β酮硫解酶缺乏症5例临床表型与基因型特征分析  

Clinical phenotypic and genotypic analysis of 5 pediatric patients withβ-ketothiolase deficiency

作　　者：张娟[1] 余朝文[1] 王明[1] 万科星 杨静[1] 袁召建[1] 廖志鸿 王冬娟[1] Zhang Juan;Yu Chaowen;Wang Ming;Wan Kexing;Yang Jing;Yuan Zhaojian;Liao Zhihong;Wang Dongjuan(Center of Clinical Molecular Medicine,National Clinical Research Center for Child Health and Disorders,Education Key Laboratory of Child Development and Disorders of Ministry of Education,Chongqing Key Laboratory of Pediatrics,Children′s Hospital of Chongqing Medical University,Chongqing 400014,China)

机构地区：[1]重庆医科大学附属儿童医院临床分子医学检测中心、国家儿童健康与疾病临床医学研究中心儿童发育疾病研究教育部重点实验室、儿科学重庆市重点实验室,重庆400014

出　　处：《中华儿科杂志》2024年第1期66-70,共5页Chinese Journal of Pediatrics

摘　　要：目的总结β酮硫解酶缺乏症(BKTD)患儿的临床表型及基因变异特点。方法回顾性分析2018年10月至2022年12月在重庆医科大学附属儿童医院诊断及随访的5例BKTD患儿的临床特征,血液生化指标、血和尿质谱检测结果及ACAT1基因变异数据。结果5例BKTD患儿中男4例、女1例,首次发病年龄为9.7~28.0月龄。急性期均表现出严重代谢性酸中毒,pH值为6.9~7.1,血糖2.3~3.4 mmol/L,尿酮体阳性(+~++++)。血串联质谱分析提示甲基巴豆酰基肉碱、甲基丙二酰基肉碱与丙二酰基肉碱明显升高,分别为0.03~0.42、0.34~1.43及0.83~3.53µmol/L,尿气相色谱质谱检测提示2-甲基-3羟基丁酸、3-羟基丁酸明显升高,伴甲基巴豆酰甘氨酸轻度升高,分别为22~202、4~6066和0~29,但经过治疗后血和尿质谱代谢产物明显降低。5例患儿ACAT1基因错义变异比例8/9,发现4种未报道变异:c.678G>T(p.Trp226Cys)、c.302A>G(p.Gln101Arg)、c.627_629dupTGA(p.Asn209_Glu210insAsp)、c.316C>T(p.Gln106Ter),前2种变异经过SIFT、PolyPhen-2和Mutation Taster软件预测为有害,c.316C>T(p.Glu106Ter)为终止变异。结论BKTD相对罕见,缺乏特异性临床表现,急性发病期常出现严重代谢性酸中毒、低血糖及酮症,ACAT1基因错义变异为BKTD的主要遗传学病因。Objective To summarize the clinical and genetic characteristics of children withβ-ketothiolase deficiency(BKTD).Methods The clinical characteristics,biochemical,markers detected by tandem mass spectrometry(MS/MS)and gas chromatography-mass spectrometry(GC/MS),as well as the variants in ACAT1 gene among 5 children with BKTD in Children′s Hospital of Chongqing Medical University between October 2018 and December 2022 were retrospectively analyzed.Results The onset age of the disease in 5 patients(4 males and 1 female)ranged from 9.7 to 28.0 months.During the acute phase,severe metabolic acidosis was observed with a pH of 6.9-7.1,as well as hypoglycaemia(2.3-3.4 mmol/L)and positive urinary ketone bodies(+-++++).Blood levels of methylcrotonyl carnitine,methylmalonyl carnitine and malonyl carnitine were 0.03-0.42,0.34-1.43 and 0.83-3.53μmol/L respectively and were significantly elevated.Urinary 2-methyl-3-hydroxybutyric acid was 22-202 and 3-hydroxybutyric acid was 4-6066,both were higher than the normal levels.Methylcrotonylglycine was mild elevated(0-29).The metabolites detected by MS/MS and GC/MS were significantly reduced after treatment.Analysis of ACAT1 gene mutation was performed in 5 children.Most variants were missense(8/9).Four previously unreported variants were identified:c.678G>T(p.Trp226Cys),c.302A>G(p.Gln101Arg),c.627_629dupTGA(p.Asn209_Glu210insAsp)and c.316C>T(p.Gln106Ter),the first 2 variants were predicted to be damaging by SIFT,PolyPhen-2 and Mutation Taster software.c.316C>T(p.Gln106Ter)is a nonsense variant.Conclusionsβ-ketothiolase deficiency is relatively rare,lacks specific clinical manifestations,however severe metabolic acidosis,hypoglycemia,and ketosis during the acute onset were consistent findings.Missense mutations in the ACAT1 gene are common genetic causes ofβ-ketothiolase deficiency.

关 键 词：DNA突变分析 串联质谱法 气相色谱-质谱法 β酮硫解酶缺乏 

分 类 号：R725.9[医药卫生—儿科]