常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病的NOTCH3基因位点及临床特点分析

文周; 周亮; 吕博文; 莫桂玲; 宋玮; 钟建新

doi:10.3969/j.issn.2095-5227.2017.03.009

常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病的NOTCH3基因位点及临床特点分析

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: NOTCH3 gene mutation and clinical features

摘要

摘要: 目的探讨常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy，CADASIL)的NOTCH3基因表达、临床表现和磁共振特点。方法 2009-2016年中国金域检测中心对831例中国大陆临床可疑CADASIL者进行基因学分析并得出结果，南方医科大学附属南方医院及南方医科大学附属新会医院在其中的NOTCH3基因阳性患者中选取21例CADASIL作为CADASIL组。另将32例CADASIL评分量表> 14分且NOTCH3基因阴性的患者列为相似CADASIL(CADASIL-like)组。对两组的临床特点及磁共振结果进行分析。结果在831例检查者中，NOTCH3基因阳性的患者共275例，共有71个位点突变，其中4号外显子有100例，11号外显子有97例。NOTCH3基因11号外显子p.(Arg544Cys)是国内的最常见的突变位点，变异率为23.27%。脑白质高信号是CADASIL影像学常见表现，两组几乎所有的患者都表现出明显的脑白质病变，而且多表现为双边和对称性，CADASIL组阳性率为95.2%，CADASIL-like组阳性率为100%。磁共振成像结果发现两组外囊白质病变比例均较高，差异无统计学意义(71.4% vs 71.9%，P> 0.05)，而颞极受累比例的差异有统计学意义(42.9% vs 12.5%，P< 0.05)。在多发性腔梗的发生率上，CADASIL组(95.2%)与CADASIL-like组(90.6%)阳性率差异无统计学意义(P> 0.05)。CADASIL组磁共振SWI像微出血的阳性率为76.2%(16/21)，与CADASIL-like组的阳性率46.9%(15/32)差异有统计学意义(P< 0.05)。结论本组突变的NOTCH3基因主要集中在4号和11号外显子，11号外显子p.R544C是最常见的突变位点。广泛对称、双边分布的脑室旁和深部白质病变在CADASIL病变中常见，颞极的改变是CADASIL的特征，SWI像发现脑微出血可作为CADASIL的特征表现。

Abstract: Objective To investigate the NOTCH3 gene locus, clinical manifestation and MRI features of autosomal dominant hereditary cerebral arteriopathy with subcortical infarcts and white matter encephalopathy (CADASIL). Methods Genetic testing were performed in 831 cases of suspected CADASIL from 2009 to 2016, and 21 patients with CADASIL were selected as CADASIL group from NOTCH3 positive patients from Xinhui Hospital or Nanfang Hospital affliated to Southern Medical University. Another 32 patients with CADASIL score of more than 14 points served as CADASIL-like group. The clinical features and magnetic resonance imaging results of the two groups were analyzed. Results We have screened out 275 patients carrying NOTCH3 gene in 831 cases, with total of 71 mutant sites, in which 100 patients carried excon 4 mutant and 97 patients carried excon 11 mutant. Excon 11 p.R544C in Notch3 gene was found to be the maximum frequency of mutant site with mutation rate of 23.27%. White matter high signal intensity (WMHs) was the common expression in iconography and almost showed in all patients (95.2% in CADASIL group and 100% in CADASIL-like group). WMHs was always bilateral and symmetric. The rates of external capsule involvement in two groups were high with no statistically signifcant difference (71.4% in CADASIL group vs 71.9% in CADASIL-like group, P> 0.05). However, temporal pole involvement rate in CADASIL group was statistically signifcantly higher than that in CADASIL-like group (42.9% vs 12.5%, P< 0.05).The occurrence rates of multi-lacunar infarcts were 95.2% in CADASIL group and 90.6% in CADASIL-like group (P< 0.05). Cerebral microbleeds were observed in 76.2% (16/21) cases in CADASIL group and 46.9% (15/32) cases in CADASIL-like gruop with signifcant difference (P< 0.05). Conclusion In our study, NOTCH3 mutations most commonly occur in exon 4 and exon 11, and R544C in exon 11 accounted for nearly one fourth of the pedigrees, In CADASIL cases, bilateral, and symmetrical white matter lesions widely exist, with frequent involvement of temporal pole and cerebral microbleeds.

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