title: Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke.
abstract: OBJECTIVE
  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, 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.
  
  
  METHODS
  Caucasian 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.
  
  
  RESULTS
  Of 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.
  
  
  CONCLUSIONS
  CADASIL cases are rare and only detected in SVD patients with confluent leukoaraiosis. No definite FD cases were detected.
authors: Stroke and Dementia Research Centre, St George's University of London, London, United Kingdom.
authors: Laura L
authors: LL
authors: Kilarski
authors: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors: Loes C A
authors: LC
authors: Rutten-Jacobs
authors: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors: Steve
authors: S
authors: Bevan
authors: Department of Haematology, Lysosomal Storage Disorders Unit, Royal Free Hospital and University College Medical School, London, United Kingdom.
authors: Rob
authors: R
authors: Baker
authors: Department of neurology, Leeds General Infirmary, Leeds, United Kingdom.
authors: Ahamad
authors: A
authors: Hassan
authors: Department of Haematology, Lysosomal Storage Disorders Unit, Royal Free Hospital and University College Medical School, London, United Kingdom.
authors: Derralynn A
authors: DA
authors: Hughes
authors: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors: Hugh S
authors: HS
authors: Markus
mesh_terms: D017668:Age of Onset; D046589:CADASIL / Q000150:complications* / Q000453:epidemiology* / Q000235:genetics; D015331:Cohort Studies; D000795:Fabry Disease / Q000150:complications* / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D015995:Prevalence; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics; D059409:Stroke, Lacunar / Q000150:complications* / Q000235:genetics; D006113:United Kingdom / Q000453:epidemiology; D000519:alpha-Galactosidase / Q000235:genetics
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000519:alpha-Galactosidase