徐州地区新生儿希特林蛋白缺乏症筛查和基因突变分析

Screening strategy and genetic mutation analysis of citrin deficiency among newborns in Xuzhou

目的通过筛查了解徐州地区新生儿希特林蛋白缺乏所致新生儿肝内胆汁淤积症(neonatal intrahepatic cholestasis caused by cirtin deficiency,NICCD)的发病情况、临床特征和基因突变特点。方法对2015年9月至2020年9月徐州地区采用串联质谱技术进行遗传代谢病筛查的新生儿进行前瞻性研究,筛查疑似的患儿进一步通过尿有机酸及SLC25A13基因突变分析确诊,对确诊病例的临床表现、生化指标改变、基因突变特点、治疗及预后进行分析。结果共筛查活产新生儿468494名,疑似患儿112例,进行尿有机酸分析95例,SLC25A13基因突变分析95例,共确诊NICCD患儿13例,患病率1∶36038。多数患儿早期表现为黄疸消退延迟、喂养困难及体重不增等。生化指标改变包括胆汁酸升高、肝功能异常、甲胎蛋白异常升高、低血糖、血红蛋白降低、凝血功能异常及血氨增高等。血氨基酸及酰基肉碱谱检测提示瓜氨酸、蛋氨酸、精氨酸、酪氨酸、苯丙氨酸等特异性升高,部分伴酰基肉碱轻度升高;尿有机酸分析主要表现为4-羟基苯乳酸和4-羟基苯丙酮酸升高。13例患儿均进行基因检测,共检出13种突变类型,分别为c.852;55delTATG、c.511dupG、c.1638;660dup、IVS16ins3kb、c.1078C>T、c.615+5G>A、c.742G>A、c.44G>A、c.1311+1G>A、c.1399C>T、c.889G>T、c.1177+1G>A、c.1841+3;841+4del,其中c.852;55delTATG最常见,5种为新发变异,新发变异中c.1841+3;841+4del、c.511dupG和c.889G>T预测为有害变异。确诊病例予以饮食管理和对症治疗,均于1岁内症状缓解,生化指标明显改善。结论徐州地区NICCD患病率为1∶36038,c.852;55delTATG变异出现频率最高。共检测出5个新发变异位点,扩展了SLC25A13基因变异谱。NICCD患儿多数预后良好,需早期诊断和治疗,终身随访。

Objective To study the incidence,clinical features and genetic mutation profiles of neonatal intrahepatic cholestasis caused by citrin deficiency(NICCD)using screening strategy.Methods From September 2015 to September 2020,neonates in Xuzhou area were prospectively screened for genetic metabolic diseases using tandem mass spectrometry.Suspected infants were further confirmed using urinary organic acid test and SLC25A13 gene mutation analysis.The clinical manifestations,biochemical and gene mutation results,treatment and prognosis of the confirmed cases were analyzed.Results A total of 468,494 live-birth newborns were screened with 112 cases suspected and 95 cases received urinary organic acid test and SLC25A13 gene mutation analysis.13 cases of NICCD were diagnosed with a prevalence of 1/36,038.Most confirmed cases presented with delayed disappearance of neonatal jaundice,feeding difficulties and poor weight gain.Biochemical changes included increased bile acid,abnormal liver enzymes,increased alpha-fetoprotein,hypoglycemia,decreased hemoglobin,abnormal coagulation function and increased blood ammonia.Tandem mass spectrometry showed increased citrulline,methionine,arginine,tyrosine and phenylalanine,and in some cases with slightly increased acylcarnitine.Urine organic acid analysis mainly showed increased 4-hydroxyphenyllactic acid and 4-hydroxyphenylpyruvate.All confirmed cases received genetic mutation tests and a total of 13 mutation loci were detected,including c.852_855delTATG,c.511dupG,c.1638_1660dup,IVS16ins3kb,c.1078C>T,c.615+5G>A,c.742G>A,c.44G>A,c.1311+1G>A,c.1399C>T,c.889G>T,c.1177+1G>A,c.1841+3_1841+4del,among which,c.852_855delTATG was the most common one.A total of 5 novel mutation loci were discovered in this study with c.1841+3_1841+4del,c.511dupG and c.889G>T predicted as pathogenic variants.Special formula of lactose-free and fortified medium-chain triglyceride(MCT)were used in confirmed cases and most of the symptoms were relieved within 1 year and abnormal indicators significantly improved.Conclusions The prevalence of NICCD in Xuzhou was 1/36,038.c.852_855delTATG mutation is the most frequent one.Five novel mutation loci are discovered,expanding the SLC25A13 gene mutation spectrum.Most infants with NICCD have a good prognosis,requiring early diagnosis,treatment and life-long follow-up.