Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy

Engelke, U.F., van Outersterp, R.E., Merx, J., van Geenen, F.A., van Rooij, A., Berden, G., Huigen, M.C., Kluijtmans, L.A., Peters, T.M., Al-Shekaili, H.H., Leavitt, B.R., de Vrieze, E., Broekman, S., van Wijk, E., Tseng, L.A., Kulkarni, P., Rutjes, F.P., Mecinovic, J., Struys, E.A., Jansen, L.A., Gospe, S.M., Mercimek-Andrews, S., Hyland, K., Willemsen, M.A., Bok, L.A., Van Karnebeek, C.D., Wevers, R.A., Boltje, T.J., Oomens, J., Martens, J., Coene, K.L.
The Journal of Clinical Investigation   131(15): (Journal)
Registered Authors
de Vrieze, Erik, van Wijk, Erwin
Diagnostics, Epilepsy, Genetic diseases, Metabolism
MeSH Terms
  • Aldehyde Dehydrogenase/deficiency
  • Aldehyde Dehydrogenase/metabolism
  • Animals
  • Biomarkers/metabolism
  • Child
  • Epilepsy/genetics
  • Epilepsy/metabolism*
  • Female
  • Humans
  • Metabolomics*
  • Mice
  • Mice, Knockout
  • Pipecolic Acids/metabolism*
  • Spectrophotometry, Infrared
  • Zebrafish/genetics
  • Zebrafish/metabolism
34138754 Full text @ Journal of Clin. Invest.
Pyridoxine-dependent epilepsy (PDE-ALDH7A1), also known as antiquitin deficiency, is an inborn error of lysine metabolism that presents with refractory epilepsy in newborns. Bi-allelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important co-factor pyridoxal-5'-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but despite this treatment, intellectual disability may occur. Early diagnosis and treatment, preferably based on newborn screening, potentially optimize long-term clinical outcome. However, the currently known diagnostic PDE-ALDH7A1 biomarkers are incompatible with newborn screening procedures. Combining of the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy, we were able to discover a novel biomarker for PDE-ALDH7A1,2S,6S- and 2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP), and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP)as biomarker. We demonstrated the applicability of 2-OPP as a PDE-ALDH7A1 biomarker in newborn screening. Additionally, we showed that 2-OPP accumulates in brain tissue of patients and aldh7a1 knock-out mice, and induced epilepsy-like behavior in a zebrafish model system. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes