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New Advances for Newborn Screening of Inborn Errors of Metabolism by Capillary Electrophoresis-Mass Spectrometry (CE-MS)

  • Meera Shanmuganathan
  • Philip Britz-McKibbinEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1972)

Abstract

Expanded newborn screening of inborn errors of metabolism (IEM) based on tandem mass spectrometry (MS/MS) technology is one of the most successful preventative healthcare initiatives for presymptomatic diagnosis and treatment of rare yet treatable genetic diseases in the population. However, confirmatory testing of presumptive screen-positive cases is required using high efficiency separations for improved specificity in order to improve the positive predictive value (PPV) for certain classes of IEMs. Here, we describe recent advances using capillary electrophoresis-mass spectrometry (CE-MS) for reliable second-tier screening or confirmatory testing based on targeted analysis of amino acids, acylcarnitines, nucleosides, and other classes of polar metabolites associated with IEMs. Additionally, nontargeted metabolite profiling enables the identification of unknown biomarkers of clinical significance for other genetic diseases that are currently screened by bioassays and/or mutation panels, such as cystic fibrosis (CF). Noteworthy, CE-MS allows for resolution of isobaric/isomeric interferences without complicated sample handling that is ideal when analyzing volume-restricted biospecimens from neonates/infants, including dried blood spots and sweat specimens. New developments to improve concentration sensitivity, as well as enhance sample throughput and quality control for unambiguous confirmatory testing of IEMs will also be discussed when using multiplexed separations based on multisegment injection-CE-MS.

Key words

Newborn screening Inborn errors of metabolism Capillary electrophoresis Mass spectrometry Metabolomics Dried blood spots Amino acids Acylcarnitines Cystic fibrosis 

Notes

Acknowledgements

The author wishes to acknowledge funding support from National Science and Engineering Research Council of Canada, Cystic Fibrosis Canada, and Genome Canada.

References

  1. 1.
    Levy PA (2010) An overview of newborn screening. J Dev Behav Pediat 31:622–631CrossRefGoogle Scholar
  2. 2.
    Chace DH (2009) Mass spectrometry in newborn and metabolic screening: historical perspective and future directions. J Mass Spectrom 44:163–170CrossRefGoogle Scholar
  3. 3.
    Sweetman L (2010) Newborn screening by tandem mass spectrometry. Clin Chem 47:1937–1938Google Scholar
  4. 4.
    Zytkovicz TH et al (2001) Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots. Clin Chem 47:1945–1955PubMedGoogle Scholar
  5. 5.
    Wilcken B et al (2009) Expanded newborn screening: outcome in screened and unscreened patients at age 6 years. Pediatrics 124:e241–e248CrossRefGoogle Scholar
  6. 6.
    American College of Medical Genetics Newborn Screening Expert Group (2006) Newborn screening: toward a uniform screening panel and system--executive summary. Pediatrics 117:S296–S307CrossRefGoogle Scholar
  7. 7.
    Burlina AB et al (2018) Newborn screening for lysosomal storage disorders by tandem mass spectrometry in North East Italy. J Inhert Metabol Dis 41:209–219CrossRefGoogle Scholar
  8. 8.
    Ia Marca G et al (2013) Tandem mass spectrometry, but not T-cell receptor excision circle analysis, identifies newborns with late-onset adenosine deaminase deficiency. J Allergy Clin Immunol 131:1604–1610CrossRefGoogle Scholar
  9. 9.
    Ia Marca G et al (2013) Diagnosis of immunodeficiency caused by a purine nucleoside phosphorylase defect by using tandem mass spectrometry on dried blood spots. J Allergy Clin Immunol 131:1604–1610CrossRefGoogle Scholar
  10. 10.
    Gurian EA et al (2006) Expanded newborn screening for biochemical disorders: the effect of a false-positive result. Pediatrics 117:915–1921CrossRefGoogle Scholar
  11. 11.
    Tarini BA, Christakis DA, Welch HG (2006) State newborn screening in the tandem mass spectrometry era: more tests, more false-positive results. Pediatrics 117:448–456CrossRefGoogle Scholar
  12. 12.
    Lehotay DC et al (2011) LC-MS/MS progress in newborn screening. Clin Biochem 44:21–31CrossRefGoogle Scholar
  13. 13.
    Minkler PE et al (2015) Quantitative acylcarnitine determination by UPLC-MS/MS—going beyond tandem MS acylcarnitine “profiles”. Mol Genet Metabol 116:231–241CrossRefGoogle Scholar
  14. 14.
    Seo JY et al (2014) Steroid profiling for congenital adrenal hyperplasia by tandem mass spectrometry as a second-tier test reduces follow-up burdens in a tertiary care hospital: a retrospective and prospective evaluation. J Perinat Med 42:121–127CrossRefGoogle Scholar
  15. 15.
    Kuehnbaum NL et al (2013) New advances in separation science for metabolomics: resolving chemical diversity in a post-genomic era. Chem Rev 113:2437–2468CrossRefGoogle Scholar
  16. 16.
    Miller JH 4th et al (2012) A quantitative method for acylcarnitines and amino acids using high resolution chromatography and tandem mass spectrometry in newborn screening dried blood spot analysis. J Chromatogr B 903:142–149CrossRefGoogle Scholar
  17. 17.
    Roy C et al (2016) Quantitative analysis of amino acids and acylcarnitines combined with untargeted metabolomics using ultra-high performance liquid chromatography and quadrupole time-of-flight mass spectrometry. J Chromatogr B 1027:40–49CrossRefGoogle Scholar
  18. 18.
    Farez-Vidal ME et al (2008) Multi-mutational analysis of fifteen common mutations of the glucose 6-phosphate dehydrogenase gene in the Mediterranean population. Clin Chim Acta 395:94–98CrossRefGoogle Scholar
  19. 19.
    Suksangpleng T et al (2017) A novel system for newborn screening of thalassemia and hemoglobinopathies using capillary electrophoresis is superior than isoelectric focusing. Blood 130:2089Google Scholar
  20. 20.
    Klingenberg O et al (2017) HbA1c analysis by capillary electrophoresis – comparison with chromatography and an immunological method. Scand J Clin Lab Invest 77:458–464CrossRefGoogle Scholar
  21. 21.
    Barbas C et al (2002) Evaluation of filter paper collection of urine samples for detection and measurement of organic acidurias by capillary electrophoresis. J Chromatogr B 780:73–82CrossRefGoogle Scholar
  22. 22.
    Boulat O et al (2001) Separation of free amino acids in human plasma by capillary electrophoresis with laser induced fluorescence: potential for emergency diagnosis of inborn errors of metabolism. J Chromatogr B 754:217–228CrossRefGoogle Scholar
  23. 23.
    Lochman P et al (2003) High-throughput capillary electrophoretic method for determination of total aminothiols in plasma and urine. Electrophoresis 24:1200–1207CrossRefGoogle Scholar
  24. 24.
    Vernez L, Thormann W, Krahenbuhl S (2000) Analysis of carnitine and acylcarnitines in urine by capillary electrophoresis. J Chromatogr A 895:309–316CrossRefGoogle Scholar
  25. 25.
    Friedecky D, Adam T, Bartak P (2002) Capillary electrophoresis for detection of inherited disorders of purine and pyrimidine metabolism: a selective approach. Electrophoresis 23:565–571CrossRefGoogle Scholar
  26. 26.
    Senk P, Kozak L, Foret F (2004) Capillary electrophoresis and mass spectrometry for screening of metabolic disorders in newborns. Electrophoresis 25:1447–1456CrossRefGoogle Scholar
  27. 27.
    Ramautar R et al (2017) CE-MS for metabolomics: developments and applications in the period 2014-2016. Electrophoresis 38:190–202CrossRefGoogle Scholar
  28. 28.
    Lindenburg PW et al (2014) Capillary electrophoresis-mass spectrometry using a flow-through microvial interface for cationic metabolome analysis. Electrophoresis 35:1308–1314CrossRefGoogle Scholar
  29. 29.
    Hirayama A et al (2012) Sheathless capillary electrophoresis-mass spectrometry with a high sensitivity porous sprayer for cationic metabolome analysis. Analyst 137:5026–5033CrossRefGoogle Scholar
  30. 30.
    Peuchen EH et al (2017) Evaluation of a commercial electrokinetically pumped sheath-flow nanospray coupled to an automated capillary zone electrophoresis system. Anal Bioanal Chem 409:1789–1795CrossRefGoogle Scholar
  31. 31.
    Kuehnbaum NL et al (2013) Multisegment injection-capillary electrophoresis-mass spectrometry: a high throughput method for metabolomics with high data fidelity. Anal Chem 85:10664–10669CrossRefGoogle Scholar
  32. 32.
    Hirayama A et al (2012) Amino acid analysis by capillary electrophoresis-mass spectrometry. Methods Mol Biol 828:77–82CrossRefGoogle Scholar
  33. 33.
    Prior A et al (2016) Enantioselective capillary electrophoresis-mass spectrometry of amino acids in cerebrospinal fluid using a chiral derivatizing agent and volatile surfactant. Anal Chim Acta 940:150–158CrossRefGoogle Scholar
  34. 34.
    Lee J et al (2015) Rapid diagnosis of metabolic disorders based on a achiral separation by gas chromatography with a dual column. Anal Lett 48:231–240CrossRefGoogle Scholar
  35. 35.
    Jeong JS et al (2013) Amino acid analysis of dried blood spots for diagnosis of phenylketonuria using capillary electrophoresis-mass spectrometry equipped with a sheathless electrospray ionization interface. Anal Bioanal Chem 405:8063–8072CrossRefGoogle Scholar
  36. 36.
    Chalcraft KR, Britz-McKibbin P (2009) Newborn screening of inborn errors of metabolism by CE-ESI-MS: a second-tier method with improved specificity and sensitivity. Anal Chem 81:307–314CrossRefGoogle Scholar
  37. 37.
    Lee R, Niewzcas L, Britz-McKibbin P (2007) Integrative metabolomics for characterizing unknown low-abundance metabolites by capillary electrophoresis-mass spectrometry with computer simulations. Anal Chem 79:403–415CrossRefGoogle Scholar
  38. 38.
    Oglesbee D et al (2008) Second-tier test for quantification for alloisoleucine and branched-chain amino acids in dried blood spots to improve newborn screening for maple syrup urine disease. Clin Chem 54:542–549CrossRefGoogle Scholar
  39. 39.
    DiBattista A et al (2017) Temporal signal pattern recognition in mass spectrometry: a method for rapid identification and accurate quantification of biomarkers for inborn errors of metabolism with quality assurance. Anal Chem 89:8112–8121CrossRefGoogle Scholar
  40. 40.
    Nori de Macedo A et al (2017) Characterization of the sweat metabolome in screen-positive cystic fibrosis infants: revealing mechanisms beyond impaired chloride transport. ACS Cent Sci 3:904–914CrossRefGoogle Scholar
  41. 41.
    DiBattista A et al (2018) Metabolic signatures of cystic fibrosis identified in dried blood spots for newborn screening without carrier identification. J Proteome Res. https://doi.org/10.1021/acs.jproteome.8b00351
  42. 42.
    Chalcraft KR et al (2009) Virtual quantification of metabolites by capillary electrophoresis-electrospray ionization-mass spectrometry: predicting ionization efficiency without chemical standards. Anal Chem 81:2506–2515CrossRefGoogle Scholar
  43. 43.
    Gan-Schreier H et al (2010) Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. J Pediatr 156:427–432CrossRefGoogle Scholar
  44. 44.
    D'Agostino LA et al (2011) Comprehensive plasma thiol redox status determination for metabolomics. J Proteome Res 10:592–603CrossRefGoogle Scholar
  45. 45.
    Yamamoto M et al (2016) Robust and high throughput method for anionic metabolite profiling: preventing polyimide aminolysis and capillary fractures in capillary electrophoresis-mass spectrometry. Anal Chem 88:10710–10719CrossRefGoogle Scholar
  46. 46.
    Lee R, Britz-McKibbin P (2009) Differential rates of glutathione oxidation for assessment of cellular redox status and antioxidant capacity by capillary electrophoresis-mass spectrometry: an elusive biomarker of oxidative stress. Anal Chem 81:7047–7056CrossRefGoogle Scholar
  47. 47.
    Azab S, Ly R, Britz-McKibbin P (2018) A Robust Method for High Throughput Screening of Fatty Acids by Multisegment Injection-Nonaqueous Capillary Electrophoresis-Mass Spectrometry with Stringent Quality Control. Anal. Chem. https://doi.org/10.1021/acs.analchem.8b05054.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Chemistry and Chemical BiologyMcMaster UniversityHamiltonCanada

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