Metabolomics Profile in ABAT Deficiency Pre- and Post-treatment

  • Mary Kay Koenig
  • Penelope E. BonnenEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 43)


Metabolomic profiling is an emerging technology in the clinical setting with immediate diagnostic potential for the population of patients with Inborn Errors of Metabolism. We present the metabolomics profile of two ABAT deficiency patients both pre- and posttreatment with flumazenil. ABAT deficiency, also known as GABA-transaminase deficiency, is caused by recessive mutations in the gene ABAT and leads to encephalopathy of variable severity with hypersomnolence, hypotonia, hypomyelination, and seizures. Through metabolomics screening of multiple patient tissues, we identify 2-pyrrolidinone as a biomarker for GABA that is informative in plasma, urine, and CSF. These data will enable noninvasive diagnostic testing for the population of patients with disorders of GABA metabolism.


ABAT ABAT deficiency Flumazenil GABA GABA-T Metabolomics Pyrrolidinone Seizures 



Research reported in this publication was supported by National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS083726 to PEB. We thank the families for participating in this study.


  1. Besse A, Wu P, Bruni F et al (2015) The GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism. Cell Metab 21:417–427CrossRefGoogle Scholar
  2. Besse A, Petersen AK, Hunter JV et al (2016) Personalized medicine approach confirms a milder case of ABAT deficiency. Mol Brain 9:93CrossRefGoogle Scholar
  3. Callery PS, Stogniew M, Geelhaar LA (1979) Detection of the in vivo conversion of 2-pyrrolidinone to gamma-aminobutyric acid in mouse brain. Biomed Mass Spectrom 6:23–26CrossRefGoogle Scholar
  4. Dehaven CD, Evans AM, Dai H et al (2010) Organization of GC/MS and LC/MS metabolomics data into chemical libraries. J Cheminform 2:9CrossRefGoogle Scholar
  5. Evans AM, DeHaven CD, Barrett T et al (2009) Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Anal Chem 81:6656–6667CrossRefGoogle Scholar
  6. Fasolato C, Bertazzon A, Previero A et al (1988) Effect of 2-pyrrolidone on the concentration of GABA in rat tissues. Pharmacology 36:258–264CrossRefGoogle Scholar
  7. Grove J, Schechter PJ, Tell G et al (1982) Artifactual increases in the concentration of free GABA in samples of human cerebrospinal fluid are due to degradation of homocarnosine. J Neurochem 39:1061–1065CrossRefGoogle Scholar
  8. Haegele KD, Schwartz JJ, Schoun J et al (1987) 2-Pyrrolidinone in human cerebrospinal fluid: a major constituent of total gamma-aminobutyric acid. J Neurochem 49:1402–1406CrossRefGoogle Scholar
  9. Hyder F, Petroff OA, Mattson RH et al (1999) Localized 1H NMR measurements of 2-pyrrolidinone in human brain in vivo. Magn Reson Med 41:889–896CrossRefGoogle Scholar
  10. Jaeken J, Casaer P, de Cock P et al (1984) Gamma-aminobutyric acid-transaminase deficiency: a newly recognized inborn error of neurotransmitter metabolism. Neuropediatrics 15:165–169CrossRefGoogle Scholar
  11. Kish SJ, Perry TL, Hansen S (1979) Regional distribution of homocarnosine, homocarnosine-carnosine synthetase and homocarnosinase in human brain. J Neurochem 32:1629–1636CrossRefGoogle Scholar
  12. Koenig MK, Hodgeman R, Riviello JJ et al (2017) Phenotype of GABA-transaminase deficiency. Neurology 88:1919–1924CrossRefGoogle Scholar
  13. Lundgren DW, Hankins J (1978) Metabolism of putrescine to 2-pyrrolidone by rat liver slices. J Biol Chem 253:7130–7133PubMedGoogle Scholar
  14. Medina-Kauwe LK, Tobin AJ, De Meirleir L et al (1999) 4-Aminobutyrate aminotransferase (GABA-transaminase) deficiency. J Inherit Metab Dis 22:414–427CrossRefGoogle Scholar
  15. Nakamura J, Miwa T, Mori Y et al (1991) Comparative studies on the anticonvulsant activity of lipophilic derivatives of gamma-aminobutyric acid and 2-pyrrolidinone in mice. J Pharmacobiodyn 14:1–8CrossRefGoogle Scholar
  16. Petroff OA, Rothman DL (1998) Measuring human brain GABA in vivo: effects of GABA-transaminase inhibition with vigabatrin. Mol Neurobiol 16:97–121CrossRefGoogle Scholar
  17. Petroff OA, Behar KL, Mattson RH et al (1996) Human brain gamma-aminobutyric acid levels and seizure control following initiation of vigabatrin therapy. J Neurochem 67:2399–2404CrossRefGoogle Scholar
  18. Riekkinen PJ, Ylinen A, Halonen T et al (1989) Cerebrospinal fluid GABA and seizure control with vigabatrin. Br J Clin Pharmacol 27(Suppl 1):87S–94SCrossRefGoogle Scholar
  19. Rothman DL, Behar KL, Prichard JW et al (1997) Homocarnosine and the measurement of neuronal pH in patients with epilepsy. Magn Reson Med 38:924–929CrossRefGoogle Scholar
  20. Sasaki H, Mori Y, Nakamura J et al (1991) Synthesis and anticonvulsant activity of 1-acyl-2-pyrrolidinone derivatives. J Med Chem 34:628–633CrossRefGoogle Scholar

Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  1. 1.Department of PediatricsUniversity of Texas Health Science CenterHoustonUSA
  2. 2.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA

Personalised recommendations