β-酮硫解酶缺乏症的临床及基因诊断  

Retrospective analysis on clinical data and genetic variations of patients with β-ketothiolase deficiency

作　　者：徐烽[1] 韩连书[1] 邱文娟[1] 张惠文[1] 季文君[1] 陈婷[1] 占霞 叶军[1] 顾学范[1] Xu Feng;Han Lianshu;Qiu Wenjuan;Zhang Huiwen;Ji Wenjun;Chen Ting;Zhan Xia;Ye Jun;Gu Xuefan(Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China)

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,小儿内分泌与遗传代谢病研究室,200092

出　　处：《中华医学遗传学杂志》2019年第3期199-202,共4页Chinese Journal of Medical Genetics

基　　金：国家重点研发计划精准医学研究专项(2016YFC0905100;2016YFC0901505).

摘　　要：目的探讨β-酮硫解酶缺乏症(β-ketothiolase deficiency,BKD)患者的临床及基因变异特点。方法对8例BKD患者的临床特征、血/尿串联质谱检测结果及基因变异进行回顾分析。结果血串联质谱检测提示甲基巴豆酰基肉碱(C5:1)与3-羟基异戊酰基肉碱(C5-OH)显著增高,分别为0.43(0.20~0.89)μmol/L和1.37(0.98~3.40)μmol/L。所有患者的尿气相色谱质谱检测提示2-甲基-3-羟基丁酸与甲基巴豆酰甘氨酸水平均明显增高,分别为56.04(7.69~182.20)和42.83(9.20~127.01)。5例患者治疗后尿2-甲基-3-羟基丁酸明显下降(P < 0.05)。7例(78.6%)患者ACAT1基因存在错义变异,42.8%的患者携带c.1124A>G(p.N375S)错义变异,该变异频率为28.6%。共发现4种新致病变异:c.229delG(p.E77KfsTer10),c.373G>T(p.V125F),c.419T>G(p.L140R)和c.72+1G>A;其中2种变异(c.373G>T及c.419T>G)相关氨基酸位点高度保守,经PolyPhen2及PROVEAN软件评估均具有致病性;c.72+1G>A经Human Splicing Finder软件评估,提示可能破坏相邻的野生型供体位点,影响RNA剪切。结论对有不明原因神经系统损害症状且伴有酮性代谢性酸中毒的患者需常规进行血/尿质谱筛查,以早期发现BKD,同时进行ACAT1基因检测以明确诊断。Objective To summarize the clinical, biochemical and molecular characteristics of 8 patients with β-ketothiolase deficiency (BKD). Methods Clinical characteristics, biochemical markers detected by tandem mass spectrometry (MS-MS) and gas chromatography-mass spectrometry (GC-MS), and variations of ACAT1 gene of the 8 patients were reviewed. Results Three patients were diagnosed by newborn screening and were asymptomatic. Five patients showed dyspnea and metabolic acidosis through high risk screening. Blood methylcrotonyl carnitine (C5: 1) were 0.43 (0.20 - 0.89)μmol/L and 3-hydroxyisovaleryl carnitine(C5-OH)were 1.37 (0.98-3.40)μmol/L. Both were significantly higher than those of healthy controls (P < 0.01). Urinary 2-methyl-3-hydroxybutyric acid was 56.04 (7.69 - 182.20) and methylcrotonyl glycine was 42.83 (9.20 - 127.01), both were higher than normal levels. In 5 patients urinary 2-methyl-3-hydroxybutyric acid level was remarkably decreased (P<0.05) after treatment. Analysis of ACAT1 gene mutation was performed in six families. Missense variations were detected in 78.6% of the cases. 42.8% of the 7 BKD patients have carried c. 1124A>G (p.N375S) variant, which accounted for 28.6% of all 14 mutant alleles. Four novel variants, namely c. 229delG (p.E77KfsTer10), c. 373G>T(p.V125F), c. 419T>G (p.L140R) and c. 72+ 1G>A, were discovered. Pathogenicity assessment of two highly conservative missense variants (p.V125F) and (p.L140R) were 0.994 and 1.0 (Scores obtained from PolyPhen2), and PROVEAN scores were -4.652 and -5.399, respectively. c. 72+ 1g>a was suspected (by Human Splicing Finder) to alter the wild type donor motif and most probably affect the splicing. Conclusion Clinicians should consider MS/MS and GC/MS testing for those with unexplained neurological symptoms and metabolic acidosis in order to attain early diagnosis of BKD. Genetic testing should be used to confirm the diagnosis.

关 键 词：β-酮硫解酶缺乏 串联质谱 气相色谱质谱 ACAT1基因 

分 类 号：R725.8[医药卫生—儿科] R440[医药卫生—临床医学]