质谱技术联合基因分析进行β-酮硫解酶缺乏症的产前诊断  

Mass spectrometry combined with gene analysis for prenatal diagnosis of β-ketothiolase deficiency

作　　者：徐烽[1] 韩连书[1] 季文君[1] 陈婷[1] 占霞 叶军[1] 顾学范[1] XU Feng;HAN Lian-shu;JI Wen-jun;CHEN Ting;ZHAN Xia;YE Jun;GU Xue-fan(Depatment of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, Chin)

机构地区：[1]上海交通大学医学院附属新华医院上海市儿科医学研究所内分泌/遗传科,上海200092

出　　处：《发育医学电子杂志》2018年第1期25-29,共5页Journal of Developmental Medicine (Electronic Version)

基　　金：国家重点研发计划(2016YFC0901505;2016YFC0905100)

摘　　要：目的采用质谱技术及基因分析技术,探讨β-酮硫解酶缺乏症(β-ketothiolase deficiency,BKD)的产前诊断方法。方法分析1例BKD患儿的临床特征、血尿串联质谱特点及基因检测结果。其母亲再次妊娠后,于妊娠17周抽取羊水,利用串联质谱检测羊水中异戊烯酰基肉碱(C5︰1)及3-羟基异戊酰基肉碱(C5-OH)水平,气相质谱检测羊水中2-甲基-3-羟基丁酸及甲基巴豆酰甘氨酸水平,羊水细胞进行基因检测,判断胎儿是否为BKD患儿。结果先证者临床表现为反应差、呼吸困难、乏力等,代谢性酮症酸中毒急性发作死亡。其母亲再次妊娠,羊水C5︰1、C5-OH、2-甲基-3-羟基丁酸及甲基巴豆酰甘氨酸水平均正常,提示胎儿正常,出生后新生儿质谱血尿检测正常。其母亲第3次妊娠,羊水中C5︰1水平增高(0.26μmol/L),C5-OH正常;2-甲基-3-羟基丁酸增高(0.8 mmol/mol肌酐),甲基巴豆酰甘氨酸水平正常;羊水细胞ACAT1基因检测发现c.1124A>G(p.N375S)纯合错义突变,与先证者一致,提示此胎儿为BKD患儿。结论质谱技术联合基因分析有助于BKD的产前诊断。Objective To evaluate the method of measuring acylcarnitine and organic acid in amniotic fluid by tandem mass spectrometry and gas chromatography-mass spectrometry for the prenatal diagnosis of β-ketothiolase deficiency（BKD）.Methods The clinical characteristics,metabolites spectrum of the tandem mass spectrometry and gas chromatography-mass spectrometry and the genetic analysis in a patient with β-ketothiolase deficiency（BKD） were analyzed.When the mother was pregnant again,she was being carried out the amniocentesis at 17 weeks of gestation.The level of tiglylcarnitine（C5：1） and 3-hydroxyisovlerylcarnitine（C5-OH） were detectd by tandem mass spectrometry.2-methyl-3-hydroxybutyric acid and methylcrotonyl glycine were detectd by gas chromatography-mass spectrometry.Meanwhile,gene mutation test of the amniotic fluid cells were performed to confirm the diagnosis of the fetus.Results The clinical features of the proband included poor reaction,dyspnea and fatigue,who finally died after an acute onset of metabolic ketoacidosis.When the mother was pregnant for the second time,the amniotic fluids showed normal level of C5：1,C5-OH,2-methyl-3-hydroxybutyric acid and methylcrotonyl glycine,indicating the fetus was normal.And it has been confirmed normal by blood tandem mass spectrometry and urine gas chromatography-mass spectrometry after birth.When the mother was pregnant for the third time,C5：1 and 2-methyl-3-hydroxybutyric acid levels were remarkably increased in the amniotic fluids,while C5-OH and methylcrotonyl glycine were normal,indicating BKD most possibly.Mutation analysis of ACAT1 gene was performed in the amniotic fluid cells,illustrating homozygous c.1124 AG（p.N375 S） mutation,the same as the BKD proband.Therefore,the fetus was diagnosed with BKD.Conclusion A combined spectrometry measurements of the amniotic fluid with gene mutation analysis is helpful in BKD prenatal diagnosis.

关 键 词：β-酮硫解酶缺乏 串联质谱 气相色谱质谱 ACAT1基因 产前诊断 

分 类 号：R714.55[医药卫生—妇产科学]