Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke |
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Authors: | Laura L. Kilarski Loes C. A. Rutten-Jacobs Steve Bevan Rob Baker Ahamad Hassan Derralynn A. Hughes Hugh S. Markus UK Young Lacunar Stroke DNA Study |
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Affiliation: | 1. Stroke and Dementia Research Centre, St George’s University of London, London, United Kingdom.; 2. Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.; 3. Department of Haematology, Lysosomal Storage Disorders Unit, Royal Free Hospital and University College Medical School, London, United Kingdom.; 4. Department of neurology, Leeds General Infirmary, Leeds, United Kingdom.; King Faisal Specialist Hospital and Research center, SAUDI ARABIA, |
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Abstract: | Background and PurposeCerebral 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, likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence in a well-defined, MRI-verified cohort of apparently sporadic patients with lacunar infarct.MethodsCaucasian patients with lacunar infarction, aged ≤70 years (mean age 56.7 (SD8.6)), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. Patients with a previously confirmed monogenic cause of stroke were excluded. All MRI’s and clinical histories were reviewed centrally. Screening was performed for NOTCH3 and GLA mutations.ResultsOf 994 subjects five had pathogenic NOTCH3 mutations (R169C, R207C, R587C, C1222G and C323S) all resulting in loss or gain of a cysteine in the NOTCH3 protein. All five patients had confluent leukoaraiosis (Fazekas grade ≥2). CADASIL prevalence overall was 0.5% (95% CI 0.2%-1.1%) and among cases with confluent leukoaraiosis 1.5% (95% CI 0.6%-3.3%). No classic pathogenic FD mutations were found; one patient had a missense mutation (R118C), associated with late-onset FD.ConclusionCADASIL cases are rare and only detected in SVD patients with confluent leukoaraiosis. No definite FD cases were detected. |
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