线粒体精氨酰tRNA合成酶基因缺陷致早发癫痫脑病二例并文献复习

Early onset epileptic encephalopathy caused by mitochondrial arginyl-tRNA synthetase gene deficiency:report of two cases and literature review

目的总结2例线粒体精氨酰tRNA合成酶(RARS2)基因变异致早发癫痫脑病患儿的临床特征并进行文献复习。方法回顾性分析2017年1月至2018年12月首次就诊于首都医科大学附属北京儿童医院神经内科的2例RARS2基因变异致脑桥小脑发育不良6型(PCH6)患儿的临床特征和基因变异位点。以“RARS2”“pontocerebellar hypoplasia type 6”“early onset epileptic encephalopathy”为检索词,检索中国知网、万方数据库及PubMed数据库(建库至2020年5月),选取有RARS2基因变异且临床资料完整的文献进行复习总结该病临床特征。结果2例(例1男、例2女)患儿分别在2月龄和29日龄以早发癫痫脑病起病,临床表现为癫痫、发育落后、小头畸形和血乳酸升高。例2还伴有生后呼吸困难、低血糖、代谢性酸中毒。2例患儿起病时头颅磁共振成像均正常,分别在4月龄(例1)和8月龄(例2)复查提示大、小脑萎缩,无脑桥萎缩改变。全外显子测序发现例1(p.Arg560His,p.Arg6His)和例2(p.Arg254Trp,p.Phe5Ser)在RARS2基因杂合变异,均为未报道的新变异。检索符合条件的英文文献17篇,无中文文献。排除资料不全病例,共有20个家系34例PCH6(包括本组2例)。所有患儿均有不同程度的发育落后,94%(32/34)在3月龄内起病,93%(28/30)伴发癫痫,89%(25/28)有渐进性小头畸形。药物难治性癫痫占71%(20/28)。共发现31个变异位点,以错义变异为主(68%,21/31)。结论RARS2基因变异致PCH6多于3月龄内发病,以早发癫痫脑病为特征,多数为药物难治性癫痫,伴发育落后、小头畸形和乳酸升高,头颅磁共振成像提示大脑或脑桥小脑渐进性萎缩。

Objective To summarize the clinical features of two early onset epileptic encephalopathy(EOEE)patients with arginyl-tRNA synthetase(RARS2)gene variations and to review related literature.Methods The clinical data and genetic features of two pontocerebellar hypoplasia type 6(PCH6)patients with RARS2 variation diagnosed by the Department of Neurology,Beijing Children's Hospital from January 2017 to December 2018 were analyzed retrospectively.A literature search with"RARS2""pontocerebellar hypoplasia type 6"and"early onset epileptic encephalopathy"as key words was conducted at China national knowledge infrastructure(CNKI),Wanfang Data Knowledge Service Platform and PubMed(up to May 2020),literature about RARS2 gene variation patients and their complete clinical data were chosen and reviewed.Results The onset age of the two cases(1 male,1 female)were 2 months and 29 days respectively and the early onset symptom of them was epileptic encephalopathy.The main symptoms included seizures,development delay,microcephaly and lactic acidosis.In addition to these symptoms,the female also had dyspnea,hypoglycemia and metabolic acidosis after birth.Brain magnetic resonance imaging(MRI)of the two patients were normal at first.Follow up at four-month(case 1)and eight-month(case 2)MRI showed atrophy of cerebral and cerebellar,but the pons was not affected.All four heterozygous variations in RARS2 gene revealed by whole-exome sequencing(p.Arg560His and p.Arg6His from case 1,p.Arg254Trp and p.Phe5Ser from case 2)were novel.No eligible reports were found in Chinese journals,while 17 reports were found in English literature.Excluded cases with incomplete data together with these two cases,a total of 34 patients from 20 families were found.All patients had developmental delay while 94%(32/34)patients showed the initial symptoms within 3 months,93%(28/30)patients were diagnosed as epilepsy,89%(25/28)patients had progressively microcephaly and 52%(16/31)cases did not show the pons atrophy on brain MRI.Twenty of 28 cases(71%)were refractory epilepsy.There were 31 types of gene variations and most of them were missense variations(21/31,68%).Conclusions The majority of PCH6 cases caused by RARS2 gene variation show the initial symptoms within 3 months,characterized by EOEE,most of them are refractory epilepsy,accompanied by developmental delay,microcephaly and increased lactic acid.Brain MRI indicates progressive cerebral or pontocerebellar atrophy.