6 pathogenic variants and hemorrhagic stroke, adjusting for age and hypertension. Nine patients (5.7%) carried pathogenic heterozygous ABCC6 variants. Hemorrhagic stroke was more frequent in ABCC6-related CSVD than in CADASIL (55.6% vs 13.6%, P = 0.039) and undetermined CSVD (55.6% vs 10.3%, P = 0.010). Multivariate analysis confirmed an independent association (odds ratio 8.4, 95% CI 2.0-38.4, P = 0.004). On MRI, ABCC6-related CSVD showed fewer anterior temporal lesions but more multiple microbleeds than CADASIL. The direction of these findings remained consistent when biallelic cases were included. These findings indicate a distinct, hemorrhage-predominant CSVD phenotype associated with ABCC6 in Japanese patients, support a contributory role of ABCC6, and warrant validation in larger, multi‑ethnic cohorts.