β酮硫解酶缺陷病患儿的临床表型与ACAT1基因突变分析  

Analysis of clinical phenotype and ACAT1 gene mutation in a family affected with β-ketothiolase deficiency

作　　者：温鹏强[1] 陈占玲[3] 王国兵[1] 苏喆[1] 张秀薇[3] 唐根[1] 崔冬[1] 刘晓红[2] 李成荣[1] 

机构地区：[1]广东省深圳市儿童医院儿科研究所,518038 [2]广东省深圳市儿童医院新生儿科,518038 [3]广东省东莞市人民医院内分泌科,523059

出　　处：《中华医学遗传学杂志》2016年第3期286-291,共6页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金（81102227）;深圳市医学重点学科专项经费（2001818、200LB19）;深圳市科技计划项目（医疗卫生类）重点项目（201201005）;深圳市科技计划项目（医疗卫生类）一般项目（201302107、201401053、201402042）;广东省医学科研基金（A2012582、A2013604）;东莞市医疗卫生科技计划一般项目（20131051010102）;深圳市科技研发资金基础研究项目（JCYJ20140416141331464,JCYJ20150403100317055,JCYJ20150403100317073）

摘　　要：目的探讨β-酮硫解酶缺陷病患JDN床表型特点及致病基因ACAT1突变类型。方法收集病例临床资料，分析患儿临床表现与生化代谢改变特点。提取1对同卵双胞胎先证者及其姐姐和父母的外周血基因组DNA，应用PCR扩增产物直接测序法对ACAT1基因进行突变分析。结果先证者临床表现为无诱因的发热呕吐和严重的酮症酸中毒，血pH7．164，碳酸氢盐4．0mmol／L，尿酮＋＋＋＋。尿液气相色谱质谱分析显示先证者尿中β-羟基丁酸、2-甲基-3-羟基丁酸、甲基巴豆酰甘氨酸大量增高；血液串联质谱分析显示争羟基丁酰肉碱（C4-OH）、异戊酰肉碱（C5：1）、3-羟基异戊酰肉碱（C5-OH）含量明显增高。先证者父母临床表型正常，先证者胞姐也为患儿。DNA直接测序结果显示，2例先证者及姐姐的ACAn基因第7外显子存在c．622C〉T（p．R208x）和c．653C〉T（p．S218F）复合杂合突变；先证者母亲携带有ACAT1基因第7外显子c．622C〉T（p．R208X）杂合突变，父亲携带有ACAT1基因第7外显子c．653C〉T（p．S218F）杂合突变；在100名正常对照中未检测到该突变。经检索HGMD（The Human Gene Mutation Database）等数据库，c．653C〉T（p．S218F）突变为未报道过的新突变。结论β酮硫解酶缺陷病临床上以酮症酸中毒为主要表现，尿液气相色谱质谱分析和血液串联质谱分析对疾病的诊断有着重要提示作用，ACAT1基因突变分析是诊断本病的金标准。ACAT1基因第7外显子c．622C〉T（p．R208X）和c．653C〉T（p．S218F）复合杂合突变为该β-酮硫解酶缺陷病家系发病的分子遗传学基础。Objective To investigate the clinical phenotype and ACAT1 gene mutation in a family affected with β-ketothiolase deficiency （BKTD）. Methods Clinical features and laboratory test data were collected. The probands were monozygotic twin brothers. Genomic DNA was isolated from peripheral blood leukocytes obtained from the probands and their family members. Molecular genetic testing of the ACAT1 gene was carried out. Results The probands have presented with fever, vomiting and severe ketoacidosis. By arterial blood gas testing, pH was determined to be 7. 164, bicarbonate was 4. 0 mmol/L, and urine ketone was ＋＋＋＋. Urinary organic acid gas chromatography-mass spectrometry analysis showed excessive excretion of 3-hydroxybutyric acid, 2-methyl-3-hydroxybutyric acid and tiglylglycine. Increased 3- hydroxybutyrylcarnitine （C4-OH）, tiglylcarnitine （C5 ： 1） and 3-hydroxyisovalerylearnitine （C5-OH） levels. The clinical phenotype of proband＇s parents were both normal, but an elder sister turned out to be an affected patient. Genetic analysis has identified two heterozygous mutations [c. 622C〉 T（p. R208X） and c. 653C〉T（p. S218F）] in the proband, which were respectively detected in the mother and father. The c. 653C〉T（p. S218F） mutation was not found among the 100 healthy controls and has not been included in the Human Gene Mutation Database （HGMD）. Conclusion The primary clinical manifestations of BKTD is ketoacidosis. Urine organic acid and blood aeylcarnitine analyses play an important role in the diagnosis of the disease. The compound heterozygous of ACATI gene mutations probably underlie the BKTD in our patient.

关 键 词：β-酮硫解酶 线粒体乙酰乙酰辅酶A硫解酶 酮症酸中毒 2-甲基-3-羟基丁酸 甲基巴豆酰甘氨酸 ACAT1基因 

分 类 号：R725.9[医药卫生—儿科]