Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3, and characterized by recurrent cerebral ischemic events without vascular risk factors, mood disturbance, and dementia. MRI testing shows cerebral white matter hyperintensities, especially in the external capsule and temporal pole. Typical mutations are cysteine-related missense ones located in one of 34 EGF-like repeats (EGFr) in the NOTCH3 receptor. To identify genotype–phenotype correlations, 179 Japanese CADASIL probands were recruited. Of the 68 mutations identified, p.Cys388Arg, p.Cys435Phe, p.Gly481Cys, p.Cys743Tyr, and p.Cys1009Phe were novel ones. The genotype–phenotype correlation was analyzed based on the three most common mutations: p.Arg75Pro, p.Arg141Cys, and p.Arg182Cys. p.Arg141Cys showed typical CADASIL phenotypes, whereas p.Arg75Pro showed mild and atypical phenotypes, a low frequency of stroke/TIA, high frequency of hypertension, and low frequency of temporal pole lesions. p.Arg182Cys showed various initial symptoms other than stroke/TIA. Subsequently, we analyzed the effect of the mutation location on the age at onset of stroke/TIA. We found that mutations in EGFr 1–6 excluding the cysteine-sparing mutation p.Arg75Pro were significantly correlated with a younger age at onset of stroke/TIA compared with those in EGFr 7–34. This was in agreement with a recent European report, suggesting that the effect of the mutation location is a consensus finding in CADASIL worldwide.

脑常染色体显性遗传性动脉病变伴皮质下梗死和白质脑病（CADASIL）是由NOTCH3引起的遗传性脑小血管疾病并具有反复发作的脑缺血事件的特征，而没有血管危险因素，情绪紊乱和痴呆。MRI检查显示大脑白质过高，特别是在外囊和颞极。典型的突变是位于NOTCH3受体中34个EGF样重复序列（EGFr）之一中的半胱氨酸相关的错义突变。为了确定基因型与表型的相关性，招募了179位日本CADASIL先证者。在鉴定出的68个突变中，p.Cys388Arg，p.Cys435Phe，p.Gly481Cys，p.Cys743Tyr和p.Cys1009Phe是新颖的。基于三种最常见的突变：p.Arg75Pro，p.Arg141Cys和p.Arg182Cys，分析了基因型与表型的相关性。p.Arg141Cys显示典型的CADASIL表型，而p.Arg75Pro显示轻度和非典型表型，中风/ TIA发生率低，高血压的频率高，颞极病变的频率低。p.Arg182Cys显示除卒中/ TIA以外的各种初始症状。随后，我们分析了突变位置对中风/ TIA发病年龄的影响。我们发现，与EGFr 7–34中相比，除半胱氨酸保留突变p.Arg75Pro外，EGFr 1–6中的突变与中风/ TIA发病年龄的降低显着相关。这与最近的欧洲报告一致，表明突变位置的影响是全球CADASIL的共识。我们发现，与EGFr 7–34中相比，除半胱氨酸保留突变p.Arg75Pro外，EGFr 1–6中的突变与中风/ TIA发病年龄的降低显着相关。这与最近的欧洲报告一致，表明突变位置的影响是全球CADASIL的共识。我们发现，与EGFr 7–34中相比，除半胱氨酸保留突变p.Arg75Pro外，EGFr 1–6中的突变与中风/ TIA发病年龄的降低显着相关。这与最近的欧洲报告一致，表明突变位置的影响是全球CADASIL的共识。