儿童线粒体疾病相关癫痫62例的临床和遗传特征

Clinical and genetic characteristics of 62 children with mitochondrial epilepsy

目的总结儿童线粒体疾病相关癫痫的临床特点和遗传特征。方法对2011年10月至2018年12月在北京儿童医院神经内科就诊,基因确诊的62例线粒体疾病相关癫痫患儿的临床资料进行回顾性总结,对癫痫控制情况进行随访,按治疗结果分为有效组和无效组,应用t检验或χ2检验进行组间比较。结果62例中男33例、女29例,发病年龄为3.38(0~12.00)岁;癫痫发作类型以局灶性运动发作最多(68%,42例),其余依次为全面性或继发性全面性强直阵挛发作(32%,20例),肌阵挛发作(23%,14例),痉挛发作(7例),强直发作(4例),失神、失张力、阵挛发作各1例;癫痫持续状态16例(26%),其中持续性部分性癫痫6例;52%(32例)的患儿有2种或2种以上发作类型。线粒体脑肌病伴高乳酸血症和卒中样发作(MELAS)29例,Leigh综合征(LS)11例,联合氧化磷酸化缺乏症6例,肌阵挛癫痫伴破碎红纤维5例,Alpers综合征4例,脑桥小脑发育不良6型、线粒体缺失综合征9型各2例,ACAD9基因缺陷致线粒体复合物Ⅰ缺乏症、进行性空泡脑白质病、生物素酶缺乏症各1例。线粒体DNA(mtDNA)变异40例(65%),其中26例为m.3243A>G变异,6例为m.8344A>G变异,3例为m.8993T>G/C变异,m.3271T>C、m.3481G>A、m.3946G>A、m.13094T>C、m.14487T>C变异各1例;核DNA(nDNA)变异22例(35%),其中编码线粒体氨酰tRNA合成酶的基因7例,POLG基因和编码复合物Ⅰ的基因各4例,SUCLG1、SDHA基因各2例,PDHA1、BTD、TRIT1基因各1例。随访43例,随访时间为20(3~84)个月,其中癫痫治疗有效组19例(44%),无效组24例(56%)。癫痫治疗有效组与无效组起病年龄、发作时病程差异无统计学意义[3.42(0~11.50)岁比0.92(0~9.50)岁,0(0~7.00)年比0(0~4.83)年,t=1.662、0.860,P=0.104、0.395]。有效组与无效组使用抗癫痫药数量<2种的例数分别为12例和9例,≥2种分别为7例和15例、癫痫首发例数分别为13例和15例、非首发分别为6例和9例、mtDNA变异例数分别为14例和11例,nDNA变异例数分别为5例和13例,差异均无统计学意义(χ2=2.794、0.164、3.380,P=0.095、0.686、0.066)。结论儿童线粒体疾病相关癫痫发作类型多样,以局灶性运动发作最常见,其次为全面性或继发性全面性强直阵挛发作,多数患儿存在2种以上发作类型。MELAS是最常见的临床表型,其次为LS;基因变异以mtDNA变异为主,其中m.3243A>G变异是最常见的热点变异,其次为编码线粒体氨酰tRNA合成酶的基因变异。

Objective To summarize the clinical and genetic characteristics of children with mitochondrial epilepsy.Methods Clinical data of 62 children who were clinically and genetically diagnosed with mitochondrial epilepsy by the Department of Neurology,Beijing Children′s Hospital from October 2011 to December 2018 were analyzed retrospectively,and the control of epilepsy was followed up.T test orχ2 test were used to analyze the related factors affecting the prognosis of epilepsy between the effective group and the ineffective group.Results Of the 62 patients,33 were male and 29 were female.The age of onset was 3.38(0-12.00)years;for the type of seizures,68%(42/62)of the patients had focal seizures,generalized or secondary generalized tonic-clonic seizures were seen in 32%(20/62),myoclonic seizures in 23%(14/62),spastic seizures in 7 cases,tonic seizures in 4 cases,absence seizure,atonic seizure and clonic seizure in 1 case each;16 cases(26%)had status epilepticus,of whom 6 cases had epilepsia partialis continua;52%(32/62)had 2 or more types of seizures.The clinical phenotypes were mitochondrial encephalopathy,lactic acidosis,and stroke-like episodes(MELAS)in 29 cases,Leigh syndrome(LS)in 11 cases,combined oxidative phosphorylation deficiency in 6 cases,myoclonus epilepsy with ragged-red fibers in 5 cases,Alpers syndrome in 4 cases,pontocerebellar hypoplasia type 6 and mitochondrial DNA depletion syndrome 9 in 2 cases each,mitochondrial complexⅠdeficiency nuclear type 20,progressive cavitating leukoencephalopathy,and biotinidase deficiency in 1 case each.Of the 62 cases,40 cases(65%)had mitochondrial DNA(mtDNA)variations,of which 26 cases had m.3243A>G variants,6 cases had m.8344A>G variants,and 3 cases had m.8993T>G/C variants,m.3271T>C,m.3481G>A,m.3946G>A,m.13094T>C,m.14487T>C variant was in 1 case each;nuclear DNA(nDNA)variations were identified in 22 cases(35%),of which 7 cases carrying variations in mitochondrial ammonia acyl tRNA synthetase coding gene,mutations in POLG and the gene encoding complexⅠwere in 4 cases each,variations in SUCLG1 and SDHA genes were in 2 cases each,and variations in PDHA1,BTD and TRIT1 genes were in 1 case each.Forty-three patients were followed up,and the follow-up time was 20(3-84)months.According to the follow-up results,the anti-epilepsy treatment was effective in 19 cases(44%)and ineffective in other 24 cases(56%).The onset age of the effective group was 3.42(0-11.50)years and that of the ineffective group was 0.92(0-9.50)years.The onset duration of the effective group was 0(0-7.00)years and that of the ineffective group was 0(0-4.83)years.There was no significant difference between the effective group and the ineffective group(t=1.662,0.860;P=0.104,0.395).In the effective group and the ineffective group,12 cases and 9 cases used less than 2 kinds of antiepileptic drugs,7 cases and 15 cases used more than or equal to 2 kinds of antiepileptic drugs,13 and 15 cases had first epilepsy,6 and 9 cases had non-first epilepsy,14 and 11 cases had mtDNA variation,5 and 13 cases had nDNA variation,respectively.There was no significant difference between the two groups(χ2=2.794,0.164,3.380;P=0.095,0.686,0.066).Conclusions The types of seizures with mitochondrial epilepsy in children varied,with focal motor seizures being the most common,followed by generalized or secondary generalized tonic-clonic seizures.Most children have more than two types of seizures.MELAS is the most common clinical phenotype,followed by LS;mtDNA variation is the dominant gene variation,of which m.3243A>G variation is the most common hotspot variation,followed by gene variation encoding mitochondrial aminoacyl tRNA synthase.