Objective To explore the correlation between ATP1A3 genotype and phenotype in children with alternating hemiplegia of childhood (AHC).Methods This was a retrospective study.The clinical data and peripheral blood DNA of AHC patients were collected in Peking University First Hospital from August 2005 to December 2017.ATP1A3 gene mutations were screened by Sanger sequencing or next generation sequencing (NGS).AHC patients were divided into difference groups according to different hotspot mutations.SPSS 23.0 was used to analyze the correlation between genotype and phenotype.Variance analysis was used to compare the measurement data between groups.Chi square test was used to compare the categorical data between groups.Kruskal-Wallis test was used to compare the unidirectional ordered data between groups.Least-significant difference(LSD) was used to compare the data between two groups.Results A total of 119 AHC patients were recruited,including 68 males and 51 females.The onset age of 113 (95.0％) patients was within 18 months.There were 119 cases (100.0％) with hemiplegic seizures,109 cases (91.6％) with abnormal eyeball movements,104 cases (87.4％) with dystonia,31 cases (26.1％) with autonomic neurological symptoms,31 cases (26.1％) with epileptic seizures and 117 cases (98.3％) with long-term developmental delay.In 113 patients (95.0％) with ATP1A3 gene mutations,111 were de novo mutation and 2 were genetic mutations.A total of 39 mutation types were found,including 37 missense mutations and 2 deletion mutations.Seventeen of them were novel mutations.The three hotspot mutations were D801N (n=34,30.1％),E815K (n=20,17.7％) and G947R (n=13,11.5％).The age of onset of D801N and E815K were earlier than G947R ((3.1±2.1)and (2.3±2.3)vs.(6.4t7.7) months,P=0.004 and 0.003).The age of first hemiplegic events of D801N and E815K were earlier than G947R((6.4±3.1) and (6.8±3.3) vs.(11.4± 10.1) months,P=0.004 and 0.016).More patients with E815K mutations presented epilepsy than those with D801N (P=0.003) and G947R (P=0.001).More patients with E815K mutations presented greater motor and intellectual disability than the patients with D801N (P=0.001) and G947R mutations (P=0.001).Conclusions ATP1A3 gene is the main causative gene of AHC.Three hotspot mutations,D801N,E815K and G947R,were found.Hotspot mutation E815K is associated with the most severe phenotype,which presented an earlier age at the time of the first paroxysmal manifestation and first hemiplegic event,severer developmental delay and a greater proportion of epilepsy.%目的 探讨儿童交替性偏瘫(AHC)患儿的ATP1A3基因型与表型的相关性.方法 本研究为回顾性病例研究.收集2005年8月至2017年12月在北京大学第一医院儿科神经专业门诊及病房住院的AHC患儿病例资料,采集患儿及其家系成员外周血DNA,采用Sanger测序的方法或靶向捕获二代测序技术癫痫基因检测包检测筛查ATP1A3基因突变.根据携带ATP1A3基因突变类型的不同进行分组.分析基因型与表型之间的相关性.组间比较采用方差分析、x2检验、Kruskal-Wallis检验或LSD法.结果 共收集AHC患儿119例,其中男68例、女51例.发病年龄≤18月龄者113例(95.0％),＞18月龄6例.有偏瘫发作者119例(100.0％),眼球运动异常者109例(91.6％),肌张力不全者104例(87.4％),自主神经症状者31例(26.1％),癫痫发作31例(26.1％).117例(98.3％)患儿存在不同程度的智力、运动发育落后.119例AHC患儿中,ATP1A3基因突变筛查阳性者113例(95.0％),其中111例为新生突变,2例为遗传突变.共发现39种突变类型,其中错义突变37种,缺失突变2种,17种为国际未报道的新突变.3种热点突变:D801N突变共34例(30.1％)、E815K突变20例(17.7％)和G947R突变13例(11.5％).AHC患儿起病年龄D801N组与E815K组均早于G947R组[(3.1±2.1)、(2.3±2.3)比(6.4±7.7)月龄,P=0.004、0.003].首次偏瘫发作年龄D801N组与E815K组也均早于G947R组[(6.4±3.1)与(6.8±3.3)比(11.4±10.1)月龄,P=0.004、0.016].合并癫痫比例及智力、运动落后严重程度,E815K组患儿均高于D801N组(P=0.003及0.001)和G947R组(P=0.001及0.001).结论 ATP1A3基因突变也是中国AHC患儿的主要致病基因,3种热点突变(D801N、E815K和G947R)与国际报道一致;热点突变E815K具有更严重的临床表型,表现为起病年龄及偏瘫出现年龄早,易合并癫痫发作,智力、运动发育落后更严重.
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