KCNA2基因相关发育及癫痫性脑病患儿的基因型及表型特点

目的探讨KCNA2基因相关发育及癫痫性脑病(DEE)患儿的基因型及表型特点。方法回顾性病例总结,收集2017年3月至2019年6月在北京大学第一医院儿科就诊的KCNA2基因变异阳性的8例患儿的病例资料,总结其临床表现、基因型及脑电图特点。结果8例KCNA2基因变异的癫痫患儿中男5例、女3例,起病年龄1日龄~11月龄,末次随访年龄4月龄~7岁2月龄。共检测到c.1214C>T(功能缺陷型)和c.1120A>G(功能获得型合并功能缺失型)两种变异类型。6例(例1~6)携带c.1214C>T基因变异,起病年龄为5~11月龄,均出现多种癫痫发作类型,起病前智力、运动发育正常,起病后均有不同程度倒退;可获得的首次脑电图记录示2例为Rolandic区放电,1例为Rolandic区合并广泛性放电,2例为后头部著的广泛性放电(均在病程中逐渐合并或转移至Rolandic区),1例为后头部合并广泛性放电。5例病程中Rolandic区放电达到睡眠期癫痫性电持续状态(ESES)。6例至末次随访均仍接受多种抗癫痫药物联合治疗,其中2例分别在6岁8月龄和5岁8月龄时发作控制。2例(例7、8)患儿携带c.1120A>G基因变异,均在1日龄起病,表现为癫痫发作频繁且难以控制,自幼严重发育落后,均有小头畸形,例8前额宽;至末次随访均仍有频繁发作;例7起病早期脑电图为颞区放电,末次随访3月龄时为后头部和颞区为主多灶性放电,例8起病早期脑电图正常,2月龄复查示爆发抑制,末次随访1岁时为后头部放电。结论KCNA2基因变异可导致伴有多种癫痫发作类型的难治性DEE。功能缺失型c.1214C>T变异最为常见,临床表型为婴儿期起病,脑电图病程中常出现Rolandic区的ESES放电现象;c.1120A>G变异为功能获得型合并功能缺失型,患儿为新生儿期起病,表型与前者有重叠但程度更重。

Genotype and phenotype of children with KCNA2 gene related developmental and epileptic encephalopathy

Objective To investigate the genotype and phenotype of children with KCNA2 gene related developmental and epileptic encephalopathy(DEE).Methods Clinical data including the manifestations and electroencephalogram of 8 children with KCNA2 variants treated in the Department of Pediatrics,Peking University First Hospital from March 2017 to June 2019 were collected and analyzed retrospectively.Results Among the 8 epileptic patients with KCNA2 variants,5 were males and 3 were females.The age of onset was from 1 day to 11 months.The age at last follow-up ranged from 4 months to 86 months.Two variants including c.1214C>T(loss-of-function)and c.1120A>G(gain-and loss-of-function)were identified.The variant of c.1214C>T was found in six patients(case 1-6).For these patients,the age of onset was from 5 to 11 months and they were characterized by multiple seizure types.All had focal seizures and had normal development before seizure onset with developmental regression after seizure onset.The first electroencephalogram showed epileptic discharges in Rolandic region in two,epileptic discharges in Rolandic region combined with generalized discharge in one,generalized discharge with posterior predominance in two(combined with or transferred to Rolandic region during the course)and epileptic discharges in posterior region combined with generalized discharge in one.And in 5 of them the Rolandic discharges developed into epileptic electrical status(ESES)during sleep.All the six patients were still treated with a combination of multiple antiepileptic drugs.Two of them had seizure controlled at 80 months and 68 months,respectively.The variant of c.1120A>G were identified in two of eight patients(case 7 and 8)and they had seizure onset on the 1st day after birth.Their epileptic seizures were frequent and difficult to control.They had remarkably developmental delay and microcephaly since birth.One case(case 8)had a wide forehead.They had frequent seizures up to the last follow-up.In case 7,the early electroencephalogram showed epileptic discharges in temporal region,and interictal electroencephalogram at 3 months of age showed multifocal discharge with posterior and temporal region predominance.In case 8,the early electroencephalogram was normal and electroencephalogram showed burst suppression at 2 months of age,and it developed epileptiform discharge in posterior region at 1 year of age.Conclusions KCNA2 gene variants can lead to DEE with multiple seizures types.Among them,loss-of-function c.1214C>T is the most common,and these patients have seizure onset at infancy with Rolandic discharges tended to develop into to ESES pattern.The variant of c.1120A>G is a gain-of-and loss-of-function variant,patients with c.1120A>G have seizure onset in neonatal period,the phenotype overlaps with the former but is more severe.