SYNGAP1基因相关儿童癫痫临床特点和基因分析

Clinical characteristics and gene analysis of SYNGAP1-related epilepsy in children

目的总结SYNGAP1基因相关儿童癫痫的临床特点。方法回顾性收集首都医科大学附属北京儿童医院神经内科2017年3月至2020年10月就诊的13例SYNGAP1基因变异相关癫痫患儿,并进行随访,对其临床特点、脑电图、头颅影像学、基因结果、治疗等进行总结。结果13例患儿(男4例、女9例)随访到12例,末次随访年龄5岁7月龄(3岁1月龄至9岁)。癫痫发作起病年龄为2岁(4月龄至3岁),发作类型包括眼睑肌阵挛伴或不伴失神(9例)、肌阵挛发作(5例)、不典型失神(4例)、可疑失张力发作(4例)、跌倒发作(6例,具体发作类型不详),发作频率每日数次到百余次。4例表型类似肌阵挛-失张力综合征。10例发作有诱因,包括进食(5例)、情绪(5例)、发热(3例)、声音(2例)、劳累(2例)等。10例患儿脑电图提示9例发作间期广泛性或局灶性痫样放电,监测到不典型失神4例、肌阵挛发作2例和眼睑肌阵挛伴失神发作1例。12例中9例加用丙戊酸钠均有效(发作减少50%以上),5例联用左乙拉西坦3例有效,至末次随访3例发作相对控制(6个月至1年1个月),余7例仍有发作(数日1次或每日数次)。13例均存在发育落后(语言落后为著),2例重度,10例中度,1例轻度。13例患儿携带SYNGAP1基因变异,均为新生变异,包括12个变异位点。其中移码变异4个,无义变异4个,错义变异2个,剪切位点变异2个。结论SYNGAP1基因相关儿童癫痫起病年龄较早,发作类型多样,主要发作类型为眼睑肌阵挛伴或不伴失神,还可有肌阵挛发作、不典型失神、跌倒发作等。丙戊酸治疗多有效,部分可为药物难治性癫痫。患儿存在不同程度发育迟缓,以语言落后为著。

Objective To summarize the clinical characteristics of SYNGAP1-related epilepsy in children.Methods Data of 13 patients with SYNGAP1 gene variants diagnosed with epilepsy at Department of Neurology,Beijing Children's Hospital were collected retrospectively from March 2017 to October 2020 and the patients were followed up.The clinical features,electroencephalogram(EEG),brain imaging,gene results and treatment were summarized.Results Twelve patients were followed up successfully among the 13 patients with SYNGAP1 variants.The last follow-up age was 5 years and 7 months(3 years and 1 month to 9 years).The onset age of seizures was 2 years(4 months to 3 years).Seizure types included eyelid myoclonia with or without absence(9 cases),myoclonic seizure(5 cases),atypical absence(4 cases),suspicious atonic seizures(4 cases),unclassified fall attack(6 cases),and the frequency of seizures varied from several times to more than 100 times per day.Four cases had the mimic phenotype of myoclonic astatic epilepsy.The seizures of 10 cases could be triggered by eating(5 cases),emotion(5 cases),fever(3 cases),voice(2 cases),fatigue(2 cases),etc.Electroencephalography(10 cases)showed interictal generalized or focal epileptiform discharges(9 cases),and atypical aphasia(4 cases),myoclonic seizure(2 cases)and eyelid myoclonic seizure(1 case)were monitored.Of the 12 cases,9 were added with valproate,all of which were effective(the frequency of seizures reduced>50%).Five cases received combined levetiracetam,in 3 the treatments were effective.To last follow-up,3 cases were seizure free from 6 months to 1 year and 1 month,but the remaining 7 cases still had seizures,one or several times per day.All 13 cases had developmental retardation(speech ability impaired mostly),2 cases were severe,10 cases were moderate,1 case was mild.The SYNGAP1 gene variants of 13 patients were all de novo,including 12 variants.Among them,4 were frameshift variants,4 were nonsense variants,2 were missense variants and 2 were splice site variants.Conclusions Patients with SYNGAP1-related epilepsy have an early onset age and many seizure types.The main seizure type is eyelid myoclonia with or without absence,and other seizure types include myoclonic seizure,atypical absence,unclassified fall attack,etc.Valproate is effective in most patients,but seizures in some patients might be intractable.Most patients have developmental delay(mainly moderate and severe),speech ability impaired mostly.