Abstract 26: Prevalence of CADASIL and Fabry Disease in a Large Cohort of MRI defined Younger onset Lacunar Stroke

Abstract

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene, is the most common monogenic disorder causing lacunar stroke and cerebral small vessel disease (SVD). Fabry disease (FD) due to mutations in the GLA gene has been suggested as an underdiagnosed cause of stroke, and one feature is SVD. Previous studies reported varying prevalence of CADASIL and FD in stroke, most likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence of CADASIL and FD in a well-defined, MRI verified cohort of patients with lacunar infarct. Methods: Caucasian patients with lacunar infarction, aged <=70 years (mean age 56.7 (SD8.5), range 20-70), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. All MRI’s and clinical histories were reviewed centrally. CADASIL screening was performed using denaturing high performance liquid chromatography (DHPLC) and sequencing in cases with a suspected variant. Exons 3, 4 5, 6, 8, 11, 18, 19 and 22 were screened which has been shown to detect 90% of mutations in a UK population. FD screening was performed using high-resolution melt curve analysis with sequencing confirmation. Results: Of 1,049 subjects four had pathogenic NOTCH3 mutations (R169C, R207C, R587C and C1222G) all resulting in loss of gain of a cysteine in the NOTCH3 protein. All four patients had confluent leukoaraiosis (Fazekas grade ≥2), and three had multiple infarcts. CADASIL prevalence overall was 0.4 (95% CI 0.1%-0.9%) and among cases with confluent leukoaraiosis 1.2% (95% CI 0.4%-2.8%). One additional patient had a missense mutation in the GLA gene (R118C) of uncertain significance; conflicting data exists pathogenicity of this mutation. Conclusions: CADASIL cases can be detected in younger onset apparently sporadic lacunar stroke, but are rare. FD screening in this patient group has a minimal pick-up.