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Advances in analytical mass spectrometry to improve screening for inherited metabolic diseases

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Abstract

Gas chromatography/mass spectrometry became available more than 30 years ago and has subsequently profoundly contributed not only in the identification of a wide range of inborn errors but also as a key tool for clinical diagnostic screening of genetic metabolic disease. Due to extraordinary advances in liquid chromatography and mass spectrometry (MS) developed in the last decade, the utilisation of MS and the potential number of applications for the purpose of metabolic screening is currently undergoing considerable expansion. Conclusion: This overview aims to describe only current new developments in clinically most relevant applications, in particular with focus on low molecular weight compounds.

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Abbreviations

CAH :

congenital adrenal hyperplasia

CDG :

congenital disorders of glycosylation

ESI :

electrospray ionisation

GC/MS :

gas chromatography/mass spectrometry

IEM :

inborn errors of metabolism

LC :

liquid chromatography

MALDI-TOF :

matrix-assisted laser desorption/ionisation time-of-flight

MS :

mass spectrometry

MS/MS :

tandem mass spectrometry

3-MCC :

3-methylcrotonyl-CoA carboxylase

NBS :

newborn screening

17OHP :

17-hydroxyprogesterone

PKU :

phenylketonuria

SLO :

Smith-Lemli-Opitz

References

  1. Almeida AM, Henthorn JS, Davies SC (2001) Neonatal screening for haemoglobinopathies: the results of a 10-year programme in an English Health Region. Br J Haematol 112: 32–35

    Article  CAS  PubMed  Google Scholar 

  2. Amirkhani A, Heldin E, Markides KE, Bergquist J (2002) Quantitation of tryptophan, kynurenine and kynurenic acid in human plasma by capillary liquid chromatography-electrospray ionization tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 780: 381–387

    Article  CAS  PubMed  Google Scholar 

  3. Bodamer OA, Bloesch SM, Gregg AR, Stöckler-Ipsiroglu S, O’Brien WE (2001) Analysis of guanidinoacetate and creatine by isotope dilution electrospray tandem mass spectrometry. Clin Chim Acta 308: 173–178

    Article  CAS  PubMed  Google Scholar 

  4. Carpenter KH, Wiley V (2002) Application of tandem mass spectrometry to biochemical genetics and newborn screening. Clin Chim Acta 322: 1–10

    Article  CAS  PubMed  Google Scholar 

  5. Chace DH, Millington DS, Terada N, Kahler SG, Roe CR, Hofman LF (1993) Rapid diagnosis of phenylketonuria by quantitative analysis for phenylalanine and tyrosine in neonatal blood spots by tandem mass spectrometry. Clin Chem 39: 66–71

    Google Scholar 

  6. Chace DH, DiPerna JC, Naylor EW (1999) Laboratory integration and utilization of tandem mass spectrometry in neonatal screening: a model for clinical mass spectrometry in the next millennium. Acta Paediatr Suppl 88: 45–47

    Article  CAS  PubMed  Google Scholar 

  7. Chace DH, DiPerna JC, Mitchell BL, Sgroi B, Hofman LF, Naylor EW (2001) Electrospray tandem mass spectrometry for analysis of acylcarnitines in dried postmortem blood specimens collected at autopsy from infants with unexplained cause of death. Clin Chem 47: 1166–1182

    CAS  PubMed  Google Scholar 

  8. Dalluge JJ (2002) Mass spectrometry: an emerging alternative to traditional methods for measurement of diagnostic proteins, peptides and amino acids. Curr Protein Pept Sci 3: 181–190

    CAS  PubMed  Google Scholar 

  9. Davies SC, Cronin E, Gill M, Greengross P, Hickman M, Normand C (2000) Screening for sickle cell disease and thalassaemia: a systematic review with supplementary research. Health Technol Assess 4: 1–99

    CAS  Google Scholar 

  10. Dell A, Morris HR (2001) Glycoprotein structure determination by mass spectrometry. Science 291: 2351–2356

    Article  CAS  PubMed  Google Scholar 

  11. Ferdinandusse S, Overmars H, Denis S, Waterham HR, Wanders RJ, Vreken P (2001) Plasma analysis of di- and trihydroxycholestanoic acid diastereoisomers in peroxisomal alpha-methylacyl-CoA racemase deficiency. J Lipid Res 42: 137–141

    CAS  PubMed  Google Scholar 

  12. Fingerhut R, Röschinger W, Muntau AC, Dame T, Kreischer J, Arnecke R, Superti-Furga A, Troxler H, Liebl B, Olgemöller B et al (2001) Hepatic carnitine palmitoyltransferase 1 deficiency: acylcarnitine profiles in blood spots are highly specific. Clin Chem 47: 1763–1768

    CAS  PubMed  Google Scholar 

  13. Ford RE, Magera MJ, Kloke KM, Chezick PA, Fauq A, McConnell JP (2001) Quantitative measurement of porphobilinogen in urine by stable-isotope dilution liquid chromatography-tandem mass spectrometry. Clin Chem 47: 1627–1632

    CAS  PubMed  Google Scholar 

  14. Gempel K, Gerbitz KD, Casetta B, Bauer MF (2000) Rapid determination of total homocysteine in blood spots by liquid chromatography-electrospray ionization-tandem mass spectrometry. Clin Chem 46: 122–123

    CAS  PubMed  Google Scholar 

  15. Gerber SA, Scott CR, Turecek F, Gelb MH (2001) Direct profiling of multiple enzyme activities in human cell lysates by affinity chromatography/electrospray ionization mass spectrometry: application to clinical enzymology. Anal Chem 73: 1651–1657

    Article  CAS  PubMed  Google Scholar 

  16. Gibson KM, Burlingame TG, Hogema B, Jakobs C, Schutgens RB, Millington D, Roe CR, Roe DS, Sweetman L, Steiner RD et al (2000) 2-Methylbutyryl-coenzyme A dehydrogenase deficiency: a new inborn error of L-isoleucine metabolism. Pediatr Res 47: 830–833

    CAS  PubMed  Google Scholar 

  17. Grünewald S, Matthijs G, Jaeken J (2002) Congenital disorders of glycosylation: a review. Pediatr Res 52: 618–624

    Article  PubMed  Google Scholar 

  18. Harms E, Roscher AA, Grüters A, Heinrich U, Genzel-Boroviczény O, Rossi R, Schulze A, Zabransky S (2002) Neue Screening-Richtlinien. Monatsschr Kinderheilkd 150: 1424–1429

    Article  Google Scholar 

  19. Holzinger A, Röschinger W, Lagler F, Mayerhofer PU, Lichtner P, Kattenfeld T, Thuy LP, Nyhan WL, Koch HG, Muntau AC et al (2001) Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA carboxylase deficiency. Hum Mol Genet 10: 1299–1306

    Article  CAS  PubMed  Google Scholar 

  20. Ito T, van Kuilenburg AB, Bootsma AH, Haasnoot AJ, van Cruchten A, Wada Y, van Gennip AH (2000) Rapid screening of high-risk patients for disorders of purine and pyrimidine metabolism using HPLC-electrospray tandem mass spectrometry of liquid urine or urine-soaked filter paper strips. Clin Chem 46: 445–452

    CAS  PubMed  Google Scholar 

  21. Jensen UG, Brandt NJ, Christensen E, Skovby F, Norgaard-Pedersen B, Simonsen H (2001) Neonatal screening for galactosemia by quantitative analysis of hexose monophosphates using tandem mass spectrometry: a retrospective study. Clin Chem 47: 1364–1372

    CAS  PubMed  Google Scholar 

  22. Johnson DW (2000) A rapid screening procedure for the diagnosis of peroxisomal disorders: quantification of very long-chain fatty acids, as dimethylaminoethyl esters, in plasma and blood spots, by electrospray tandem mass spectrometry. J Inherit Metab Dis 23: 475–486

    Article  CAS  PubMed  Google Scholar 

  23. Johnson DW, ten Brink HJ, Schuit RC, Jakobs C (2001) Rapid and quantitative analysis of unconjugated C(27) bile acids in plasma and blood samples by tandem mass spectrometry. J Lipid Res 42: 9–16

    CAS  PubMed  Google Scholar 

  24. Johnson DW, ten Brink HJ, Jakobs C (2001) A rapid screening procedure for cholesterol and dehydrocholesterol by electrospray ionization tandem mass spectrometry. J Lipid Res 42: 1699–1705

    CAS  PubMed  Google Scholar 

  25. Kao PC, Machacek DA, Magera MJ, Lacey JM, Rinaldo P (2001) Diagnosis of adrenal cortical dysfunction by liquid chromatography-tandem mass spectrometry. Ann Clin Lab Sci 31: 199–204

    CAS  PubMed  Google Scholar 

  26. Kiernan UA, Black JA, Williams P, Nelson RW (2002) High-throughput analysis of hemoglobin from neonates using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Clin Chem 48: 947–949

    CAS  PubMed  Google Scholar 

  27. Kishi N, Mano N, Asakawa N (2001) Direct injection method for quantitation of endogenous leukotriene E4 in human urine by liquid chromatography/electrospray ionization tandem mass spectrometry with a column-switching technique. Anal Sci 17: 709–713

    CAS  PubMed  Google Scholar 

  28. Kushnir MM, Urry FM, Frank EL, Roberts WL, Shushan B (2002) Analysis of catecholamines in urine by positive-ion electrospray tandem mass spectrometry. Clin Chem 48: 323–331

    CAS  PubMed  Google Scholar 

  29. Lacey JM, Magera MJ, Matern D, O’Brien JF (2000) A method for the determination of transferrin isoforms by liquid chromatography-mass spectrometry. J Inherit Metab Dis 23[Suppl 1]: 179

  30. Lai CC, Tsai CH, Tsai FJ, Wu JY, Lin WD, Lee CC (2002) Monitoring of congenital adrenal hyperplasia by microbore HPLC-electrospray ionization tandem mass spectrometry of dried blood spots. Clin Chem 48: 354–356

    CAS  PubMed  Google Scholar 

  31. Leushner J (2001) MALDI TOF mass spectrometry: an emerging platform for genomics and diagnostics. Expert Rev Mol Diagn 1: 11–18

    CAS  PubMed  Google Scholar 

  32. Levy HL, Albers S (2000) Genetic screening of newborns. Annu Rev Genomics Hum Genet 1: 139–177

    Article  CAS  PubMed  Google Scholar 

  33. Li Y, Ogata Y, Freeze HH, Scott CR, Turecek F, Gelb MH (2003) Affinity capture and elution/electrospray ionization mass spectrometry assay of phosphomannomutase and phosphomannose isomerase for the multiplex analysis of congenital disorders of glycosylation types Ia and Ib. Anal Chem 75: 42–48

    Article  CAS  PubMed  Google Scholar 

  34. Liebl B, von Kries R, Nennstiel-Ratzel U, Muntau AC, Röschinger W, Olgemöller B, Zapf A, Roscher AA (2001) Ethical and legal aspects in newborn screening. Monatsschr Kinderheilkd 149: 1326–1335

    Article  Google Scholar 

  35. Lindgren JA, Hokfelt T, Dahlen SE, Patrono C, Samuelsson B (1984) Leukotrienes in the rat central nervous system. Proc Natl Acad Sci U S A 81: 6212–6216

    CAS  PubMed  Google Scholar 

  36. Magera MJ, Lacey JM, Casetta B, Rinaldo P (1999) Method for the determination of total homocysteine in plasma and urine by stable isotope dilution and electrospray tandem mass spectrometry. Clin Chem 45: 1517–1522

    CAS  PubMed  Google Scholar 

  37. Magera MJ, Stoor AL, Helgeson JK, Matern D, Rinaldo P (2001) Determination of homovanillic acid in urine by stable isotope dilution and electrospray tandem mass spectrometry. Clin Chim Acta 306: 35–41

    Article  CAS  PubMed  Google Scholar 

  38. Mann M, Hendrickson RC, Pandey A (2001) Analysis of proteins and proteomes by mass spectrometry. Annu Rev Biochem 70: 437–473

    CAS  PubMed  Google Scholar 

  39. Manning NJ, Maloney M, Olpin SE, Pollitt RJ, Bonham JR, Heap SJ, Downing M (2001) Analysis of dicarboxylic-acylcarnitines by electrospray-tandem mass spectrometry (ESI-MSMS) without derivatisation. Implications for neonatal screening and routine diagnosis. J Inherit Metab Dis 24[Suppl 1]: 6

  40. Mayatepek E, Flock B (1998) Leukotriene C4-synthesis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome. Lancet 352: 1514–1517

    Article  CAS  PubMed  Google Scholar 

  41. Martin-Girardeau A, Renou-Gonnord MF (2000) Optimization of a capillary electrophoresis-electrospray mass spectrometry method for the quantitation of the 20 natural amino acids in childrens blood. J Chromatogr B Biomed Sci Appl 742: 163–171

    Article  CAS  PubMed  Google Scholar 

  42. Meikle PJ, Ranieri E, Ravenscroft EM, Hua CT, Brooks DA, Hopwood JJ (1999) Newborn screening for lysosomal storage disorders. Southeast Asian J Trop Med Public Health 30[Suppl 2]: 104–110

  43. Mendes P (2002) Emerging bioinformatics for the metabolome. Brief Bioinform 3: 134–145

    PubMed  Google Scholar 

  44. Millington DS, Roe CR, Maltby DA (1984) Application of high resolution fast atom bombardment and constant B/E ratio linked scanning to the identification and analysis of acylcarnitines in metabolic disease. Biomed Mass Spectrom 11: 236–241

    CAS  PubMed  Google Scholar 

  45. Mills K, Mills PB, Clayton PT, Johnson AW, Whitehouse DB, Winchester BG (2001) Identification of alpha(1)-antitrypsin variants in plasma with the use of proteomic technology. Clin Chem 47: 2012–2022

    CAS  PubMed  Google Scholar 

  46. Moebius FF, Fitzky BU, Glossmann H (2000) Genetic defects in postsqualene cholesterol biosynthesis. Trends Endocrinol Metab 11: 106–114

    Article  CAS  PubMed  Google Scholar 

  47. Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GH, Bromberg IL, Cerone R et al (1985) The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 37: 1–31

    CAS  PubMed  Google Scholar 

  48. Mushtaq I, Logan S, Morris M, Johnson AW, Wade AM, Kelly D, Clayton PT (1999) Screening of newborn infants for cholestatic hepatobiliary disease with tandem mass spectrometry. BMJ 319: 471–477

    CAS  PubMed  Google Scholar 

  49. Naylor EW, Chace DH (1999) Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism. J Child Neurol 14[Suppl 1]: S4–S8

  50. Niehues R, Hasilik M, Alton G, Korner C, Schiebe-Sukumar M, Koch HG, Zimmer KP, Wu R, Harms E, Reiter K et al (1998) Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy. J Clin Invest 101: 1414–1420

    CAS  PubMed  Google Scholar 

  51. Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J (1998) Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr 157[Suppl 2]: S77–S83

  52. Petritis K, Chaimbault P, Elfakir C, Dreux M (2000) Parameter optimization for the analysis of underivatized protein amino acids by liquid chromatography and ionspray tandem mass spectrometry. J Chromatogr A 896: 253–263

    Article  CAS  PubMed  Google Scholar 

  53. Rashed MS, Ozand PT, Bucknall MP, Little D (1995) Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids profiling using automated electrospray tandem mass spectrometry. Pediatr Res 38: 324–331

    CAS  PubMed  Google Scholar 

  54. Roberts NB, Amara AB, Morris M, Green BN (2001) Long-term evaluation of electrospray ionization mass spectrometric analysis of glycated hemoglobin. Clin Chem 47: 316–321

    CAS  PubMed  Google Scholar 

  55. Rohlff C (2001) Proteomics in neuropsychiatric disorders. Int J Neuropsychopharmacol 4: 93–102

    Article  CAS  PubMed  Google Scholar 

  56. Roscher AA, Fingerhut R, Liebl B, Olgemöller B (2002) Expanded newborn screening using tandem mass spectrometry. Monatsschr Kinderheilkd 149: 1297–1303

    Article  Google Scholar 

  57. Rule G, Henion J (1999) High-throughput sample preparation and analysis using 96-well membrane solid-phase extraction and liquid chromatography-tandem mass spectrometry for the determination of steroids in human urine. J Am Soc Mass Spectrom 10: 1322–1327

    Article  CAS  PubMed  Google Scholar 

  58. Santer R, Fingerhut R, Lässker U, Wightman PJ, Fitzpatrick DR, Olgemöller B, Roscher AA (2003) Tandem mass spectrometric determination of malonylcarnitine: diagnosis and neonatal screening of malonyl-CoA decarboxylase deficiency. Clin Chem 49: 660–662

    CAS  PubMed  Google Scholar 

  59. Shigematsu Y, Hata I, Nakai A, Kikawa Y, Sudo M, Tanaka Y, Yamaguchi S, Jakobs C (1996) Prenatal diagnosis of organic acidemias based on amniotic fluid levels of acylcarnitines. Pediatr Res 39: 680–684

    CAS  PubMed  Google Scholar 

  60. Smith WE, Millington DS, Koeberl DD, Lesser PS (2001) Glutaric acidemia, type I, missed by newborn screening in an infant with dystonia following promethazine administration. Pediatrics 107: 1184–1187

    CAS  PubMed  Google Scholar 

  61. Spahr CS, Davis MT, McGinley MD, Robinson JH, Bures EJ, Beierle J, Mort J, Courchesne PL, Chen K, Wahl RC et al (2001) Towards defining the urinary proteome using liquid chromatography-tandem mass spectrometry. I. Profiling an unfractionated tryptic digest. Proteomics 1: 93–107

    PubMed  Google Scholar 

  62. Stevens RD, Hillman SL, Worthy S, Sanders D, Millington DS (2000) Assay for free and total carnitine in human plasma using tandem mass spectrometry. Clin Chem 46: 727–729

    CAS  PubMed  Google Scholar 

  63. Turecek F (2002) Mass spectrometry in coupling with affinity capture-release and isotope-coded affinity tags for quantitative protein analysis. J Mass Spectrom 37: 1–14

    Article  CAS  PubMed  Google Scholar 

  64. Van Lenthe H, van Kuilenburg AB, Ito T, Bootsma AH, van Cruchten A, Wada Y, van Gennip AH (2000) Defects in pyrimidine degradation identified by HPLC-electrospray tandem mass spectrometry of urine specimens or urine-soaked filter paper strips. Clin Chem 46: 1916–1922

    PubMed  Google Scholar 

  65. Valianpour F, Wanders RJ, Overmars H, Vreken P, Van Gennip AH, Baas F, Plecko B, Santer R, Becker K, Barth PG (2002) Cardiolipin deficiency in X-linked cardioskeletal myopathy and neutropenia (Barth syndrome, MIM 302060): a study in cultured skin fibroblasts. J Pediatr 141: 729–733

    Article  CAS  PubMed  Google Scholar 

  66. Vaz FM, Melegh B, Bene J, Cuebas D, Gage DA, Bootsma A, Vreken P, van Gennip AH, Bieber LL, Wanders RJ (2002) Analysis of carnitine biosynthesis metabolites in urine by HPLC-electrospray tandem mass spectrometry. Clin Chem 48: 826–834

    CAS  PubMed  Google Scholar 

  67. Vreken P, Valianpour F, Overmars H, Barth PG, Selhorst JJ, van Gennip AH, Wanders RJ (2000) Analysis of plasmenylethanolamines using electrospray tandem mass spectrometry and its application in screening for peroxisomal disorders. J Inherit Metab Dis 23: 429–433

    Article  CAS  PubMed  Google Scholar 

  68. Whitfield PD, Sharp P, Johnson D, Taylor R, Fletcher J, Hopwood JJ, Meikle PJ (2000) Rapid diagnosis of lysosomal storage disorders by tandem mass spectrometry. J Inherit Metab Dis 23[Suppl 1]: 19

  69. Whitfield PD, Sharp PC, Johnson DW, Nelson P, Meikle PJ (2001) Characterization of urinary sulfatides in metachromatic leukodystrophy using electrospray ionization-tandem mass spectrometry. Mol Genet Metab 73: 30–37

    Article  CAS  PubMed  Google Scholar 

  70. Wilcken B, Wiley V, Carpenter K (2000) Two years of routine newborn screening by tandem mass spectrometry (MS/MS) in New South Wales, Australia. J Inherit Metab Dis 23[Suppl 1]: 4

  71. Yap S, Naughten E (1998) Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years’ experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inherit Metab Dis 21: 738–747

    Article  PubMed  Google Scholar 

  72. Zimmerman PA, Hercules DM, Naylor EW (1997) Direct analysis of filter paper blood specimens for identification of Smith-Lemli-Opitz syndrome using time-of-flight secondary ion mass spectrometry. Am J Med Genet 68: 300–304

    Article  CAS  PubMed  Google Scholar 

  73. Zschocke J, Ruiter JP, Brand J, Lindner M, Hoffmann GF, Wanders RJ, Mayatepek E (2000) Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: a novel inborn error of branched-chain fatty acid and isoleucine metabolism. Pediatr Res 48: 852–855

    CAS  PubMed  Google Scholar 

  74. Zytkovicz TH, Fitzgerald EF, Marsden D, Larson CA, Shih VE, Johnson DM, Strauss AW, Comeau AM, Eaton RB, Grady GF (2001) Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program. Clin Chem 47: 1945–1955

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Research Center, Department of Biochemical Genetics and Molecular Biology, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University, Lindwurmstrasse 4, 80337, Munich, Germany

    Wulf Röschinger & Adelbert A. Roscher

  2. Laboratory Becker, Olgemöller and Colleagues, Munich, Germany

    Bernhard Olgemöller & Ralph Fingerhut

  3. Public Health Newborn Screening Center of the State of Bavaria, Oberschleißheim, Germany

    Bernhard Liebl

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  1. Wulf Röschinger
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  2. Bernhard Olgemöller
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  3. Ralph Fingerhut
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  4. Bernhard Liebl
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  5. Adelbert A. Roscher
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Correspondence to Wulf Röschinger.

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Röschinger, W., Olgemöller, B., Fingerhut, R. et al. Advances in analytical mass spectrometry to improve screening for inherited metabolic diseases. Eur J Pediatr 162 (Suppl 1), S67–S76 (2003). https://doi.org/10.1007/s00431-003-1356-y

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