Proton NMR Spectroscopy of Body Fluids

  • Udo Engelke
  • Angelina Goudswaard
  • Ron WeversEmail author


The laboratory diagnosis of inherited metabolic diseases cannot always be achieved by analysis of amino acids, organic acids, and other small molecules alone. Often, however, additional investigations also do not lead to the diagnosis while there is a strong suspicion of a metabolic disease. In such cases 1H-NMR spectroscopy of body fluids has been applied as a complementary technique, in fact a last resort to find the diagnosis (Engelke et al. 2007a, b, 2008; Moolenaar et al. 1999, 2001a, b). 1H-NMR spectroscopy of body fluids requires minimal or no sample pretreatment. The resulting spectra show the majority of proton-containing compounds. They provide an overall view on metabolism. This holistic view makes NMR spectroscopy a cornerstone of metabolomics. In the diagnostics of hereditary metabolic diseases, this is a major advantage compared to other techniques. 1H-NMR spectroscopy of body fluids may be considered as an alternative analytical approach for diagnosing known but also as yet unknown inborn errors of metabolism.


Nuclear Magnetic Resonance Nuclear Magnetic Resonance Spectrum Inborn Error Nuclear Magnetic Resonance Spectroscopy Proton Nuclear Magnetic Resonance Spectroscopy 
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.


  1. Abeling NG, van Gennip AH, Bakker HD, Heerschap A, Engelke U, Wevers RA (1995) Diagnosis of a new case of trimethylaminuria using direct proton NMR spectroscopy of urine. J Inherit Metab Dis 18:182–184PubMedCrossRefGoogle Scholar
  2. Engelke UF, Tangerman A, Willemsen MA, Moskau D, Loss S, Mudd SH, Wevers RA (2005) Dimethyl sulfone in human cerebrospinal fluid and blood plasma confirmed by one-dimensional 1H and two-dimensional 1H-13C NMR. NMR Biomed 18:331–336PubMedGoogle Scholar
  3. Engelke UF, Kremer B, Kluijtmans LA, van der Graaf M, Morava E, Loupatty FJ, Wanders RJ, Moskau D, Loss S, van den Bergh E, Wevers RA (2006) NMR spectroscopic studies on the late onset form of 3-methylglutaconic aciduria type I and other defects in leucine metabolism. NMR Biomed 19:271–278PubMedGoogle Scholar
  4. Engelke UFH, Oostendorp M, Wevers RA (2007a) NMR spectroscopy of body fluids as a metabolomics approach to inborn errors of metabolism. In: Lindon JC, Nicholson JK, Holmes E (eds) The handbook of metabonomics and metabolomics. Elsevier, Amsterdam, pp 375–412Google Scholar
  5. Engelke UF, Moolenaar SH, Hoenderop SMGC, Morava E, van der Graaf M, Heerschap A, Wevers RA (2007b) Handbook of 1H-NMR spectroscopy in inborn errors of metabolism: body fluid NMR spectroscopy and in vivo MR spectroscopy, 2nd edn. SPS Verlagsgesellschaft, HeilbronnGoogle Scholar
  6. Engelke UF, Sass JO, Van Coster RN et al (2008) NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism. NMR Biomed 21:138–147PubMedGoogle Scholar
  7. Engelke UF, Zijlstra FS, Mochel F, Valayannopoulos V, Rabier D, Kluijtmans LA, Perl A, Verhoeven-Duif NM, de Lonlay P, Wamelink MM, Jakobs C, Morava E, Wevers RA (2010a) Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency. Biochim Biophys Acta 1802(11):1028–1035PubMedCentralPubMedCrossRefGoogle Scholar
  8. Engelke U, Kwast H, Artuch R, Pineda M, Wevers RA (2010b) Identification of urocanylglycine in urocanase deficiency. J Inherit Metab Dis 33(Suppl 1):39Google Scholar
  9. Huck JH, Verhoeven NM, Struys EA, Salomons GS, Jakobs C, van der Knaap MS (2004) Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy. Am J Hum Genet 74:745–751PubMedCentralPubMedCrossRefGoogle Scholar
  10. Lehnert W, Hunkler D (1986) Possibilities of selective screening for inborn errors of metabolism using high-resolution 1H-FT-NMR spectrometry. Eur J Pediatr 145:260–266PubMedCrossRefGoogle Scholar
  11. Maschke S, Wahl A, Azaroual N, Boulet O, Crunelle V, Imbenotte M, Foulard M, Vermeersch G, Lhermitte M (1997) 1H-NMR analysis of trimethylamine in urine for the diagnosis of fish-odour syndrome. Clin Chim Acta 263:139–146PubMedCrossRefGoogle Scholar
  12. Mochel F, Boildieu N, Barritault J, Sarret C, Eymard-Pierre E, Seguin F, Schiffmann R, Boespflug-Tanguy O (2010) Elevated CSF N-acetylaspartylglutamate suggests specific molecular diagnostic abnormalities in patients with white matter diseases. Biochim Biophys Acta 1802:1112–1117PubMedCentralPubMedCrossRefGoogle Scholar
  13. Mochel F, Sedel F, Vanderver A, Engelke UF, Barritault J, Yang BZ, Kulkarni B, Adams DR, Clot F, Ding JH, Kaneski CR, Verheijen FW, Smits BW, Seguin F, Brice A, Vanier MT, Huizing M, Schiffmann R, Durr A, Wevers RA (2009) Cerebellar ataxia with elevated cerebrospinal free sialic acid (CAFSA). Brain 132:801–809PubMedCentralPubMedCrossRefGoogle Scholar
  14. Moolenaar SH, Poggi Bach J, Engelke UF, Corstiaensen JM, Heerschap A, de Jong JG, Binzak BA, Vockley J, Wevers RA (1999) Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: NMR spectroscopy study. Clin Chem 45:459–464PubMedGoogle Scholar
  15. Moolenaar SH, van der Knaap MS, Engelke UF et al (2001a) In vivo and in vitro NMR spectroscopy reveal a putative novel inborn error involving polyol metabolism. NMR Biomed 14:167–176PubMedGoogle Scholar
  16. Moolenaar SH, Gohlich-Ratmann G, Engelke UF, Spraul M, Humpfer E, Dvortsak P, Voit T, Hoffmann GF, Brautigam C, van Kuilenburg AB, van Gennip A, Vreken P, Wevers RA (2001b) beta-Ureidopropionase deficiency: a novel inborn error of metabolism discovered using NMR spectroscopy on urine. Magn Reson Med 46:1014–1017PubMedCrossRefGoogle Scholar
  17. Oostendorp M, Engelke UF, Willemsen MA, Wevers RA (2006) Diagnosing inborn errors of lipid metabolism with proton nuclear magnetic resonance spectroscopy. Clin Chem 52:1395–1405PubMedCrossRefGoogle Scholar
  18. Podadera P, Areas JA, Lanfer Marquez UM (2005) Diagnosis of suspected trimethylaminuria by NMR spectroscopy. Clin Chim Acta 351:149–154PubMedCrossRefGoogle Scholar
  19. Wevers RA, Engelke U, Heerschap A (1994) High-resolution 1H-NMR spectroscopy of blood plasma for metabolic studies. Clin Chem 40:1245–1250PubMedGoogle Scholar
  20. Wevers RA, Engelke U, Wendel U, de Jong JG, Gabreëls FJ, Heerschap A (1995) Standardized method for high-resolution 1H-NMR of cerebrospinal fluid. Clin Chem 41:744–751PubMedGoogle Scholar
  21. Wishart DS, Lewis MJ, Morrissey JA, Flegel MD, Jeroncic K, Xiong Y, Cheng D, Eisner R, Gautam B, Tzur D, Sawhney S, Bamforth F, Greiner R, Li L (2008) The human cerebrospinal fluid metabolome. J Chromatogr B 871:164–173CrossRefGoogle Scholar
  22. Wolf NI, Willemsen MA, Engelke UF, van der Knaap MS, Pouwels PJ, Harting I, Zschocke J, Sistermans EA, Rating D, Wevers RA (2004) Severe hypomyelination associated with increased levels of N-acetylaspartylglutamate in CSF. Neurology 62:1503–1508PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Laboratory Medicine, Laboratory of Genetic, Endocrine and Metabolic Diseases (HP 830)Radboud University Medical CenterNijmegenThe Netherlands

Personalised recommendations