Prevalence and Atypical Clinical Characteristics of NOTCH3 Mutations Among Patients Admitted for Acute Lacunar Infarctions
Prevalence and Atypical Clinical Characteristics of NOTCH3 Mutations Among Patients Admitted for Acute Lacunar Infarctions
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DOI：
10.3389/fnagi.2020.00130
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发表时间：
2020-05
影响因子：
4.8
通讯作者：
Takashi Okada;K. Washida;K. Irie;S. Saito;Michio Noguchi;Tsutomu Tomita;M. Koga;K. Toyoda;Shuhei Okazaki;T. Koizumi;I. Mizuta;T. Mizuno;M. Ihara
中科院分区：
文献类型：
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作者：
Takashi Okada;K. Washida;K. Irie;S. Saito;Michio Noguchi;Tsutomu Tomita;M. Koga;K. Toyoda;Shuhei Okazaki;T. Koizumi;I. Mizuta;T. Mizuno;M. Ihara
目的：伴有皮质下梗塞和白质脑病的常染色体显性遗传性脑动脉病 (CADASIL) 是最常见的遗传性小血管疾病，据报道发病率为 2-5/100,000 人。近期有报道称，部分NOTCH3基因突变患者表现出不典型的CADASIL临床症状。假设在某些腔隙性梗塞病例中 CADASIL 诊断不足，本研究旨在检查因腔隙性梗塞入院的风险最高的患者中 NOTCH3 基因突变的患病率。方法： 2011年1月至2018年4月，我院收治腔隙性脑梗死患者1094例，其中31例无高血压但患有脑白质疾病（Fazekas量表2级或3级）的患者进行NOTCH3基因突变基因分析（一期）。此外，还对 54 名 60 岁或以下的患者进行了 NOTCH3 突变分析（第 2 阶段）。通过基因组 DNA 直接测序，对 NOTCH3 外显子 2-24 进行突变分析，这些外显子编码 NOTCH3 受体的表皮生长因子样重复结构域。结果：三名患者出现 NOTCH3 p.R75P 突变：两名患者在 1 期队列中，一名患者在 2 期队列中。在60岁或以下以及无高血压但有中重度白质病变的患者中，p.R75P的携带频率为3.5%（3/85），显着高于日本一般人群（4.7KJPN）（比值比[95% CI] = 58.2 [11.6–292.5]）。所有三名携带NOTCH3突变的患者都有中风家族史，患者平均年龄为51.3岁。所有三名患者均在外囊中显示白质病变，但在颞极中未发现白质病变。 3 名患者的 CADASIL 和 CADASIL 量表-J 评分分别为 6、17、7（平均 10.0）和 13、20、10（平均 14.3）。结论：在因腔隙性梗塞住院的患者中，p.R75P 患病率可能高于之前估计的水平。由于 CADASIL 的非典型临床和神经影像学特征，NOTCH3 p.R75P 突变可能导致早发性腔隙性梗塞患者漏诊。尽管没有颞叶白质病变，但早发、有中风家族史、外囊病变和无高血压可能有助于预测潜在的 NOTCH3 突变。
Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary small vessel disease, with reported frequencies of 2-5/100,000 individuals. Recently, it has been reported that some patients with NOTCH3 gene mutations show atypical clinical symptoms of CADASIL. Assuming that CADASIL is underdiagnosed in some cases of lacunar infarction, this study was designed to examine the prevalence of NOTCH3 gene mutations in the patients at highest risk who were admitted for lacunar infarctions. Methods: From January 2011 to April 2018, 1,094 patients with lacunar infarctions were admitted to our hospital, of whom 31 patients without hypertension but with white matter disease (Fazekas scale 2 or 3) were selected and genetically analyzed for NOTCH3 gene mutations (Phase 1). Furthermore, 54 patients, who were 60 years or younger, were analyzed for NOTCH3 mutations (Phase 2). NOTCH3 exons 2–24, which encode the epidermal growth factor-like repeat domain of the NOTCH3 receptor, were analyzed for mutations by direct sequencing of genomic DNA. Results: Three patients presented NOTCH3 p.R75P mutations: two in the Phase 1 and one in the Phase 2 cohort. Among patients aged 60 years or younger and those without hypertension but with moderate-to-severe white matter lesions, the carrier frequency of p.R75P was 3.5% (3/85), which was significantly higher than that in the Japanese general population (4.7KJPN) (odds ratio [95% CI] = 58.2 [11.6–292.5]). All three patients with NOTCH3 mutations had family histories of stroke, and the average patient age was 51.3 years. All three patients also showed white matter lesions in the external capsule but not in the temporal pole. The CADASIL and CADASIL scale-J scores of the three patients were 6, 17, 7 (mean, 10.0) and 13, 20, 10 (mean, 14.3), respectively. Conclusion: Among patients hospitalized for lacunar infarctions, the p.R75P prevalence may be higher than previously estimated. The NOTCH3 p.R75P mutation may be underdiagnosed in patients with early-onset lacunar infarctions due to the atypical clinical and neuroimaging features of CADASIL. Early-onset, presence of family history of stroke, external capsule lesions, and absence of hypertension may help predict underlying NOTCH3 mutations despite no temporal white matter lesions.