Introduction: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary small-vessel disease caused by biallelic HTRA1 mutations. Although its genetic basis is known, clinical severity, mutation type, and geographic distribution vary widely. To date, no systematic pooled analysis has examined genotype–phenotype correlations. We conducted a systematic review and pooled analysis of published cases to identify clinical, imaging, and genetic predictors of CARASIL severity. Methods: A PRISMA-guided search of PubMed, Embase, Scopus, and Web of Science (inception–January 2025) identified genetically confirmed CARASIL cases. Studies without genetic confirmation, insufficient data, or duplicate reports were excluded. Extracted variables included demographics, clinical features, MRI findings, mutation type and exon, and zygosity. Disease severity was classified by functional status and rate of progression. Associations were assessed using chi-square tests, and independent predictors were identified by ordinal logistic regression. Results: Thirty-five patients from 21 publications (14 case reports, 7 series) were included. Mean age at presentation was 35.7 years; 51% were male and 74% were of Asian descent. Homozygosity was present in 83%. Missense mutations clustered in exon 4 (57%), while substitution mutations were confined to exon 2, which occurred exclusively in non-Asian patients. Clinically, 42.6% had ischemic strokes, 68.1% cognitive impairment, and 83% MRI microbleeds/lacunes. Severe disease occurred in 44.7% of cases. Severity was significantly associated with stroke history (p=0.001), homozygosity (p=0.023), and cognitive impairment (p=0.001). Regression analysis confirmed prior stroke (OR 3.2, 95% CI 1.5–6.8, p=0.004) and MRI microbleeds (OR 2.1, 95% CI 1.1–4.2, p=0.036) as independent predictors of severe disease. Exon 2 substitutions were associated with milder disease (p=0.023). Conclusion: CARASIL severity is influenced by genetic and clinical factors. Missense exon 4 mutations and homozygosity—common in Asian patients—are linked to severe disease, while exon 2 substitutions are associated with milder forms. Stroke history and MRI microbleeds independently predict higher severity. These findings highlight the value of early genetic and neuroimaging evaluation and underscore the need for prospective CARASIL registries to refine genotype–phenotype risk stratification.
Thatikala et al. (2026) studied this question.