【作者】 孙宇；

【导师】 马爱华；

【作者基本信息】 山东大学 ， 儿科学（专业学位）， 2021， 硕士

【摘要】 背景:发育性癫痫性脑病(developmental and epileptic encephalopathy,DEE)是一组进行性精神运动功能障碍疾病,由脑发育障碍和癫痫共同致病。发育性癫痫性脑病具有病因复杂、药物控制不佳的特点,严重影响患儿,尤其是婴幼儿的发育,是儿童神经系统疾病中的难题。近年来,随着精准医学的研究逐渐兴起,基因检测在遗传性疾病的诊疗中发挥了重要作用。有将近三分之一的DEE患儿具有遗传性病因。目前已经明确了部分DEE致病基因,根据相关致病机制的治疗也有了一定的成效。基因检测为明确病因、指导治疗及预后提供了新的理论基础和诊疗手段。目前国内DEE的研究报道较少,相关临床及基因信息还有待完善。目的:回顾性分析267例发育性癫痫性脑病患儿的诊疗资料及90例患儿的基因信息,总结临床特点,对影响预后的因素进行分析,归纳发育性癫痫性脑病的基因表型谱。方法:收集自2015年6月1日至2020年5月31日于山东省立医院小儿神经科门诊及病房确诊的267例发育性癫痫性脑病儿童的临床资料,对部分患儿及其父母进行全外显子测序,回顾性分析患儿的临床特点及基因突变情况,随访患儿治疗及发育情况。结果:1.267例患儿中,男女比例为1.59:1。中位发病年龄为6.3月龄,194例(73%)的患儿在1岁以内发病。2.267例患儿中,癫痫综合征分型有West综合征82例(30.7%),Dravet综合征50例(18.7%),Lennox-Gastaut综合征15例(5.6%),大田原综合征14例(5.2%),早期肌阵挛脑病3例(1.1%),分型不明103例(38.6%)。3.267例患儿中,明确癫痫综合征的患儿临床及脑电图表现典型,分型不明的患儿癫痫发作及脑电图没有特征性表现。4.267例患儿中,49例(18.4%)患儿有异常出生史;38例(14.2%)患儿有癫痫或智力低下家族史;有17例(6.4%)患儿查体存在非神经系统的阳性体征;头颅MRI检查异常的患儿有118例(44.2%)。5.疗效显著组和疗效不佳组比较,两组在诊断时间分布(P<0.001)的差异有统计学意义,在发病年龄、发病到初次就诊时间、发病到诊断时间、出生史、家族史、查体、MRI结果(P>0.05)的差异没有统计学意义。6.267例患儿均使用至少2种抗癫痫药物治疗,使用药物数量中位数为3种(2,7),使用2种药物治疗的患儿最多,有122例(45.7%)。疗效显著组和疗效不佳组比较,药物使用数量(P=0.006)差异有统计学意义。在West综合征患儿中,不同疗效组是否使用ACTH(P<0.001)的差异有统计学意义。7.截至随访时间,267例患儿中,药物治疗癫痫完全控制105例(39.3%),显效 64 例(24.0%),有效 33 例(12.4%),无效 65 例(24.3%)。有 148 例(55.4%)患儿存在全面性发育落后,39例(14.6%)患儿有运动发育落后,18例(6.8%)患儿有语言发育落后,8例(3.0%)患儿有认知发育落后,54例(20.2%)患儿发育恢复正常。癫痫综合征分型不明的患儿和癫痫控制良好的患儿发育情况改善较好。8.90例患儿完善了全外显子测序。其中26例(26/90,28.9%)患儿有明确致病变异基因,39例(39/90,43.3%)患儿变异基因疑似致病,25例(25/90,27.8%)患儿基因变异临床意义未明。致病性及疑似致病性变异的基因包括SCN1A、KCNQ2、SCN2A、KCNT1、MECP2、STXBP1、PRRT2、SCN9A、RYR3、TSC1等45个。基因突变以离子通道基因为主。基因与表型具有异质性。结论:1.发育性癫痫性脑病患儿发病年龄早,常有多种发作形式,以全身性痉挛发作和全身性强直阵挛发作最常见。2.发育性癫痫性脑病患儿癫痫综合征分型以West综合征和Dravet综合征多见,分型不明的患儿在癫痫发作形式、临床特点、脑电图表现没有明显规律。3.发育性癫痫性脑病患儿癫痫完全控制率低。癫痫综合征分型不明的患儿和癫痫控制良好的患儿发育情况改善较好。4.发育性癫痫性脑病患儿突变基因以离子通道相关基因为主,SCN1A基因突变例数最多。各基因突变型与表型具有异质性。更多还原

【Abstract】 BackgroundDevelopmental and epileptic encephalopathy(DEE)is a group of progressive psychomotor dysfunction,caused by brain development and epilepsy.DEE is characterized by complicated etiology,poor drug control and has severe influences on on the development of young children,which is a challenge in children’s nervous system diseases.With the development of research in precision medicine,genetic testing has played an important role in the diagnosis and treatment of genetic diseases.There are nearly one third of DEE children have genetic causes.At present some pathogenic genes of DEE have been identified,and treatments according to relevant pathogenic mechanisms have also achieved certain results.Genetic testing provides a new theoretical basis and diagnostic means for the determination of etiology,guidance of treatment and prediction of prognosis.There are few studies on DEE in China,and the relevant clinical and genetic information needs to be improved.ObjectiveThe diagnosis and treatment data of 267 children with DEE were retrospectively analyzed to summarize the clinical features,analyze the prognostic factors,and summarize the genes and phenotypes of DEE.MethodsWe collected the clinical data of 267 children with DEE diagnosed in the Department of Pediatric Neurology of Shandong Provincial Hospital from June 2015 to May 2020.Whole exome sequencing was performed on some of the children and their parents.We retrospectively analyzed the clinical characteristics and gene mutations,followed up the treatment and development of the children.Results1.Among the 267 DEE children,the male to female ratio of 1.59:1.The median onset age was 6.3 month old,and the peak onset age was under 1 year of age(73%).2.Among the 267 DEE children,82(30.7%)were diagnosed with West syndrome,50(18.7%)were diagnosed with Dravet syndrome,15(5.6%)were diagnosed with Lennox-Gastaut syndrome,14(5.2%)were diagnosed with Ohtahara syndrome,3(1.1%)were diagnosed with early myoclonic encephalopathy and 103(38.6%)were diagnosed with unknown type of epileptic syndrome.3.Among the 267 children,the clinical and EEG manifestations of the children with epileptic syndrome were typical,while the children with unknown classification had no characteristic manifestations of epileptic seizure and EEG.4.Among the 267 DEE children,49(18.4%)had abnormal birth history;38(14.2%)had a family history of epilepsy or mental retardation;17(6.4%)had positive signs of non-nervous system on physical examination;118(44.2%)had abnormal MRI.5.Compared with the group with significant treatment effect and the group with poor treatment effect,there was statistically significant difference in the distribution of diagnosis time between the two groups(P<0.001),while there was no statistically significant difference in the age of onset,time from onset to first time seeing a doctor,time from onset to diagnosis,birth history,family history,physical examination and MRI results(P>0.05).6.All the 267 DEE children were treated with at least two drugs for epilepsy,with a median of three drugs(2,7).122(45.7%)children received two drugs for epilepsy,which were the main type.There was statistically significant difference in the amount of drugs used between the group with significant treatment effect and the group with poor treatment effect(P=0.006).In children with West syndrome,there was a statistically significant difference in whether ACTH was used in different treatment response groups(P<0.001).7.Up to the follow-up time,among the 267 children,105(39.3%)had complete control of epilepsy,64(24.0%)showed significant effect,33(12.4%)were effective,and 65(24.3%)were ineffective.There were 148(55.4%)children with global developmental delay,39(14.6%)children with motor developmental delay,18(6.8%)children with language developmental delay,8(3.0%)children with intellectual developmental delay,and 54(20.2%)children returned to normal.The development of children with unknown classification and children with well epilepsy control improved better.8.90 children completed the whole exome sequencing analysis.Among them,26(26/90,28.9%)cases were detected pathogenic genetic variation,39(39/90,43.3%)cases were detected likely pathogenic genetic variation,and 25(25/90,27.8%)cases were detected uncertain pathogenic genetic variation.There were 45 pathogenic and likely pathogenic mutated genes,including SCN1A,KCNQ2,SCN2A,KCNT1,MECP2,STXBP1,PRRT2,SCN9A,RYR3,TSC1,et al.The mutated gene was mainly related to channel genes.Genes and phenotypes were heterogeneous.Conclusions1.Children with DEE were early onset.They had a variety of seizure forms and systemic spasms and generalized tonic-clonic seizures were the most common forms.2.Among the DEE children,West syndrome and Dravet syndrome were the main types of epileptic syndrome.There was no obvious regularity in the form of seizures,clinical characteristics and EEG of the children with unknown type of epileptic syndrome.3.The rate of well-controlled epilepsy of DEE children was low.The development of children with unknown classification and children with well epilepsy control improved better.4.The mutated gene was mainly related to channel genes.Different gene mutations can cause same epilepsy syndrome.The SCN1A gene had the highest number of mutations.Genes and phenotypes were heterogeneous.更多还原