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中华妇幼临床医学杂志(电子版) ›› 2022, Vol. 18 ›› Issue (03) : 307 -314. doi: 10.3877/cma.j.issn.1673-5250.2022.03.009

论著

非典型良性家族性新生儿癫痫患儿的诊治及文献复习
宁俊杰1,2, 乔莉娜1,2,†()   
  1. 1四川大学华西第二医院儿童重症医学科、出生缺陷与相关妇儿疾病教育部重点实验室，成都　610041
    2国家卫生健康委员会时间生物学重点实验室（四川大学），成都　610041
  • 收稿日期:2021-12-01 修回日期:2022-05-15 出版日期:2022-06-01
  • 通信作者: 乔莉娜

Atypical benign familial neonatal epilepsy: a case report and literature review

Junjie Ning1,2, Lina Qiao1,2,†()   

  1. 1Department of Pediatric Intensive Care Unit, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
    2NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu 610041, Sichuan Province, China
  • Received:2021-12-01 Revised:2022-05-15 Published:2022-06-01
  • Corresponding author: Lina Qiao
  • Supported by:
    Central Government Fund of Guiding Local Scientific and Technological Development for Sichuan Province(2021ZYD0105)
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引用本文：

宁俊杰, 乔莉娜. 非典型良性家族性新生儿癫痫患儿的诊治及文献复习[J]. 中华妇幼临床医学杂志(电子版), 2022, 18(03): 307-314.

Junjie Ning, Lina Qiao. Atypical benign familial neonatal epilepsy: a case report and literature review[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2022, 18(03): 307-314.

目的

探讨非典型良性家族性新生儿癫痫(BFNE)患儿的临床特征、家系调查及基因突变分析，并总结我国KCNQ基因突变所致癫痫患儿的遗传学特点。

方法

选择2021年2月，于四川大学华西第二医院确诊的1例延迟在3个月龄癫痫发病的BFNE患儿(先证者)为研究对象。回顾性分析其临床表现、家系调查及基因检测结果等。以"KCNQ基因""癫痫"为中文关键词，以"KCNQ gene""seizures""epilepsy""convulsion"为英文关键词，对中国知网、万方数据知识服务平台(年限设定为上述数据库建库至今)，以及Google Scholar、PubMed数据库(年限设定为2000年1月至2020年12月)进行检索，总结我国KCNQ基因突变癫痫患儿的遗传学特点。本研究遵循的程序符合2013年新修订的《世界医学协会赫尔辛基宣言》要求。与本例患儿监护人签署临床研究知情同意书。

结果

①本例患儿为3个月龄女婴，因"反复抽搐1 d"入院。其头颅MRI未见异常；脑电图结果提示多灶性癫痫波发放。调查本例患儿家系3代8人发现，先证者(本例患儿)及其父亲、祖父均发生婴儿期惊厥，非新生儿期发病，其父亲、祖父的BFNE均于1岁左右消失。对本例患儿经左乙拉西坦抗癫痫治疗至9个月龄后抽搐发作停止，随访至1岁1个月亦未再发。②本例患儿及其父亲、祖父基因检测结果显示，均存在KCNQ 2基因2号外显子存在c.373dupG(p.A125fs)杂合突变。与BFNE相关。③文献复习结果：根据本研究设定的检索策略，共检索到129篇国内关于KCNQ基因突变致癫痫发作的相关研究文献，纳入研究的中国患儿为129例，加上本例患儿共计130例。这130例患儿中，72例的起病年龄为0~28 d，56例为29 d至2岁，2例>2岁；KCNQ 2、3基因突变各为119例与11例；随访105例，51例患儿合并智力/发育障碍，其中KCNQ 2、3基因突变各为50例与1例，5例患者死亡，均为KCNQ 2基因突变，其余患儿智力/发育正常。本组130例KCNQ基因突变致癫痫患儿中，108例接受药物治疗患儿的治疗有效率为69.4%(75/108)，105例接受随访患儿的死亡率为4.8%(5/105)。

结论

KCNQ 2基因c.373dupG(p.A125fs)突变，可能为本例患儿家系BFNE发病的分子遗传学致病机制。国内KCNQ基因突变致癫痫患儿以KCNQ 2基因突变为主，患儿多于2岁内起病，并且KCNQ 2基因突变癫痫患儿相较于KCNQ 3基因突变患儿预后更差。

关键词: KCNQ 2钾通道, 移码突变, 抗惊厥药, 基因检测, 遗传突变, 系谱, 癫痫，正常新生儿
Objective

To explore the clinical features, lineage identification and gene mutation analysis of children with atypical benign familial neonatal epilepsy (BFNE), and to summarize the genetic characteristics of children with epilepsy caused by KCNQ gene mutation in China.

Methods

A case of BFNE who was diagnosed in West China Second University Hospital, Sichuan University in February 2021 was selected into this study for retrospective analysis of its clinical manifestations, lineage identifieation, genetic testing results and other clinical data. Taking " KCNQ gene" " epilepsy" " seizures" " epilepsy" " convulsion" as Chinese and English keywords, search CNKI, Wanfang Data Knowledge Service Platform (from database construction to nowadays), as well as Google Scholar and Pubmed database (from January 2000 to December 2020) to summarize genetic characteristics of KCNQ gene mutation-positive epilepsy patients in China. The procedure followed in this study met requirements of the Helsinki Declaration of the World Medical Association revised in 2013.

Results

① Clinical characteristics of this girl were as follows. This case was a 3-month-old girl who was admitted to hospital due to " recurrent convulsions for 1 d" . Skull MRI results showed no abnormalities. Electroencephalogram results suggested multifocal epileptic wave release. Eight people from 3 generations of this lineage were investigated. In this case, the proband, his father and grandfather had convulsions in infancy, and the BFNE of his father and grandfather disappeared at 1 year old. This child was treated with levetiracetam for 9 months and followed up to 1 year and 1 month. The child did not have convulsions until now. ②Genetic test results showed that c. 373dupG (p.A125fs) heterozygous mutation was found in the second exon of KCNQ 2 gene in this case, which was associated with benign convulsion of neonates. c. 373dupG(p.A125fs) heterozygous variation was also found in the second exon of KCNQ 2 gene in this case′s father and grandfather. ③Results of literature review were as follows. A total of 129 domestic literatures about epilepsy caused by KCNQ gene mutation were reviewed. A total of 130 Chinese cases were enrolled, including this case. Among these 130 cases, the age of onset ranged from 0 to 28 days in 72 cases, from 29 days to 2 years in 56 cases, and older than 2 year-old in 2 cases. There were 119 cases of KCNQ 2 gene variants, 11 cases of KCNQ 3 gene variants. Among 51 cases with mental/developmental disorders, 50 cases with KCNQ 2 gene mutation and 1 patient with KCNQ 3 gene mutation. And 5 dead cases were all KCNQ 2 gene mutations. Besides, the effective rate of drug use in children with epilepsy caused by KCNQ gene mutation was 69.4%(75/108), and the mortality was 4.8%(5/105).

Conclusions

KCNQ 2 gene c. 373dupG (p.A125fs) mutation may be the genetic cause of BFNE in this lineage. Epilepsy caused by KCNQ gene mutation patients in China were mainly KCNQ 2 gene mutation, and the onset age was mainly within 2 years old. And the prognosis of KCNQ 2 gene mutation was worse than that of KCNQ 3 mutation.

Key words: KCNQ 2 potassium channel, Frameshift mutation, Anticonvulsants, Genetic testing, Genetic variation, Pedigree, Epilepsy, benign neonatal
图1 本例患儿(先证者)(女性，3个月龄)BFNE发病家系图注：BFNE为良性家族性新生儿癫痫。Ⅰ、Ⅱ、Ⅲ分别指家系第1~3代(祖、父、孙3代)。□与○为男、女性未患病者，■与●为男、女性患病者，为先证者
图2 本例BFNE患儿(女性，3个月龄)及其父亲(23岁)、祖父(47岁)KCNQ 2基因Sanger测序峰图[图2A~2C：本例患儿及其父亲、祖父的KCNQ 2基因2号外显子存在c.373dupG(p.A125fs)杂合突变]注：BFNE为良性家族性新生儿癫痫
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