多种酰基辅酶A脱氢酶缺乏症的诊疗进展
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摘要
多种酰基辅酶A脱氢酶缺乏症又称戊二酸尿症2型,是一种常染色体隐性遗传代谢病。由于编码线粒体电子转运黄素蛋白或电子转运黄素蛋白脱氢酶的基因缺陷导致线粒体电子传递链和脂肪酸代谢障碍,引起心肌、肝脏、脑、骨骼肌等多器官损伤。多种酰基辅酶A脱氢酶缺乏症患者缺乏特异性症状与体征,临床诊断困难,需要通过血液氨基酸肉碱谱、尿有机酸谱及基因分析明确诊断。根据患者对核黄素(或维生素B2)的反应,分为核黄素反应型与无反应型。核黄素反应型常为晚发型,治疗以核黄素为主,疗效良好。核黄素无反应型发病早,病情危重,治疗以苯扎贝特、左卡尼汀、辅酶Q10、3-羟基丁酸钠及低脂饮食等为主,一些患者预后不良。
Multiple acyl-CoA dehydrogenase deficiency,also known as glutaric aciduria typeⅡ,is an autosomal recessive inherited metabolic disease. It is a mitochondrial electron transport chain and fatty acid metabolism disorder caused by a defect of electron transfer flavoprotein(ETF)or ETF dehydrogenase(ETFDH),resulting in the damage to multiple organs such as myocardia,liver,brain and skeletal muscle. The clinical diagnosis of multiple acyl-CoA dehydrogenase deficiency is difficult due to the lack of specific symptoms and signs of the patients. To make a definitive diagnosis,blood aminoacids and acylcarnitine profiles,urinary organic acids profiles and gene analysis are necessary. According to the response to ribo-flavin(or vitamin B2),multiple acyl-CoA dehydrogenase deficiency could be divided into riboflavin-responsive form and riboflavin-unresponsive form. The riboflavin-responsive form is usually observed in the late-onset cases with good outcome.The patients of riboflavin-unresponsive form usually have early-onset with severe diseases. Bezafibrate, L-carnitine,coenzyme Q10,sodium-D,L-3-hydroxybutyrate and low-fat die should be considered for the treatment. Some patients with riboflavin-unresponsive form show poor outcome.
Multiple acyl-CoA dehydrogenase deficiency,also known as glutaric aciduria typeⅡ,is an autosomal recessive inherited metabolic disease. It is a mitochondrial electron transport chain and fatty acid metabolism disorder caused by a defect of electron transfer flavoprotein(ETF)or ETF dehydrogenase(ETFDH),resulting in the damage to multiple organs such as myocardia,liver,brain and skeletal muscle. The clinical diagnosis of multiple acyl-CoA dehydrogenase deficiency is difficult due to the lack of specific symptoms and signs of the patients. To make a definitive diagnosis,blood aminoacids and acylcarnitine profiles,urinary organic acids profiles and gene analysis are necessary. According to the response to ribo-flavin(or vitamin B2),multiple acyl-CoA dehydrogenase deficiency could be divided into riboflavin-responsive form and riboflavin-unresponsive form. The riboflavin-responsive form is usually observed in the late-onset cases with good outcome.The patients of riboflavin-unresponsive form usually have early-onset with severe diseases. Bezafibrate, L-carnitine,coenzyme Q10,sodium-D,L-3-hydroxybutyrate and low-fat die should be considered for the treatment. Some patients with riboflavin-unresponsive form show poor outcome.
引文
[1]Yotsumoto Y,Hasegawa Y,Fukuda S,et al.Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2[J].Mol Genet Metab,2008,94(1):61-67.
[2]Yamada K,Kobayashi H,Bo R,et al.Clinical,biochemical and molecular investigation of adult-onset glutaric acidemia type II:Characteristics in comparison with pediatric cases[J].Brain Dev,2016,38(3):293-301.
[3]Frerman FE,Goodman SI.Deficiency of electron transfer flavoprotein or electron transfer flavoprotein:ubiquinone oxidoreductase in glutaric acidemia type II fibroblasts[J].Proc Natl Acad Sci USA,1985,82(13):4517-4520.
[4]Liang WC,Ohkuma A,Hayashi YK,et al.ETFDH mutations,CoQ10 levels,and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency[J].Neuromuscul Disord,2009,19(3):212-216.
[5]Auranen M,Paetau A,Piiril?P,et al.Patient with multiple acylCoA dehydrogenation deficiency disease and FLAD1 mutations benefits from riboflavin therapy[J].Neuromuscul Disord,2017,27(6):581-584.
[6]陈俊操,陈平洋.新生儿多种酰基辅酶A脱氢酶缺乏症1例[J].中国当代儿科杂志,2013,15(12):1098-1099.
[7]陆妹,黄新文.多种酰基辅酶A脱氢酶缺乏症[M]//杨艳玲.从病例开始学习遗传代谢病.北京:人民卫生出版社,2018:179-181.
[8]李务荣,杨旭,赵丹华,等.核黄素反应性脂质沉积性肌病伴感觉共济失调性神经病3例报告[J].中风与神经疾病杂志,2012,29(3):200-203.
[9]Gautschi M,Weisstanner C,Slotboom J,et al.Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy[J].Pediatr Res,2015,77(1):91-98.
[10]丰利芳,陈晓红,李东晓,等.上呼吸道感染患儿口服尼美舒利后发生瑞氏综合征及猝死样症状[J].中国当代儿科杂志,2018,20(11):944-949.
[11]童凡,杨茹莱,赵正言.晚发性维生素B2反应型多种酰基辅酶A脱氢酶缺乏症1例[J].中国儿童保健杂志,2017,25(11):1186-1188.
[12]Béhin A,Acquaviva-Bourdain C,Souvannanorath S,et al.Multiple acyl-CoA dehydrogenase deficiency(MADD)as a cause of late-onset treatable metabolic disease[J].Rev Neurol(Paris),2016,172(3):231-241.
[13]Rijt WJV,Rebecca MHF,Sarvaas GJDM,et al.Favorable outcome after physiologic dose of sodium-D,L-3-hydroxybutyrate in severe MADD[J].Pediatrics,2014,134(4):1224-1228.
[14]Bing W,Li D,Wei L,et al.Multiple acyl-CoA dehydrogenation deficiency as decreased acyl-carnitine profile in serum[J].Neurol Sci,2015,36(6):853-859.
[15]Grünert SC.Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency[J].Orphanet J Rare Dis,2014,9(1):117.
[16]Lan MY,Fu MH,Liu YF,et al.High frequency of ETFDHc.250G>A mutation in Taiwanese patients with late-onset lipid storage myopathy[J].Clin Genet,2010,78(6):565-569.
[17]Xi J,Wen B,Lin J,et al.Clinical features and ETFDH mutation spectrum in a cohort of 90 Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency[J].J Inherit Metab Dis,2014,37(3):399-404.
[18]Zhu M,Zhu X,Qi X,et al.Riboflavin-responsive multiple Acyl-CoA dehydrogenation deficiency in 13 cases,and a literature review in mainland Chinese patients[J].J Hum Genet,2014,59(5):256-261.
[19]Fu HX,Liu XY,Wang ZQ,et al.Significant clinical heterogeneity with similar ETFDH genotype in three Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency[J].Neurol Sci,2016,37(7):1099-1105.
[20]Olsen RKJ,Andresen BS,Christensen E,et al.Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency[J].Hum Mutat,2003,22(1):12-23.
[21]Henriques BJ,Rodrigues JV,Olsen RK,et al.Role of flavinylation in a mild variant of multiple acyl-CoA dehydrogenation deficiency:a molecular rationale for the effects of riboflavin supplementation[J].J Biol Chem,2009,284(7):4222-4229.
[22]章瑞南,邱文娟,叶军,等.多种酰基辅酶A脱氢酶缺乏症儿童与成人患者临床特点比较[J].临床儿科杂志,2012,30(5):446-449.
[23]Horvath R.Update on clinical aspects and treatment of selected vitamin-responsive disordersⅡ(riboflavin and CoQ 10)[J].JInherit Metab Dis,2012,35(4):679-687.
[24]Vattemi G,Gellera C,Tomelleri G.Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency:delayed hypersensitivity reaction and efficacy of low-dose intermittent supplementation[J].Eur J Neurol,2017,24(7):e41-e42.
[25]Wen B,Dai T,Li W,et al.Riboflavin-responsive lipid-storage myopathy caused by ETFDH gene mutations[J].J Neurol Neurosurg Psychiatry,2010,81(2):231-236.
[26]Van Hove JL,Grünewald S,Jaeken J,et al.D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency(MADD)[J].Lancet,2003,361(9367):1433-1435.
[27]Yamada K,Kobayashi H,Bo R,et al.Efficacy of bezafibrate on fibroblasts of glutaric acidemia typeⅡpatients evaluated using an in vitro probe acylcarnitine assay[J].Brain Dev,2017,39(1):48-57.
[28]Yamaguchi S,Li H,Purevsuren J,et al.Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders:evaluation by in vitro probe acylcarnitine assay[J].Mol Genet Metab,2012,107(1-2):87-91.
[2]Yamada K,Kobayashi H,Bo R,et al.Clinical,biochemical and molecular investigation of adult-onset glutaric acidemia type II:Characteristics in comparison with pediatric cases[J].Brain Dev,2016,38(3):293-301.
[3]Frerman FE,Goodman SI.Deficiency of electron transfer flavoprotein or electron transfer flavoprotein:ubiquinone oxidoreductase in glutaric acidemia type II fibroblasts[J].Proc Natl Acad Sci USA,1985,82(13):4517-4520.
[4]Liang WC,Ohkuma A,Hayashi YK,et al.ETFDH mutations,CoQ10 levels,and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency[J].Neuromuscul Disord,2009,19(3):212-216.
[5]Auranen M,Paetau A,Piiril?P,et al.Patient with multiple acylCoA dehydrogenation deficiency disease and FLAD1 mutations benefits from riboflavin therapy[J].Neuromuscul Disord,2017,27(6):581-584.
[6]陈俊操,陈平洋.新生儿多种酰基辅酶A脱氢酶缺乏症1例[J].中国当代儿科杂志,2013,15(12):1098-1099.
[7]陆妹,黄新文.多种酰基辅酶A脱氢酶缺乏症[M]//杨艳玲.从病例开始学习遗传代谢病.北京:人民卫生出版社,2018:179-181.
[8]李务荣,杨旭,赵丹华,等.核黄素反应性脂质沉积性肌病伴感觉共济失调性神经病3例报告[J].中风与神经疾病杂志,2012,29(3):200-203.
[9]Gautschi M,Weisstanner C,Slotboom J,et al.Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy[J].Pediatr Res,2015,77(1):91-98.
[10]丰利芳,陈晓红,李东晓,等.上呼吸道感染患儿口服尼美舒利后发生瑞氏综合征及猝死样症状[J].中国当代儿科杂志,2018,20(11):944-949.
[11]童凡,杨茹莱,赵正言.晚发性维生素B2反应型多种酰基辅酶A脱氢酶缺乏症1例[J].中国儿童保健杂志,2017,25(11):1186-1188.
[12]Béhin A,Acquaviva-Bourdain C,Souvannanorath S,et al.Multiple acyl-CoA dehydrogenase deficiency(MADD)as a cause of late-onset treatable metabolic disease[J].Rev Neurol(Paris),2016,172(3):231-241.
[13]Rijt WJV,Rebecca MHF,Sarvaas GJDM,et al.Favorable outcome after physiologic dose of sodium-D,L-3-hydroxybutyrate in severe MADD[J].Pediatrics,2014,134(4):1224-1228.
[14]Bing W,Li D,Wei L,et al.Multiple acyl-CoA dehydrogenation deficiency as decreased acyl-carnitine profile in serum[J].Neurol Sci,2015,36(6):853-859.
[15]Grünert SC.Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency[J].Orphanet J Rare Dis,2014,9(1):117.
[16]Lan MY,Fu MH,Liu YF,et al.High frequency of ETFDHc.250G>A mutation in Taiwanese patients with late-onset lipid storage myopathy[J].Clin Genet,2010,78(6):565-569.
[17]Xi J,Wen B,Lin J,et al.Clinical features and ETFDH mutation spectrum in a cohort of 90 Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency[J].J Inherit Metab Dis,2014,37(3):399-404.
[18]Zhu M,Zhu X,Qi X,et al.Riboflavin-responsive multiple Acyl-CoA dehydrogenation deficiency in 13 cases,and a literature review in mainland Chinese patients[J].J Hum Genet,2014,59(5):256-261.
[19]Fu HX,Liu XY,Wang ZQ,et al.Significant clinical heterogeneity with similar ETFDH genotype in three Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency[J].Neurol Sci,2016,37(7):1099-1105.
[20]Olsen RKJ,Andresen BS,Christensen E,et al.Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency[J].Hum Mutat,2003,22(1):12-23.
[21]Henriques BJ,Rodrigues JV,Olsen RK,et al.Role of flavinylation in a mild variant of multiple acyl-CoA dehydrogenation deficiency:a molecular rationale for the effects of riboflavin supplementation[J].J Biol Chem,2009,284(7):4222-4229.
[22]章瑞南,邱文娟,叶军,等.多种酰基辅酶A脱氢酶缺乏症儿童与成人患者临床特点比较[J].临床儿科杂志,2012,30(5):446-449.
[23]Horvath R.Update on clinical aspects and treatment of selected vitamin-responsive disordersⅡ(riboflavin and CoQ 10)[J].JInherit Metab Dis,2012,35(4):679-687.
[24]Vattemi G,Gellera C,Tomelleri G.Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency:delayed hypersensitivity reaction and efficacy of low-dose intermittent supplementation[J].Eur J Neurol,2017,24(7):e41-e42.
[25]Wen B,Dai T,Li W,et al.Riboflavin-responsive lipid-storage myopathy caused by ETFDH gene mutations[J].J Neurol Neurosurg Psychiatry,2010,81(2):231-236.
[26]Van Hove JL,Grünewald S,Jaeken J,et al.D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency(MADD)[J].Lancet,2003,361(9367):1433-1435.
[27]Yamada K,Kobayashi H,Bo R,et al.Efficacy of bezafibrate on fibroblasts of glutaric acidemia typeⅡpatients evaluated using an in vitro probe acylcarnitine assay[J].Brain Dev,2017,39(1):48-57.
[28]Yamaguchi S,Li H,Purevsuren J,et al.Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders:evaluation by in vitro probe acylcarnitine assay[J].Mol Genet Metab,2012,107(1-2):87-91.