新生儿枫糖尿症一例的临床特征及基因突变分析

Clinical characteristics and genetic analysis of a Chinese neonate with Maple syrup urine disease

目的对一例枫糖尿症(maple syrupurine disease,MSUD)患儿进行临床特征的描述及相关致病基因的突变分析,从遗传学角度明确其发病原因。方法患儿女,生后9天因喉中痰响伴喂养困难入院,收集患儿的临床资料及影像学检查等,提取患儿及其父母的外周血基因组DNA,首先对患儿进行枫糖尿症相关致病基因BCKDHA,BCKDHB,DBT和DLD基因的外显子及其侧翼区进行一代测序,分析其可疑致病位点后对其父母进行遗传共分离验证。结果患儿表现为生后喂养困难,精神欠佳,肌张力减低,代谢性酸中毒,尿液有枫糖味等,头颅核磁示双侧大脑脚、脑干及双侧小脑半球多发异常信号,血串联质谱及尿气相色谱-质谱结果均符合枫糖尿症的诊断。基因测序结果显示患儿在BCKDHB基因上携带父源性c.550delT(p.Ser184fs)突变和母源性c.956957delTG(p.Val319fs)突变,形成复合杂合突变。这两个位点均为国际上未报道过的新突变。且ACMG标准评级均为致病性突变。结论 BCKDHB基因的c.550delT(p.Ser184fs)和c.956957delTG(p.Val319fs)复合杂合突变是该患儿的致病原因,该研究进一步扩展了BCKDHB基因的突变谱,且可为该家庭的优生优育提供一定的理论依据。

Objective:In order to identify the cause of the disease from genetics,we analysed the Clinical characteristics and mutation in associated genes of a neonate with congenital hypothyroidism. Methods:The clinical,imaging and biochemical data of a Chinese neonate hospitalized with feeding difficulties were analysed,the DNA sequences of BCKDHA,BCKDHB,DBT and DLD genes were investigated for mutation. Then the suspicious mutation was tested in the patient′s parents with Sanger sequencing. Result:The manifestations of the patient were poor feeding,low reaction,hypomyotonia,and compensatory metabolic acidosis,abnormal smells of urine. Brain MRI showed abnormal signals in bilateral cerebellum,brain stem and bilateral cerebellum. Tandem mass chromatography(MS/MS)urine gas chromatography mass spectrometry(GC/MS)showed significant abnormality. Genetic testing identified two mutations c.550 delT(p.Ser184 fs)and c.956957 delTG(p.Val319 fs)in BCKDHB gene inherited from father and mother respectively. Both of these two mutations were previously unreported and be defined as pathogenic variants according to the ACMG guideline. Conclusion:These two novel mutations,c.550 delT(p.Ser184 fs)and c.956957 delTG(p.Val319 fs)result in the patient's clinical manifestation of the classic form of MSUD,and our data expanded the mutation spectrum of the BCKDHB gene, meanwhile facilitating the future genetic counselling and prenatal diagnosis.