| Affiliation: | 1.Department of Neurology, Graduate School of Medical Sciences,Kumamoto University,Kumamoto,Japan;2.Department of Clinical Laboratory,Kumamoto University Hospital,Kumamoto,Japan;3.Department of Stroke and Cerebrovascular Medicine,Kyorin University,Mitaka,Japan;4.Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences,Kumamoto University,Kumamoto,Japan;5.Laboratory of Neuropathology,Tokyo Metropolitan Institute of Medical Science,Tokyo,Japan;6.Department of Neurology,Kumamoto Takumadai Rehabilitation Hospital,Kumamoto,Japan;7.Department of Cerebrovascular Medicine and Neurology,National Hospital Organization Kyushu Medical Center,Fukuoka,Japan;8.Department of Clinical Medicine,National Institute for Minamata Disease,Minamata,Japan;9.Department of Cell Biology and Anatomy,Hamamatsu University School of Medicine,Hamamatsu,Japan |
| 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. |
