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Journal of Inherited Metabolic Disease

, Volume 39, Issue 1, pp 131–137 | Cite as

N8-acetylspermidine as a potential plasma biomarker for Snyder-Robinson syndrome identified by clinical metabolomics

  • Lucia Abela
  • Luke Simmons
  • Katharina Steindl
  • Bernhard Schmitt
  • Massimo Mastrangelo
  • Pascal Joset
  • Mihaela Papuc
  • Heinrich Sticht
  • Alessandra Baumer
  • Lisa M. Crowther
  • Déborah Mathis
  • Anita Rauch
  • Barbara PleckoEmail author
Original Article

Abstract

Clinical metabolomics has emerged as a powerful tool to study human metabolism in health and disease. Comparative statistical analysis of untargeted metabolic profiles can reveal perturbations of metabolite levels in diseases and thus has the potential to identify novel biomarkers. Here we have applied a simultaneous genetic-metabolomic approach in twin boys with epileptic encephalopathy of unclear etiology. Clinical exome sequencing identified a novel missense mutation in the spermine synthase gene (SMS) that causes Snyder-Robinson syndrome (SRS). Untargeted plasma metabolome analysis revealed significantly elevated levels of N8-acetylspermidine, a precursor derivative of spermine biosynthesis, as a potential novel plasma biomarker for SRS. This result was verified in a third patient with genetically confirmed SRS. This study illustrates the potential of metabolomics as a translational technique to support exome data on a functional and clinical level.

Keywords

Spermine Spermidine Myoclonic Jerk HFBA Clinical Exome Sequencing 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank Annegret Flier and Joern Oliver Sass for establishing lymphoblast cultures of the twin patients.

Compliance with ethic guidelines

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.

Conflict of interests

None.

Informed consent

Consent was obtained from all patients or their legal guardians for being included in the study.

Supplementary material

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References

  1. Arena JF, Schwartz C, Ouzts L et al (1996) X-linked mental retardation with thin habitus, osteoporosis, and kyphoscoliosis: linkage to Xp21.3-p22.12. Am J Med Genet 64(1):50–58PubMedCrossRefGoogle Scholar
  2. Becerra-Solano LE, Butler J, Castaneda-Cisneros G et al (2009) A missense mutation, p.V132G, in the X-linked spermine synthase gene (SMS) causes Snyder-Robinson syndrome. Am J Med Genet A 149A(3):328–335PubMedPubMedCentralCrossRefGoogle Scholar
  3. Cason AL, Ikeguchi Y, Skinner C et al (2003) X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome. Eur J Hum Genet 11(12):937–944PubMedCrossRefGoogle Scholar
  4. Chace DH (2001) Mass spectrometry in the clinical laboratory. Chem Rev 101(2):445–477PubMedCrossRefGoogle Scholar
  5. de Alencastro G, McCloskey DE, Kliemann SE et al (2008) New SMS mutation leads to a striking reduction in spermine synthase protein function and a severe form of Snyder-Robinson X-linked recessive mental retardation syndrome. J Med Genet 45(8):539–543PubMedCrossRefGoogle Scholar
  6. Fleidervish IA, Libman L, Katz E, Gutnick MJ (2008) Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na+ channels. Proc Natl Acad Sci U S A 105(48):18994–18999PubMedPubMedCentralCrossRefGoogle Scholar
  7. Gaude E, Chignola F, Spiliotopoulos S et al (2013) muma, An R package for metabolomics univariate and multivariate statistical analysis. Curr Metabol 1(2):180–189, 110 CrossRefGoogle Scholar
  8. Igarashi K, Kashiwagi K (2010) Modulation of cellular function by polyamines. Int J Biochem Cell Biol 42(1):39–51PubMedCrossRefGoogle Scholar
  9. Kesler SR, Schwartz C, Stevenson RE, Reiss AL (2009) The impact of spermine synthase (SMS) mutations on brain morphology. Neurogenetics 10(4):299–305PubMedPubMedCentralCrossRefGoogle Scholar
  10. Kuhl C, Tautenhahn R, Bottcher C, Larson TR, Neumann S (2012) CAMERA: an integrated strategy for compound spectra extraction and annotation of liquid chromatography/mass spectrometry data sets. Anal Chem 84(1):283–289PubMedPubMedCentralCrossRefGoogle Scholar
  11. Lau AW, Brown CJ, Penaherrera M, Langlois S, Kalousek DK, Robinson WP (1997) Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicism. Am J Hum Genet 61(6):1353–1361PubMedPubMedCentralCrossRefGoogle Scholar
  12. Moco S, Collino S, Rezzi S, Martin FP (2013) Metabolomics perspectives in pediatric research. Pediatr Res 73(4 Pt 2):570–576PubMedCrossRefGoogle Scholar
  13. Patti GJ, Yanes O, Siuzdak G (2012) Innovation: metabolomics: the apogee of the omics trilogy. Nat Rev Mol Cell Biol 13(4):263–269PubMedPubMedCentralCrossRefGoogle Scholar
  14. Pegg AE (2009) Mammalian polyamine metabolism and function. IUBMB Life 61(9):880–894PubMedPubMedCentralCrossRefGoogle Scholar
  15. Pegg AE (2014) The function of spermine. IUBMB Life 66(1):8–18PubMedCrossRefGoogle Scholar
  16. Pegg AE, Michael AJ (2010) Spermine synthase. Cell Mol Life Sci 67(1):113–121PubMedPubMedCentralCrossRefGoogle Scholar
  17. Peron A, Spaccini L, Norris J et al (2013) Snyder-Robinson syndrome: a novel nonsense mutation in spermine synthase and expansion of the phenotype. Am J Med Genet A 161A(9):2316–2320PubMedCrossRefGoogle Scholar
  18. Schwender H, Ickstadt K (2008) Empirical Bayes analysis of single nucleotide polymorphisms. BMC Bioinformat 9:144CrossRefGoogle Scholar
  19. Shlomi T, Cabili MN, Ruppin E (2009) Predicting metabolic biomarkers of human inborn errors of metabolism. Mol Syst Biol 5:263PubMedPubMedCentralCrossRefGoogle Scholar
  20. SidAhmed-Mezi M, Pumain R, Louvel J, Sokoloff P, Laschet J (2010) New therapeutic targets to develop molecules active in drug-resistant epilepsies. Epilepsia 51(Suppl 3):43–47PubMedCrossRefGoogle Scholar
  21. Smith CA, O’Maille G, Want EJ et al (2005) METLIN — A metabolite mass spectral database. Ther Drug Monit 27(6):747–751PubMedCrossRefGoogle Scholar
  22. Smith CA, Want EJ, O’Maille G, Abagyan R, Siuzdak G (2006) XCMS: processing mass spectrometry data for metabolite profiling using nonlinear peak alignment, matching, and identification. Anal Chem 78(3):779–787PubMedCrossRefGoogle Scholar
  23. Snyder RD, Robinson A (1969) Recessive sex-linked mental retardation in the absence of other recognizable abnormalities. Report of a family. Clin Pediatr (Phila) 8(11):669–674CrossRefGoogle Scholar
  24. Sowell J, Norris J, Jones K, Schwartz C, Wood T (2011) Diagnostic screening for spermine synthase deficiency by liquid chromatography tandem mass spectrometry. Clin Chim Acta 412(7–8):655–660PubMedCrossRefGoogle Scholar
  25. Stojanovic I, Jelenkovic A, Stevanovic I, Pavlovic D, Bjelakovic G, Jevtovic-Stoimenov T (2010) Spermidine influence on the nitric oxide synthase and arginase activity relationship during experimentally induced seizures. J Basic Clin Physiol Pharmacol 21(2):169–185PubMedCrossRefGoogle Scholar
  26. Tautenhahn R, Bottcher C, Neumann S (2008) Highly sensitive feature detection for high resolution LC/MS. BMC Bioinformat 9:504CrossRefGoogle Scholar
  27. Wang X, Levic S, Gratton MA, Doyle KJ, Yamoah EN, Pegg AE (2009) Spermine synthase deficiency leads to deafness and a profound sensitivity to alpha-difluoromethylornithine. J Biol Chem 284(2):930–937PubMedPubMedCentralCrossRefGoogle Scholar
  28. Wikoff WR, Gangoiti JA, Barshop BA, Siuzdak G (2007) Metabolomics identifies perturbations in human disorders of propionate metabolism. Clin Chem 53(12):2169–2176PubMedCrossRefGoogle Scholar
  29. Yamamoto T, Hinoi E, Fujita H et al (2012) The natural polyamines spermidine and spermine prevent bone loss through preferential disruption of osteoclastic activation in ovariectomized mice. Br J Pharmacol 166(3):1084–1096PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© SSIEM 2015

Authors and Affiliations

  • Lucia Abela
    • 1
    • 2
    • 3
  • Luke Simmons
    • 1
    • 2
    • 3
  • Katharina Steindl
    • 3
    • 4
  • Bernhard Schmitt
    • 3
    • 5
  • Massimo Mastrangelo
    • 6
  • Pascal Joset
    • 3
    • 4
  • Mihaela Papuc
    • 3
    • 4
  • Heinrich Sticht
    • 7
  • Alessandra Baumer
    • 4
  • Lisa M. Crowther
    • 1
    • 2
    • 3
  • Déborah Mathis
    • 8
  • Anita Rauch
    • 3
    • 4
  • Barbara Plecko
    • 1
    • 2
    • 3
    Email author
  1. 1.Division of Child NeurologyUniversity Children’s Hospital ZurichZurichSwitzerland
  2. 2.Children’s Research CentreUniversity Children’s Hospital ZurichZurichSwitzerland
  3. 3.Radiz–Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare DiseasesUniversity of ZurichZurichSwitzerland
  4. 4.Institute of Medical GeneticsUniversity of ZurichSchlierenSwitzerland
  5. 5.Division of Epilepsy and NeurophysiologyUniversity Children’s Hospital ZurichZurichSwitzerland
  6. 6.Pediatric Neurology UnitV. Buzzi Children’s Hospital, ICPMilanItaly
  7. 7.Institute for BiochemistryUniversity of Erlangen-NuernbergErlangenGermany
  8. 8.Division of Clinical Chemistry and BiochemistryUniversity Children’s Hospital ZurichZurichSwitzerland

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