NOTCH3基因c.520T>G突变致CADASIL一家系报告及文献复习

CADASIL Caused by the NOTCH3 c.520T>G mutation:a Family Report

目的:研究探讨一CADASIL家系的临床特征及基因突变情况。方法:收集同一家系中3例CADASIL患者的临床资料,并对3例患者及先证者之兄进行全外显子测序(Whole Exome Sequencing, WES)。结果:该家系中3例患者临床表现多样,女性患者均有头痛病史,先证者及先证者之姐中年起病,先证者临床表现缺乏特异性,主要表现为头昏,认知功能检查正常,心理评估示轻度焦虑抑郁状态。先证者之姐主要表现为假性球麻痹及锥体束受损,认知功能检查示重度痴呆。先证者之女自4岁起诊断为癫痫-失神发作,认知功能检查示轻度认知功能障碍。影像学显示该家系3例患者均有脑白质病变,且随着年龄增大呈进行性发展,WES显示3例患者均存在NOTCH3基因第4外显子区域杂合突变:c.520T>G,导致氨基酸改变p.Cys174Gly。结论:NOTCH3基因c.520T>G所致该家系的临床表现具有多样性,且该家系中下一代起病较早,临床表现可与父代具有较大异质性,影像学表现可在青少年时期出现,并呈现进行加重的趋势。WES显示该家系中NOTCH3基因突变为第4外显子的杂合突变,该位点突变致CADASIL为国内首次报道。

Objective: To investigate the clinical features and gene mutation of a CADASIL pedigree. Methods: Clinical data of 3 CADASIL patients from the same family were collected, and whole exon sequencing was performed on 3 patients and the elder brother of the proband. Results: The clinical manifestations of the 3 patients in this family were diverse, and all the female patients had a history of headache. The onset of the disease occurred in the middle age of the proband and the elder sister of the proband. The clinical manifestations of propositie patients are lack of specificity, mainly manifested as dizziness, normal cognitive function examination, and mild anxiety and depression in psychological evaluation. The elder sister of the proband mainly showed pseudobulbar paralysis and impaired pyramidal tract, and cognitive function examination showed severe dementia. The daughter of the proband had been diagnosed with epileptia-aphasia since she was 4 years old. The head MRI showed that the white matter of the 3 members of the family fell into a pattern that gradually developed with age. WES showed that the 4 exon of the NOTCH3 gene had a heterozygous mutation: c.520 T > G,which led to the amino acid change p.cys174 gly. Conclusion: The clinical expression of this family family caused by NOTCH3 gene c.520 T > G showed diversity. Moreover, the next generation of this family had earlier onset of disease, and its clinical expression could be more heterogeneous than that of its nadraden. The imaging expression of this family family could emerge in the adolescent period and show a tendency of aggravation. WES showed that the mutation of NOTCH3 gene in the family was a heterozygous mutation of exon 4,and the mutation of this site to CADASIL was first reported in China.