一例非典型乙基丙二酸脑病患儿的临床及遗传学分析

Clinical and genetic analysis of a case with atypical ethyl malonate encephalopathy

目的对1例运动发育迟缓、语言发育迟缓并倒退且伴有轻型迁延型腹泻的3岁4月患儿进行临床和遗传学分析，明确病因。方法通过对患儿的临床检查，采集该患儿及其家系成员的病史，并应用实验室检查、遗传代谢病筛查和新一代测序技术，对该家系进行临床和遗传学分析。结果患儿临床表现为不能独站及独走、语言发育落后并倒退，伴有轻型迁延型腹泻。实验室检查血乳酸、血糖等正常，尿液中乙基丙二酸增高，血尿筛查提示为“短链酰基辅酶A脱氢酶缺乏症可能”。头颅磁共振提示双侧基底节病变、双侧侧脑室髓鞘化不良及胼胝体发育不良，2岁8月、3岁4月复查头颅磁共振病变均有好转。尿有机酸乙基丙二酸升高，血液丁酰基肉碱增高，血尿遗传代谢病筛查怀疑短链酰基辅酶A脱氢酶缺乏症。新一代测序发现ETHE1基因存在c．2T〉A和c．488G〉A复合杂合突变，分别遗传自父亲和母亲，生物信息学预测为致病性。诊断为乙基丙二酸脑病。结论该患儿为ETHE1基因突变引起的乙基丙二酸脑病。ETHE1基因c．2T〉A（p．M1K）突变尚未见报道。新一代测序技术为分析该类疾病提供了强有力的诊断工具。

Objective To delineate the clinical and genetic characteristics of a girl featuring motor retardation, language retardation and regression, and light persisting diarrhea. Methods The patient was clinically examined and tested by tandem mass spectrometry and next generation sequencing. Results The proband could not stand and walk alone, and had light persisting diarrhea. She manifested language development retardation and regression. Laboratory tests were all normal, but the screening of metabolic disorders for urine and blood showed deficiency of short chain coenzyme A dehydrogenase due to elevated ethylmalonic acid and butyryl carnitine. By next generation sequencing, two compound heterozygous mutations of the ETHEl gene, c. 2T〉A and c. 488G〉A, were discovered in the proband, which were respectively inherited from her father and mother. Bioinformatics analysis predicted both mutations to be pathogenic. The patient was diagnosed with ethylmalonic encephalopathy. Vitamin B1 , B2 , Coenzyme Q10, and L-carnitine were prescribed. The patient deteriorated and required liver transplantation at 4-year-l- month. Conclusion Based on the clinical and genetic analysis, the proband was diagnosed with ethylmalonic encephalopathy caused by ETHEl gene mutation. Next generation sequencing has provided a powerful tool for the diagnosis of such disorders.