title: CADASIL with cord involvement associated with a novel and atypical NOTCH3 mutation.
abstract: BACKGROUND
  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary cause of cerebral small-vessel disease associated with one of many recognised mutations of the NOTCH3 gene. Spinal cord involvement is not a recognised feature. The authors describe a unique CADASIL pedigree that manifested a stereotypical pattern of cord lesions, in association with a novel and atypical NOTCH3 mutation.
  
  
  METHODS
  Clinical, radiological, laboratory and genetic characterisation of three affected family members. The associated NOTCH3 mutation was further evaluated by site-directed mutagenesis, immunohistochemistry, CBF1-transcription reporter assay, and screened for in 100 unrelated pathologically confirmed multiple sclerosis (MS) patients.
  
  
  RESULTS
  Three members of a family presented with CADASIL caused by a novel NOTCH3 missense mutation, C212Y. Two daughters of the proband also manifested a distinctive pattern of cord lesions confined to the posterocentral zone, cerebral lesions showing both a demyelinating and a typical CADASIL topography, positive antinuclear antibodies and intrathecally derived oligoclonal bands. The mutation occurred in exon 4--that is, outside the Notch3 ligand-binding domain--yet unusually for this location impaired Notch function as assessed by Jagged1 signal transduction. The C212Y mutation did not occur in 100 separate MS cases.
  
  
  CONCLUSIONS
  This is the first description of an inherited pattern of cord lesions in association with CADASIL. The fact that certain features of dysregulated immunity also occurred, in association with a novel and atypical loss-of-function NOTCH3 mutation, supports evidence for functional interactions of Notch3 with the immune system, in addition to its vascular support role.
authors.affiliation: Imperial College Cerebrovascular Research Unit, Imperial College Hospitals, Charing Cross Campus, Fulham Palace Rd, London W6 8RF, UK. p.bentley@imperial.ac.uk
authors.forename: Paul
authors.initials: P
authors.lastname: Bentley
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Omar
authors.initials: O
authors.lastname: Malik
authors.forename: Richard
authors.initials: R
authors.lastname: Nicholas
authors.forename: Maria
authors.initials: M
authors.lastname: Ban
authors.forename: Stephen
authors.initials: S
authors.lastname: Sawcer
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism / Q000473:pathology; D046589:CADASIL / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000235:genetics; D020125:Mutation, Missense; D010375:Pedigree; D011180:Postmortem Changes; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D013118:Spinal Cord Diseases / Q000175:diagnosis* / Q000209:etiology; D014015:Tissue Banks
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch