Objective: To investigate the clinical characteristics, treatment and prognosis of QARS1 gene related glutaminyl-tRNA synthetase deficiency. Methods: To summarize and analyze the clinical manifestations, imaging, laboratory examination, genetic variant characteristics and treatment of three patients from the Fujian Medical University Affiliated Union Hospital, the 900th Hospital of People's Liberation Army, the First Medical Center of People's Liberation Army General Hsopital carrying compound heterozygous variations in QARS1 gene with a long-term follow-up in China. A literature search was conducted using Wanfang, Weipu, China National Knowledge Infrastructure (CNKI) and Pubmed databases with the keywords "QARS", "QARS1" and "glutaminyl-tRNA Synthetase"(up to December 2019). Results: Case 1, a female 53 days of age, was admitted to the Fujian Medical University Affiliated Union Hospital for treatment because of the complaint of repetitive seizures for one month after birth and fever for one day. The seizure occurred within the first 2 hours of life with multiple forms and often had a status as persisted from hours to days. The seizures were resistant to many anti-epilepsy drugs (AED) and ketogenic diet but later controlled by clonazepam. However, she died at the age of seven years. Case 2 (younger brother of case 1), a one-hour-old boy, was hospitalized because of seizures after birth for 1 hour. Intrauterine growth retardation was discovered during late-pregnancy. The boy presented seizures and microcephaly immediately after birth, and his epilepsy was pharmacoresisitant. Case 3, an 8-month-old girl, was admitted due to recurrent convulsions for nearly two months. The girl had mild developmental retardation and hypotonia after birth. The infantile spasm was observed at her age of 6 months and disappeared under treatment with Vitamin B6, vigabatrin combined with adreno-cortico-tropic-hormone and magnesium sulfate. However, the seizure pattern turned to tonic seizures later. She was seizures free now with clobazam and zonisamide treatment. All of them manifested as a syndrome composed of severe global developmental retardation, progressive microcephaly, hypotonia from the very beginning, mild hypoproteinemia and diffuse brain atrophy. Genetic studies revealed compound heterozygous variations of QARS1 gene which were not reported previously. A review of the literature reported a total of 22 patients from 18 unrelated families all over the world. Except for 5 cases without epilepsy,all the patients shared very similar clinical manifestations as classic pentalogy. The recommended effective treatment for epilepsy has not been reported yet. Conclusions: Glutaminyl-tRNA synthetase deficiency caused by QARS1 gene variations manifested as a clinical syndrome's pentalogy, characterized by microcephaly, cerebral atrophy, intractable early-onset epileptic encephalopathy, global developmental retardation and severe muscle hypotonia.
目的： 探讨QRAS1基因异常导致谷氨酰胺tRNA合成酶缺陷综合征的特征、治疗及预后。 方法： 总结并分析福建医科大学附属协和医院、解放军联勤保障部队第九〇〇医院、解放军总医院第一临床医学中心3例长期随访QARS1基因复合杂合变异患儿的临床表现、影像学及实验室检查、基因变异特点及治疗情况。分别以“QARS”“QARS1”“谷氨酰胺tRNA合成酶”“Glutaminyl-tRNA synthetase”为检索词，在万方、维普、中国知网、PubMed数据库中检索建库至2019年12月已报道QRAS1基因变异家系病例并进行文献复习。 结果： 例1 女，53日龄，主因“生后反复抽搐1个月余，发热1 d”收入福建协和医院治疗，生后2 h内出现抽搐，形式多样，可持续达数小时至数天；癫痫早期多药难治，生酮饮食无效，后期氯硝西泮可显著缓解；7岁余死亡。例2（例1胞弟） 男，1小时龄，主因“生后抽搐1 h”入院，其母孕晚期发现宫内发育迟缓，患儿生后即抽搐并存在小头畸形，癫痫多药难治。例3 女，8月龄，主因“反复抽搐近2个月”就诊，生后表现为发育稍落后、肌张力低，6月龄时出现婴儿痉挛，维生素B6联合氨己烯酸、促肾上腺皮质激素、硫酸镁治疗后痉挛发作消失，但出现强直发作，现氯巴占、唑尼沙胺治疗，发作控制。3例患儿均存在严重全面发育落后、进行性加重的小头畸形、初始肌张力低下、轻度低蛋白血症、广泛性脑萎缩；均为QARS1基因复合杂合变异，变异位点均未见报道。文献检索未见国内报道，国外文献10篇，涉及18个家系22例病例，除5例无癫痫发作外，余临床均表现为经典五联征，文献无推荐有效抗癫痫治疗药物。 结论： QARS1基因异常导致谷氨酰胺tRNA合成酶缺陷可引起一组以小头畸形、脑萎缩、早发性难治性癫痫性脑病、全面性发育落后、严重肌张力低下的五联征临床症候群。.
Keywords: Aminoacyl-tRNA synthetase; Epilepsy; Glutaminyl-tRNA synthetase deficiency; Microcephaly.