中链酰基辅酶A脱氢酶缺乏症新生儿筛查及随访研究
|
摘要
目的探讨中链酰基辅酶A脱氢酶缺乏症(MCADD)中国人群流行病学特征、表型、基因型及预后。方法回顾性分析2009年1月至2018年6月期间经高效液相色谱串联质谱(HPLC-MS/MS)筛查并结合基因检测诊断为MCADD的新生儿资料。结果 2 674 835例接受筛查的新生儿中诊断MCADD的12例(1/222 902)。其中10例接受基因检测,发现ACADM基因16个突变位点的13种突变类型:7种为已报道突变(p.T150Rfs*4、p.M1V、p.R206C、p.R294T、p.G310R、p.M328V、p.G362E);5种新突变(p.N194D、p.A324P、p.N366S、c.118+3A>G、c.387+1del G)和1例11号外显子缺失,以p.T150Rfs*4最常见(4/16)。ACADM基因突变位点检出率80%。未见表型-基因型相关性。确诊后给予饮食指导及对症治疗,随访4～82个月期间未见急性代谢失衡发作,除1例合并脑发育不良外均预后良好。结论 MCADD在中国南方人群相对罕见; p.T150Rfs*4为中国人群热点突变;筛查阳性的病例建议联合辛酰基肉碱检测及基因判断。
Objective To investigate the epidemiological characteristics,phenotype,genotype,and prognosis of medium-chain acyl-CoA dehydrogenase deficiency(MCADD)in the Chinese population.Methods A retrospective analysis was performed for the clinical data of the neonates who underwent screening with high-performance liquid chromatography-tandem mass spectrometry from January 2009 to June 2018 and were diagnosed with MCADD by gene detection.Results A total of 2 674 835 neonates underwent neonatal screening,among whom 12 were diagnosed with MCADD.Gene detection was performed for 10 neonates with MCADD and found 13 mutation types at 16 mutation sites of the ACADM gene,among which there were 7 reported mutations(p.T150Rfs*4,p.M1V,p.R206C,p.R294T,p.G310R,p.M328V,and p.G362E),5 novel mutations(p.N194D,p.A324P,p.N366S,c.118+3A>G,and c.387+1del G),and 1 exon 11 deletion;p.T150Rfs*4 was the most common mutation(4/16).The detection rate of mutation sites in the ACADM gene was 80%.No phenotype-genotype correlation was observed.Dietary guidance and symptomatic treatment were given after confirmed diagnosis.No acute metabolic imbalance was observed within 4-82 months of follow-up.All neonates had good prognosis except one who had brain dysplasia.Conclusions MCADD is relatively rare in southern China,and p.T150Rfs*4 is a common mutation in the Chinese population.Cases with positive screening results should be evaluated by octanoylcarnitine C8 value and gene detection.
Objective To investigate the epidemiological characteristics,phenotype,genotype,and prognosis of medium-chain acyl-CoA dehydrogenase deficiency(MCADD)in the Chinese population.Methods A retrospective analysis was performed for the clinical data of the neonates who underwent screening with high-performance liquid chromatography-tandem mass spectrometry from January 2009 to June 2018 and were diagnosed with MCADD by gene detection.Results A total of 2 674 835 neonates underwent neonatal screening,among whom 12 were diagnosed with MCADD.Gene detection was performed for 10 neonates with MCADD and found 13 mutation types at 16 mutation sites of the ACADM gene,among which there were 7 reported mutations(p.T150Rfs*4,p.M1V,p.R206C,p.R294T,p.G310R,p.M328V,and p.G362E),5 novel mutations(p.N194D,p.A324P,p.N366S,c.118+3A>G,and c.387+1del G),and 1 exon 11 deletion;p.T150Rfs*4 was the most common mutation(4/16).The detection rate of mutation sites in the ACADM gene was 80%.No phenotype-genotype correlation was observed.Dietary guidance and symptomatic treatment were given after confirmed diagnosis.No acute metabolic imbalance was observed within 4-82 months of follow-up.All neonates had good prognosis except one who had brain dysplasia.Conclusions MCADD is relatively rare in southern China,and p.T150Rfs*4 is a common mutation in the Chinese population.Cases with positive screening results should be evaluated by octanoylcarnitine C8 value and gene detection.
引文
[1]K?lvraa S,Gregersen N,Christensen E,et al.In vitro fibroblast studies in a patient with C6-C10-dicarboxylic aciduria:evidence for a defect in general acyl-CoA dehydrogenase[J].Clin Chim Acta,1982,126(1):53-67.
[2]Matern D,Rinaldo P.Medium-chain acyl-coenzyme Adehydrogenase deficiency[M]//GeneReviews:Genetic Disease Online Reviews at GeneTests-GeneClinics.Seattle:University of Washington,2015.
[3]Oerton J,Khalid JM,Besley G,et al.Newborn screening for medium chain acyl-CoA dehydrogenase deficiency in England:prevalence,predictive value and test validity based on 1.5million screened babies[J].J Med Screen,2011,18(4):173-181.
[4]Chien YH,Lee NC,Chao MC,et al.Fatty acid oxidation disorders in a chinese population in Taiwan[J].JIMD Rep,2013,11:165-172.
[5]Matern D.Acylcarnitines[M]//Blau N,Duran M,Gibson KM,et al.Physician's Guide to the Diagnosis,Treatment,and Followup of Inherited Metabolic Diseases.Heidelberg:SpringerVerlag,2014:775-784.
[6]Hall PL,Wittenauer A,Hagar A.Newborn screening for medium chain acyl-Co A dehydrogenase deficiency:performance improvement by monitoring a new ratio[J].Mol Genet Metab,2014,113(4):274-277.
[7]Lindner M,Hoffmann GF,Matern D.Newborn screening for disorders of fatty-acid oxidation:experience and recommendations from an expert meeting[J].J Inherit Metab Dis,2010,33(5):521-526.
[8]Rinaldo P.Retrospective and prospective date mining to develop continuous,covariate-adjusted reference and disease percentiles for biomarkers of metabolic disease[J].Clin Chem Lab Med,2017,55:1200-1201.
[9]Gregersen N,K?lvraa S,Rasmussen K,et al.General(mediumchain)acyl-CoA dehydrogenase deficiency(non-ketotic dicarboxylic aciduria):quantitative urinary excretion pattern of23 biologically significant organic acids in three cases[J].Clin Chim Acta,1983,132(2):181-191.
[10]Al-Hassnan ZN,Imtiaz F,Al-Amoudi M,et al.Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia:incidence,genotype,and preventive implications[J].J Inherit Metab Dis,2010,33(Suppl 3):S263-S267.
[11]Shigematsu Y,Hirano S,Hata I,et al.Newborn mass screening and selective screening using electrospray tandem mass spectrometry in Japan[J].J Chromatogr B Analyt Technol Biomed Life Sci,2002,776(1):39-48.
[12]Ensenauer R,Winters JL,Parton PA,et al.Genotypic differences of MCAD deficiency in the Asian population:novel genotype and clinical symptoms preceding newborn screening notification[J].Genet Med,2005,7(5):339-343.
[13]Janzen N,Hofmann AD,Schmidt G,et al.Non-invasive test using palmitate in patients with suspected fatty acid oxidation defects:disease-specific acylcarnitine patterns can help to establish the diagnosis[J].Orphanet J Rare Dis,2017,12(1):187.
[14]Piercy H,Machaczek K,Ali P,et al.Parental experiences o f r a i s i n g a c h i l d w i t h m e d i u m c h a i n a c y l-C o Adehydrogenase deficiency[J].Glob Qual Nurs Res,2017,4:2333393617707080.
[15]Derks TG,Van Spronsen FJ,Rake JP,et al.Safe and unsafe duration of fasting for children with MCAD deficiency[J].Eur JPediatr,2007,166(1):5-11.
[16]Dessein AF,Fontaine M,Andresen BS,et al.A novel mutation of the ACADM gene(c.145C>G)associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency:a case report[J].Orphanet J Rare Dis,2010,5:26.
[2]Matern D,Rinaldo P.Medium-chain acyl-coenzyme Adehydrogenase deficiency[M]//GeneReviews:Genetic Disease Online Reviews at GeneTests-GeneClinics.Seattle:University of Washington,2015.
[3]Oerton J,Khalid JM,Besley G,et al.Newborn screening for medium chain acyl-CoA dehydrogenase deficiency in England:prevalence,predictive value and test validity based on 1.5million screened babies[J].J Med Screen,2011,18(4):173-181.
[4]Chien YH,Lee NC,Chao MC,et al.Fatty acid oxidation disorders in a chinese population in Taiwan[J].JIMD Rep,2013,11:165-172.
[5]Matern D.Acylcarnitines[M]//Blau N,Duran M,Gibson KM,et al.Physician's Guide to the Diagnosis,Treatment,and Followup of Inherited Metabolic Diseases.Heidelberg:SpringerVerlag,2014:775-784.
[6]Hall PL,Wittenauer A,Hagar A.Newborn screening for medium chain acyl-Co A dehydrogenase deficiency:performance improvement by monitoring a new ratio[J].Mol Genet Metab,2014,113(4):274-277.
[7]Lindner M,Hoffmann GF,Matern D.Newborn screening for disorders of fatty-acid oxidation:experience and recommendations from an expert meeting[J].J Inherit Metab Dis,2010,33(5):521-526.
[8]Rinaldo P.Retrospective and prospective date mining to develop continuous,covariate-adjusted reference and disease percentiles for biomarkers of metabolic disease[J].Clin Chem Lab Med,2017,55:1200-1201.
[9]Gregersen N,K?lvraa S,Rasmussen K,et al.General(mediumchain)acyl-CoA dehydrogenase deficiency(non-ketotic dicarboxylic aciduria):quantitative urinary excretion pattern of23 biologically significant organic acids in three cases[J].Clin Chim Acta,1983,132(2):181-191.
[10]Al-Hassnan ZN,Imtiaz F,Al-Amoudi M,et al.Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia:incidence,genotype,and preventive implications[J].J Inherit Metab Dis,2010,33(Suppl 3):S263-S267.
[11]Shigematsu Y,Hirano S,Hata I,et al.Newborn mass screening and selective screening using electrospray tandem mass spectrometry in Japan[J].J Chromatogr B Analyt Technol Biomed Life Sci,2002,776(1):39-48.
[12]Ensenauer R,Winters JL,Parton PA,et al.Genotypic differences of MCAD deficiency in the Asian population:novel genotype and clinical symptoms preceding newborn screening notification[J].Genet Med,2005,7(5):339-343.
[13]Janzen N,Hofmann AD,Schmidt G,et al.Non-invasive test using palmitate in patients with suspected fatty acid oxidation defects:disease-specific acylcarnitine patterns can help to establish the diagnosis[J].Orphanet J Rare Dis,2017,12(1):187.
[14]Piercy H,Machaczek K,Ali P,et al.Parental experiences o f r a i s i n g a c h i l d w i t h m e d i u m c h a i n a c y l-C o Adehydrogenase deficiency[J].Glob Qual Nurs Res,2017,4:2333393617707080.
[15]Derks TG,Van Spronsen FJ,Rake JP,et al.Safe and unsafe duration of fasting for children with MCAD deficiency[J].Eur JPediatr,2007,166(1):5-11.
[16]Dessein AF,Fontaine M,Andresen BS,et al.A novel mutation of the ACADM gene(c.145C>G)associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency:a case report[J].Orphanet J Rare Dis,2010,5:26.