新生儿筛查检出的短/支链酰基辅酶A脱氢酶缺乏症患儿的临床表现、生化指标及基因变异分析  

Analysis of clinical features,biochemical indices and genetic variants among children with Short/branchedchain acyl-CoA dehydrogenase deficiency detected by neonatal screening

作　　者：赵涵怡 周朵[1] 缪海霞 陈迟[1] 杨建滨[1] 杨茹莱[1] 黄新文[1] Zhao Hanyi;Zhou Duo;Miao Haixia;Chen Chi;Yang Jianbin;Yang Rulai;Huang Xinwen(Department of Genetics and Metabolism,Children's Hospital Affiliated to Zhejiang University School of Medicine,National Clinical Research Center for Child Health,National Children's Regional Medical Center,Hangzhou,Zhejiang 310052,China)

机构地区：[1]浙江大学医学院附属儿童医院遗传与代谢科,国家儿童健康与疾病临床医学研究中心,国家儿童区域医疗中心,杭州310052

出　　处：《中华医学遗传学杂志》2023年第2期155-160,共6页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金(82073560)。

摘　　要：目的探讨新生儿筛查检出的短/支链酰基辅酶A脱氢酶(SBCAD)缺乏症患儿的临床表现、生化异常及致病变异。方法选取2016年1月至2021年12月在浙江大学医学院附属儿童医院接受筛查的2730852例新生儿为研究对象,进行氨基酸及2-甲基丁酰肉碱筛查,对疑似SBCAD缺乏症的患儿通过尿有机酸分析、高通量基因测序进行确诊。分析确诊患儿的临床表现、生化改变及ACADSB基因变异,指导控制蛋白摄入,补充左卡尼汀,随访观察其生长及智能发育情况。结果共确诊SBCAD缺乏症患儿12例,折算患病率为1/227571。12例SBCAD患儿初筛血异戊酰肉碱(C5)在0.6~2.1μmol/L之间,均超过正常范围;C5/乙酰基肉碱(C2)在0.02~0.12之间,其中6例超过正常范围;C5/丙酰基肉碱(C3)在0.1~1.16之间,其中5例超过正常范围;游离肉碱(C0)为18.89~58.12μmol/L,1例超过正常范围。对5例SBCAD缺乏症患儿进行治疗,3例避免高蛋白饮食,2例予左卡尼汀治疗。随访中C5为0.22~2.32μmol/L,C5/C2为0.01~0.31,C5/C3为0.14~1.7。11例患儿(除例8)新生儿筛查或随访中均出现C5或C5/C2、C5/C3一过性正常,C0为17.42~76.83μmol/L。12例患儿中9例进行了尿有机酸分析,8例2-甲基丁酰甘氨酸增高。11例患儿接受了基因分析,共发现6种ACADSB基因变异,4种错义变异c.655G>A、c.923G>A、c.461G>A、c.1165A>G,1个移码变异c.746del,1个无义变异c.275C>G,c.461G>A变异未见报道,变异频次前2位为c.1165A>G(40.9%)与c.275C>G(22.7%)。对患儿治疗随访18 d~55个月,仅1例患者出现智力发育落后,其余患者体格及智力发育正常。结论SBCAD缺乏症为罕见病,本研究新生儿筛查折算检出率为1/227571。通过新生儿筛查可实现大多无症状的患者早期干预。本研究最常见的基因变异是c.1165A>G和c.275C>G.Objective To investigate the clinical manifestations,biochemical abnormalities and pathogenic variants among children with Short/branched-chain acyl-CoA dehydrogenase(SBCAD)deficiency detected by neonatal screening.MethodsA total of 2730852 newborns were screened from January 2016 to December 2021 with liquid chromatography tandem mass spectrometry.Suspected SBCAD deficiency patients were diagnosed by urine organic acid analysis and high-throughput gene sequencing analysis.The clinical,biochemical and genetic changes of the confirmed cases were analyzed,in addition with guidance for diet and life management,L-carnitine supplement,and survey of growth and intellectual development.ResultsTwelve cases of SBCAD deficiency were diagnosed,which yielded a prevalence of 1/227571.The lsovaleryl carnitine(C5)of primary screening blood samples was between 0.6 and 2.1μmol/L,all exceeded the normal range.C5/acetyl carnitine(C2)was between 0.02 and 0.12,with 6 cases exceeding the normal range.C5/propionyl carnitine(C3)was between 0.1 and 1.16,with 5 cases exceeding the normal range.Free carnitine(Co)was between 18.89 and 58.12μmol,with 1 case exceeding the normal range.Three neonates with abnormal screening results were recommended to have appropriate restriction for protein intake and two were given L-carnitine.During follow-up,their C5 has ranged from 0.22 to 2.32μmol/L,C5/C2 has ranged from 0.01 to 0.31,C5/C3 has ranged from 0.14 to 1.7.C5 or C5/C2 and C5/C3 were transiently normal in all patients except for case 8 during the neonatal screening and follow-up.CO was 17.42~76.83μmol/L Urine organic acid analysis was carried out in 9 of the 12 cases,and 2-methylbutyroglycine was elevated in 8 cases.Urine organic acid analysis was carried out in 9 cases,and 2-methylbutyrylglycine was increased in 8 cases.Genetic analysis was carried out for 1l children,and in total 6 ACADSB gene variants were identified,which included 4 missense variants(c.655G>A,c.923G>A,c.461G>A,c.1165A>G),1 frameshift variant(c.746del)and 1 nonsense vari

关 键 词：短/支链酰基辅酶A脱氢酶缺乏症 新生儿筛查 遗传代谢病 

分 类 号：R722.11[医药卫生—儿科]