title: Homozygosity and severity of phenotypic presentation in a CADASIL family.
abstract: Most of causative mutations of the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are missense point mutations either creating or deleting one cysteine residue, inherited in a heterozygous state. Only few homozygous patients are reported to date and some of them showed phenotypic peculiarities. We here describe a CADASIL family in which a member showed homozygous mutation and compare its clinical profile with five subjects throughout three generation of the pedigree, carrying the same mutation in heterozygosity. The index patient was a 44-year-old Italian man, born from consanguineous parents (first cousins). Symptoms started at 23 years and progressing with recurrent ischemic stroke episode. Diffuse leukoencephalopathy and a severe cognitive impairment were evident, GOMs were detected in skin specimens and a homozygous p.Cys183Ser mutation of the NOTCH3 gene was found. Among the other five heterozygous relatives for the same mutation, both parents developed stroke in advanced age and all the others were clinically asymptomatic. We discuss these findings in relationship to previous data from the literature in CADASIL and in other dominant neurological disorders.
authors.affiliation: Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Bracci 2, 53100, Siena, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vinciguerra
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rufa
authors.forename: Silvia
authors.initials: S
authors.lastname: Bianchi
authors.forename: Antonio
authors.initials: A
authors.lastname: Sperduto
authors.forename: Monica
authors.initials: M
authors.lastname: De Santis
authors.forename: Alessandro
authors.initials: A
authors.lastname: Malandrini
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Dotti
authors.forename: Antonio
authors.initials: A
authors.lastname: Federico
mesh_terms: D000328:Adult; D017668:Age of Onset; D046589:CADASIL / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch