Genotype-phenotype correlations in a Scottish CADASIL cohort and comparison with sporadic small vessel disease

Abstract Introduction CADASIL is a monogenic inherited cerebral small vessel disease (SVD) caused by a mutation affecting the NOTCH3 gene. Mutation location appears to influence disease severity. We investigated the hypothesis that mutation location modifies phenotype by comparing a CADASIL population stratified by mutation site risk with a cohort of older people with sporadic SVD. Patients and methods We included adults with CADASIL and control group from the XILO-FIST trial. We recorded age at first stroke, white matter hyperintensity (WMH) volume, lacunes, cerebral microbleeds and other clinical biomarkers. We divided the CADASIL cohort into (1) two groups NOTCH3 mutations affecting epidermal growth factor-like repeat (EGFr) domains 1–6 (proximal) and EGFr domains 7–34 (distal); and (2) three groups; low, medium and high-risk based on a proposed three-tiered risk stratification. Results The CADASIL cohort included 129 people, 57 (44.2%) male, mean age 47.5 ± 11.7 years. The sporadic SVD cohort included 460 people, 317 (68.9%) male, mean age 65.7 ± 8.7 years. The CADASIL proximal group were imaged at younger age, but fewer had hypertension (14.3% v 38.1%) compared to distal mutations. Lacune count and WMH volume differed between low, medium and high-risk CADASIL mutations, and sporadic SVD. Percentage progression of WMH volume was higher in proximal CADASIL (0.26%), than distal CADASIL (0.14%) which was higher than sporadic SVD (0.05%), p 0.001. Discussion and conclusion Proximal CADASIL mutations average more extensive WMH, higher lacune count and experienced first stroke at younger age than those with distal mutations. Both groups showed imaging differences compared to sporadic SVD.