乙醛脱氢酶7家族成员A1基因突变致吡哆醇依赖性癫痫临床表型及遗传学分析  

Clinical phenotype and genetic analysis of pyridoxine dependent epilepsy induced by aldehyde dehydrogenase 7 family member A1 gene mutation

作　　者：梅道启 梅世月 郑璇 陈国洪 王媛[1] 毕文静 董世杰 胡香玉 杨秀安 王潇娜 张耀东 Mei Daoqi;Mei Shiyue;Zheng Xuan;Chen Guohong;Wang Yuan;Bi Wenjing;Dong Shijie;Hu Xiangyu;Yang Xiuan;Wang Xiaona;Zhang Yaodong(Department of Neurology,Children′s Hospital Affiliated to Zhengzhou University,Henan Children′s Hospital,Zhengzhou Children′s Hospital,Zhengzhou 450018,China;Henan Provincial Key Laboratory of Childrens Genetics and Metabolic Diseases,Henan Engineering Research Center of Childhood Neurodevelopment,Zhengzhou 450018,China;Department of Pediatrics,Pingdingshan Hospital of Traditional Chinese Medicine,Pingdingshan,Henan 467000,China;Department of Biochemistry,School of Basic Medical Science,Chengde Medical University,Chengde 067000,China)

机构地区：[1]郑州大学附属儿童医院(河南省儿童医院,郑州儿童医院)东区神经内科,450018 [2]河南省遗传代谢性疾病重点实验室,河南省儿童神经发育工程研究中心,郑州450018 [3]河南省平顶山市中医院儿科,467000 [4]承德医学院基础医学院生物化学教研室,067000

出　　处：《中华神经科杂志》2021年第3期228-235,共8页Chinese Journal of Neurology

基　　金：国家自然科学基金(81701125,81901387);河南省医学科技攻关项目(2018020633,2018020603,2018020616,LHGJ20200618);河南省高等学校重点科研项目计划(18A310029);河南省儿童神经发育工程研究中心开放课题(SG201907)。

摘　　要：目的探讨经二代测序确诊的5例吡哆醇依赖性癫痫(PDE)的临床表型、治疗及乙醛脱氢酶7家族成员A1(ALDH7A1)基因突变的遗传学特点。方法回顾性分析2018年2月至2019年11月郑州大学附属儿童医院神经内科确诊的5例以早期癫痫起病的吡哆醇依赖性癫痫患儿的临床资料,采用二代测序方法对先证者进行ALDH7A1基因测序,并对其家系成员进行一代Sanger验证,对其基因突变特点进行分析。结果在5例确诊为吡哆醇依赖性癫痫的患儿中,男女比例为4∶1,就诊年龄为出生2~10个月。临床表型中5例患儿均为新生儿期起病,有反复癫痫发作,表现为肌阵挛发作、痉挛发作或局灶性发作;应用抗癫痫药物控制发作较差,长期大剂量口服吡哆醇疗效较好;5例患儿均来自其父亲和(或)母亲的复合杂合突变;例1为剪切纯合突变c.247-2(IVS2)A>T,例2为错义突变c.584A>G(p.N195S)及无义突变c.1003C>T(p.R335*),例3为错义突变c.1553G>C(p.R518T)及c.1547A>G(p.Y516C),例4为错义突变c.1547A>G(p.Y516C)及移码突变c.1566_1568delTAC(p.522_523delCTinsC),例5为错义突变c.1061A>G(p.Y354C)及无义突变c.841C>T(p.Q281X,259)。其中c.247-2(IVS2)A>T为未报道过的新生剪切位点突变。结论吡哆醇依赖性癫痫由ALDH7A1基因突变引起,早期临床表现多以新生儿期难治性癫痫起病;抗癫痫药物治疗疗效差,经吡哆醇有效控制,对该类患者应尽早行基因分析以早期确诊。Objective To investigate the clinical phenotypes,therapy and genetic features of aldehyde dehydrogenase 7 family member A1(ALDH7A1)gene mutations in five cases of pyridoxine dependent epilepsy(PDE)with diagnosis confirmed by next generation sequencing.Methods Retrospective analysis was carried out on clinical data of five cases of PDE children with early epilepsy onset who were treated in the Department of Neurology of Children′s Hospital Affiliated to Zhengzhou University from February 2018 to November 2019.Next generation sequencing approach was used for genetic sequencing of proband ALDH7A1 gene and the first generation Sanger was used for validation of family members.And the characteristics of gene mutations were analyzed.Results Among the five children diagnosed with PDE,the male to female ratio was 4∶1 and ages at clinic visit ranged from two months to 10 months old.In clinical phenotypes,all five cases experienced onset in neonatal period,with repeated seizures,manifested as myoclonus,spasms or focal paroxysm.The administration of antiepileptic drugs performed poorly in seizure control while long term oral intake of large dose pyridoxine showed better efficacy.All the five cases of children came from compound heterozygous mutations of father and mother,i.e.slicing homozygous mutation c.247-2(IVS2)A>T,missense mutation c.584A>G(p.N195S)and nonsense mutation c.1003C>T(p.R335*),missense mutation c.1553G>C(p.R518T)and c.1547A>G(p.Y516C),missense mutation c.1547A>G(p.Y516C)and frameshift mutation c.1566_1568delTAC,missense mutation c.1061A>G(p.Y354C)and nonsense mutation c.841C>T(p.Q281X,259),among which c.247-2(IVS2)A>T was novel splicing site mutation not reported before.Conclusions PDE is induced by ALDH7A gene mutation.Early clinical manifestations are mostly onset of refractory epilepsy in neonatal period.Antiepileptic drugs perform poorly in terms of efficacy while pyridoxine can control seizure effectively.Gene analysis should be conducted on such patients for confirmed diagnosis.

关 键 词：癫痫 维生素B6 婴儿 ALDH7A1基因 

分 类 号：R742.1[医药卫生—神经病学与精神病学]