title: A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: genetic and magnetic resonance spectroscopic findings.
abstract: BACKGROUND
  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary syndrome caused by mutations of the Notch3 gene, usually localized to exons 3 and 4.
  
  
  OBJECTIVE
  To report a novel pathogenetic mutation occurring in exon 6 of the Notch3 gene, a location not previously recognized in patients with CADASIL, and to report the results of magnetic resonance spectroscopy in CADASIL.
  
  
  METHODS
  Mutation analysis of the Notch3 gene was performed in 2 patients belonging to a large kindred manifesting CADASIL, as well as in 7 clinically unaffected members of the family and 200 control chromosomes. Proton magnetic resonance spectroscopy was used to estimate metabolite resonance intensities in the 2 affected subjects.
  
  
  RESULTS
  Sequence analysis of the Notch3 gene showed a new missense mutation CGC-->TGC in codon 332 of exon 6, resulting in the replacement of an arginine residue with a cysteine. This mutation was never observed in the 7 unaffected members of the family and the 200 control chromosomes examined. Proton magnetic resonance spectroscopy showed a diffuse decrease in cerebral N-acetylaspartate, indicating the presence of widespread axonal damage.
  
  
  CONCLUSIONS
  Our findings emphasize the role of direct DNA sequence analysis for the diagnosis of CADASIL. Moreover, the results of proton magnetic resonance spectroscopy suggest that widespread axonal damage may be an early finding of the disease.
authors.affiliation: Institute of Neurology, University Magna Graecia, 88100 Catanzaro, Italy.
authors.forename: R L
authors.initials: RL
authors.lastname: Oliveri
authors.forename: M
authors.initials: M
authors.lastname: Muglia
authors.forename: N
authors.initials: N
authors.lastname: De Stefano
authors.forename: R
authors.initials: R
authors.lastname: Mazzei
authors.forename: A
authors.initials: A
authors.lastname: Labate
authors.forename: F L
authors.initials: FL
authors.lastname: Conforti
authors.forename: A
authors.initials: A
authors.lastname: Patitucci
authors.forename: A L
authors.initials: AL
authors.lastname: Gabriele
authors.forename: G
authors.initials: G
authors.lastname: Tagarelli
authors.forename: A
authors.initials: A
authors.lastname: Magariello
authors.forename: M
authors.initials: M
authors.lastname: Zappia
authors.forename: A
authors.initials: A
authors.lastname: Gambardella
authors.forename: A
authors.initials: A
authors.lastname: Federico
authors.forename: A
authors.initials: A
authors.lastname: Quattrone
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D015161:Dementia, Multi-Infarct / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007558:Italy; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch
chemical_list: C499374:NOTCH3 protein, human; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch