title: Genotypic and phenotypic spectrum of CADASIL in Japan: the experience at a referral center in Kumamoto University from 1997 to 2014.
abstract: This study elucidates the genotypic and phenotypic spectrum and histopathological findings related to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Japan. For this single-center retrospective observational study, we enrolled 215 patients who were clinically suspected of having CADASIL and were examined at Kumamoto University from 1997 to 2014, and we diagnosed CADASIL in 70 patients. We found 19 different NOTCH3 mutations in the patients, with the NOTCH3 Arg133Cys mutation being found most frequently. We also found the Arg75Pro mutation, a cysteine-sparing NOTCH3 mutation. CADASIL patients with this Arg75Pro mutation were frequently found throughout Japan, and fewer patients with the Arg75Pro mutation showed MRI hyperintensity in the anterior temporal pole compared with patients with other NOTCH3 mutations. Significantly more CADASIL patients with the NOTCH3 Arg133Cys mutation had hyperintensity in the external capsule compared with CADASIL patients with the other mutations not including the NOTCH3 Arg75Pro mutation. We also showed postmortem pathological findings of the first Japanese CADASIL case with the NOTCH3 Arg133Cys mutation, and histopathological findings of fresh frozen skin biopsy specimens of CADASIL patients. In conclusions, the spectrum of NOTCH3 mutations in Japanese CADASIL patients may be partially explained by founder effects. Genotype-phenotype correlations may exist in CADASIL, which should be considered so as to make an accurate diagnosis of CADASIL in each population. Fresh frozen skin biopsy specimens may aid detection of Notch3 deposits on vascular walls for an improved diagnosis of CADASIL.
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ueda
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Ueda
authors.forename: Akihito
authors.initials: A
authors.lastname: Nagatoshi
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Hirano
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ito
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Arai
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Uyama
authors.forename: Kota
authors.initials: K
authors.lastname: Mori
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinriki
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
mesh_terms: D000046:Academic Medical Centers; D000328:Adult; D000368:Aged; D046589:CADASIL / Q000235:genetics* / Q000473:pathology*; D054022:Cerebrum / Q000473:pathology*; D066271:External Capsule / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D012017:Referral and Consultation; D012189:Retrospective Studies; D012867:Skin / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D013702:Temporal Lobe / Q000473:pathology; D066127:White Matter / Q000473:pathology
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch