Fabry病的生物标志物研究进展
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摘要
Fabry病(FD)是一种罕见的X连锁隐性遗传溶酶体贮积病。以α?半乳糖苷酶A活性下降为特征,造成三己糖酰基鞘脂醇贮积在人体各器官、组织,导致严重并发症,影响患者预后。因此,使用特异性生物标记对患者进行早期诊断与分期、明确器官受累及监测疗效至关重要。Lyso?Gb3是建立诊断的重要生物标记,可评估致病基因突变。蛋白尿和血肌酐对监测肾损伤最有价值,肌钙蛋白I和高敏肌钙蛋白T可明确心肌损害。文章主要就FD相关靶器官如肾、心脏、神经系统损伤的标志物及其对疾病进展、疗效评价及预后评估的指导价值等进行综述。
Fabry disease(FD)is a rare X?linked lysosomal storage disorder. It is characterized by deficient activity of α?ga?lactosidase A,which causes the storage of globotriaosylceramide in tissues and organs,leading to fatal complications and poor progno?sis. Therefore,it is essential to use the possibilities of specific biomarkers for early diagnosis,identification of organ involvement and therapy monitoring. Lyso?Gb3 is a valuable biomarker to establish the diagnosis and also important for evaluating the pathogenic muta?tions. Proteinuria and creatinine are the most valuable biomarkers to detect renal damage. Troponin I and high?sensitivity assays for car?diac troponin T can identify the patients with myocardial injury. ThisarticlemainlyreviewsthemarkersofFD?relatedtargetorganssuch askidney,heartandnervoussystemdamageanditsguidingvaluefordiseaseprogression,curativeeffectandprognosisevaluation.
Fabry disease(FD)is a rare X?linked lysosomal storage disorder. It is characterized by deficient activity of α?ga?lactosidase A,which causes the storage of globotriaosylceramide in tissues and organs,leading to fatal complications and poor progno?sis. Therefore,it is essential to use the possibilities of specific biomarkers for early diagnosis,identification of organ involvement and therapy monitoring. Lyso?Gb3 is a valuable biomarker to establish the diagnosis and also important for evaluating the pathogenic muta?tions. Proteinuria and creatinine are the most valuable biomarkers to detect renal damage. Troponin I and high?sensitivity assays for car?diac troponin T can identify the patients with myocardial injury. ThisarticlemainlyreviewsthemarkersofFD?relatedtargetorganssuch askidney,heartandnervoussystemdamageanditsguidingvaluefordiseaseprogression,curativeeffectandprognosisevaluation.
引文
[1]Germain DP.Fabry disease[J].Orphanet J Rare Dis,2010,5:30.
[2]Young E,Mills K,Morris P,et al.Is globotriaosylceramide a useful biomarker in Fabry disease?[J]Acta Paediatr Suppl,2005,94(447):51-54.
[3]Togawa T,Kodama T,Suzuki T,et al.Plasma globotriaosylsphingosine as a biomarker of Fabry disease[J].Mol Genet Metab,2010,100(3):257-261.
[4]Aerts JM,Groener JE,Kuiper S,et al.Elevated globotriaosylsphingosine is a hallmark of Fabry disease[J].Proc Natl Acad Sci USA,2008,105(8):2812-2817.
[5]Ferreira S,Auray-Blais C,Boutin M,et al.Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma[J].Clin Chim Acta,2015,447:96-104.
[6]Niemann M,Rolfs A,St?rk S.Gene Mutations Versus Clinically Relevant Phenotypes Lyso-Gb3 Defines Fabry Disease[J].Circ Cardiovasc Genet,2014,7(1):8-16.
[7]Van Breemen MJ,Rombach SM,Dekker N.Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy[J].Biochim Biophys Acta,2011,1812(1):70-76.
[8]Skrunes R,Tondel C,Leh S,et al.Long-term dose-dependent agalsidase effects on kidney histology in fabry disease[J].Clin JAm Soc Nephrol,2017,12(9):1470-1479.
[9]Auray-Blais C,Ntwari A,Clarke JT,et al.How well does urinary lyso-Gb3 function as a biomarker in Fabry disease[J]?Clin Chim Acta,2010,411(23-24):1906-1914.
[10]West M,Nicholls K,Mehta A,et al.Agalsidase alfa and kidney dysfunction in Fabry disease[J].J Am Soc Nephrol,2009,20(5):1132-1139.
[11]Torralba-Cabeza MA,Olivera S,Hughes DA,et al.Cystatin Cand NT-proBNP as prognostic biomarkers in Fabry disease[J].Mol Genet Metab,2011,104(3):301-307.
[12]侯庆,陈朝红.斑马鱼在足细胞研究中的应用及其进展[J].医学研究生学报,2016,29(9):976-981.
[13]Takahashi N,Yokoi S,Kasuno K,et al.A heterozygous female with Fabry disease due to a novel alpha-galactosidase A mutation exhibits a unique synaptopodin distribution in vacuolated podocytes[J].Clin Nephrol,2015,83(5):301-308.
[14]Greka A,Mundel P.Cell biology and pathology of podocytes[J].Annu Rev Physiol,2012,74:299-323.
[15]Trimarchi H.Podocyturia:What is in a name?[J]J Transl Int Med,2015,3(2):51-56.
[16]Trimarchi H,Canzonieri R,Schiel A,et al.Podocyturia is signi ficantly elevated in untreated vs.treated Fabry adult patients[J].J Nephrol,2016,29(6):791-797.
[17]Branton MH,Schiffmann R,Sabnis SG,et al.Natural history of Fabry renal disease:influence of alpha-galactosidase A activity and genetic mutations on clinical course[J].Medicine,2002,81(2):122-138.
[18]Lepedda AJ,Fancellu L,Zinellu E,et al.Urine bikunin as a marker of renal impairment in Fabry’s disease[J].Biomed Res Int,2013,2013:205948.
[19]Seydelmann N,Liu D,Kramer J,et al.High-Sensitivity Troponin:A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease[J].J Am Heart Assoc,2016,5(6):e002839.
[20]Kramer J,Bijnens B,Stork S,et al.Left Ventricular Geometry and Blood Pressure as Predictors of Adverse Progression of Fabry Cardiomyopathy[J].PLoS One,2015,10(11):e0140627.
[21]Coats CJ,Parisi V,Ramos M,et al.Role of serum N-terminal pro-brain natriuretic peptide measurement in diagnosis of cardiac involvement in patients with anderson-fabry disease[J].Am JCardiol,2013,111(1):111-117.
[22]Feustel A,Hahn A,Schneider C,et al.Continuous cardiac troponin I release in Fabry disease[J].PLoS One,2014,9(3):e91757.
[23]Chen KH,Chien Y,Wang KL,et al.Evaluation of Proinflammatory Prognostic Biomarkers for Fabry Cardiomyopathy with Enzyme Replacement Therapy[J].Can J Cardiol,2016,32(10):1221-1229.
[24]Kaneski CR,Moore DF,Ries M,et al.Myeloperoxidase predicts risk of vasculopathic events in hemizgygous males with Fabry disease[J].Neurology,2006,67(11):2045-2047.
[25]陈后勤,吕秋石,何敏,等.急性腔隙性脑梗死患者慢性肾功能不全与脑微出血的相关性研究[J].医学研究生学报,2017,30(3):294-297.
[26]王晓妮,盛灿,韩璎.主观认知下降生物标记物研究进展[J].医学研究生学报,2015,28(4):423-426.
[27]Shu L,Vivekanandan-Giri A,Pennathur S,et al.Establishing 3-nitrotyrosine as a biomarker for the vasculopathy of Fabry disease[J].Kidney Int,2014,86(1):58-66.
[2]Young E,Mills K,Morris P,et al.Is globotriaosylceramide a useful biomarker in Fabry disease?[J]Acta Paediatr Suppl,2005,94(447):51-54.
[3]Togawa T,Kodama T,Suzuki T,et al.Plasma globotriaosylsphingosine as a biomarker of Fabry disease[J].Mol Genet Metab,2010,100(3):257-261.
[4]Aerts JM,Groener JE,Kuiper S,et al.Elevated globotriaosylsphingosine is a hallmark of Fabry disease[J].Proc Natl Acad Sci USA,2008,105(8):2812-2817.
[5]Ferreira S,Auray-Blais C,Boutin M,et al.Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma[J].Clin Chim Acta,2015,447:96-104.
[6]Niemann M,Rolfs A,St?rk S.Gene Mutations Versus Clinically Relevant Phenotypes Lyso-Gb3 Defines Fabry Disease[J].Circ Cardiovasc Genet,2014,7(1):8-16.
[7]Van Breemen MJ,Rombach SM,Dekker N.Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy[J].Biochim Biophys Acta,2011,1812(1):70-76.
[8]Skrunes R,Tondel C,Leh S,et al.Long-term dose-dependent agalsidase effects on kidney histology in fabry disease[J].Clin JAm Soc Nephrol,2017,12(9):1470-1479.
[9]Auray-Blais C,Ntwari A,Clarke JT,et al.How well does urinary lyso-Gb3 function as a biomarker in Fabry disease[J]?Clin Chim Acta,2010,411(23-24):1906-1914.
[10]West M,Nicholls K,Mehta A,et al.Agalsidase alfa and kidney dysfunction in Fabry disease[J].J Am Soc Nephrol,2009,20(5):1132-1139.
[11]Torralba-Cabeza MA,Olivera S,Hughes DA,et al.Cystatin Cand NT-proBNP as prognostic biomarkers in Fabry disease[J].Mol Genet Metab,2011,104(3):301-307.
[12]侯庆,陈朝红.斑马鱼在足细胞研究中的应用及其进展[J].医学研究生学报,2016,29(9):976-981.
[13]Takahashi N,Yokoi S,Kasuno K,et al.A heterozygous female with Fabry disease due to a novel alpha-galactosidase A mutation exhibits a unique synaptopodin distribution in vacuolated podocytes[J].Clin Nephrol,2015,83(5):301-308.
[14]Greka A,Mundel P.Cell biology and pathology of podocytes[J].Annu Rev Physiol,2012,74:299-323.
[15]Trimarchi H.Podocyturia:What is in a name?[J]J Transl Int Med,2015,3(2):51-56.
[16]Trimarchi H,Canzonieri R,Schiel A,et al.Podocyturia is signi ficantly elevated in untreated vs.treated Fabry adult patients[J].J Nephrol,2016,29(6):791-797.
[17]Branton MH,Schiffmann R,Sabnis SG,et al.Natural history of Fabry renal disease:influence of alpha-galactosidase A activity and genetic mutations on clinical course[J].Medicine,2002,81(2):122-138.
[18]Lepedda AJ,Fancellu L,Zinellu E,et al.Urine bikunin as a marker of renal impairment in Fabry’s disease[J].Biomed Res Int,2013,2013:205948.
[19]Seydelmann N,Liu D,Kramer J,et al.High-Sensitivity Troponin:A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease[J].J Am Heart Assoc,2016,5(6):e002839.
[20]Kramer J,Bijnens B,Stork S,et al.Left Ventricular Geometry and Blood Pressure as Predictors of Adverse Progression of Fabry Cardiomyopathy[J].PLoS One,2015,10(11):e0140627.
[21]Coats CJ,Parisi V,Ramos M,et al.Role of serum N-terminal pro-brain natriuretic peptide measurement in diagnosis of cardiac involvement in patients with anderson-fabry disease[J].Am JCardiol,2013,111(1):111-117.
[22]Feustel A,Hahn A,Schneider C,et al.Continuous cardiac troponin I release in Fabry disease[J].PLoS One,2014,9(3):e91757.
[23]Chen KH,Chien Y,Wang KL,et al.Evaluation of Proinflammatory Prognostic Biomarkers for Fabry Cardiomyopathy with Enzyme Replacement Therapy[J].Can J Cardiol,2016,32(10):1221-1229.
[24]Kaneski CR,Moore DF,Ries M,et al.Myeloperoxidase predicts risk of vasculopathic events in hemizgygous males with Fabry disease[J].Neurology,2006,67(11):2045-2047.
[25]陈后勤,吕秋石,何敏,等.急性腔隙性脑梗死患者慢性肾功能不全与脑微出血的相关性研究[J].医学研究生学报,2017,30(3):294-297.
[26]王晓妮,盛灿,韩璎.主观认知下降生物标记物研究进展[J].医学研究生学报,2015,28(4):423-426.
[27]Shu L,Vivekanandan-Giri A,Pennathur S,et al.Establishing 3-nitrotyrosine as a biomarker for the vasculopathy of Fabry disease[J].Kidney Int,2014,86(1):58-66.