摘要
目的探讨3-甲基戊烯二酸尿症临床特征、基因变异特点及预后。方法回顾性分析2017年2月至2019年2月上海交通大学医学院附属新华医院小儿内分泌遗传科诊治的6例3-甲基戊烯二酸尿症患儿的临床表现、生化资料、基因测序结果及治疗情况,并对患儿进行发育评估。结果6例患儿中男2例、女4例。4例为3-甲基戊烯二酸尿症Ⅰ型,2例为3-甲基戊烯二酸尿症Ⅵ型伴感音性神经耳聋、脑病及Leigh样综合征。5例患儿通过新生儿筛查确诊,1例为发病后临床诊断。4例患儿尚未发病,2例已发病患儿发病年龄分别为1和2日龄,均在新生儿期出现黄疸及呼吸异常等症状。6例患儿尿3-甲基戊烯二酸浓度为22.38~77.09 mmol/molCr,均高于正常切值。检测到2种基因11种变异,其中10种变异未被报道。4例患儿检测到7种AHU基因变异,分别为c.656-2delA、EX5-EX6 Del、c.942+3A>G、c.373C>T p.(R125W)、c.895-3C>G、c.667C>T p.(R223X)和c.894+5G>A,均未报道;2例患儿检测到4种SERAC1基因变异,包括c.548G>A p.(R138Q)、c.442C>T p.(R148X)、c.1339C>T p.(R447X)和c.973dupA p.(M325Nfs*5),仅c.442C>T p.(R148X)为已报道变异。经限制亮氨酸饮食及左卡尼汀治疗后,4例AUH基因变异患儿效果较好,2例SERAC1基因变异患儿治疗效果较差。2例已发病患儿运动发育落后和(或)智力落后,其余患儿发育正常。结论3-甲基戊烯二酸尿症患儿临床异质性明显、病情轻重不一,基因变异多为剪接变异,其次为无义变异、错义变异及移码变异,无亮氨酸饮食及口服左卡尼汀治疗对部分患儿有效,新生儿筛查有助于此病早期诊断、治疗及预后。
Objective To explore the clinical characteristics,genotypes and long-term outcomes of individuals with 3-methylglutaconic aciduria.Methods The clinical features,biochemical data,genetic test results and treatment outcomes of six children with 3-methylglutaconic aciduria admitted to the Department of Endocrinology,Genetics and Metabolism,Xinhua Hospital from February 2017 to February 2019 were retrospectively analyzed and the Gesell developmental diagnosis schedule was performed to evaluate the development of four patients.Results Among 6 children with 3-methylglutaconic aciduria 2 were males and 4 were females.Four cases had 3-methylglutaconic aciduria typeⅠand 2 cases had 3-methylglutaconic aciduria with deafness,encephalopathy,and Leigh-like syndrome.Five of 6 patients were detected by newborn screening among whom 4 remained asymptomatic,and only one had a postmortem diagnosis.Among them,4 patients remained asymptomatic,while two presented with clinical symptoms such as jaundice and dyspnea and the age of disease onset was 1 and 2 days respectively.The concentration of 3-methylglutaconic acid in urine of all affected individuals was between 22.38 and 77.09 mmol/molCr,which was above the normal value.Genetic tests were performed for all patients.Eleven variants were identified in 2 genes,of which 10 variants were novel and only c.442C>T p.(R148X)has been previously reported;Seven variants c.656-2delA,EX5-EX6 Del,c.942+3A>G,c.373C>T p.(R125W),c.895-3C>G,c.667C>T p.(R223X)and c.894+5G>A were in AUH gene.The others c.548G>A p.(R138Q),c.442C>T p.(R148X),c.1339C>T p.(R447X)and c.973dupA p.(M325Nfs*5)were in SERAC1 gene.After being treated with leucine diet restriction and L-carnitine,4 patients with AUH gene variation who were from asymptomatic phase developed normally,whereas those 2 patients with SERAC1 gene variation had a poor prognosis.During the follow-up,2 patients exhibited varying degrees of psychomotor retardation,the rest had normal course of development.Conclusions There are significant clinical heterogeneities among individuals with 3-methylglutaconic aciduria.The most common pathogenic variants are splicing variations,followed by nonsense,missense and frameshift mutations.Leucine-free diet and oral L-carnitine therapy are effective for some patients.Newborn screening is essential for early diagnosis and improvement of prognosis.
作者
凌诗颖
于玥
邱文娟
叶军
季文君
占霞
龚珠文
顾学范
韩连书
Ling Shiying;Yu Yue;Qiu Wenjuan;Ye Jun;Ji Wenjun;Zhan Xia;Gong Zhuwen;Gu Xuefan;Han Lianshu(Department of Pecliatric Endocrinology and Genetics,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China)
出处
《中华儿科杂志》
CAS
CSCD
北大核心
2021年第8期695-699,共5页
Chinese Journal of Pediatrics
基金
国家重点研发计划(2016YFC0901505)。
