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Novel biomarkers for pyridoxine-dependent epilepsy identified using untargeted metabolomics and infrared ion spectroscopy

Date of news: 7 July 2021

Together with researchers of the Translational Metabolic Laboratory (Radboudumc) we have discovered novel biomarkers for pyridoxine-dependent epilepsy (PDE-ALDH7A1) by combining untargeted metabolomics and infrared ion spectroscopy. The results have recently been published in the Journal of Clinical Investigation.

Pyridoxine-dependent epilepsy is an inborn error of metabolism that manifesting as severe epilepsy in newborns. The underlying biochemistry of this condition relates to a secondary depletion of vitamin B6 which is a critical cofactor for many processes in the body. While current treatment strategies using vitamin B6 supplementation effectively resolves epilepsy in patients treatment must be started as early as possible – ideally in the first days of life. For this, diagnosis in newborn screening would ideally enable early detection and allow the initiation of personalized treatment therapy in patients. Using state-of-the-art liquid chromatography/mass spectrometry-based metabolomics techniques a new molecular feature of mass-to-charge ratio (m/z) 186.1123 was detected in PDE patient body fluids. However, the molecular structure of this detected compound was not possible to identify using standard techniques.


In order to identify this new molecular feature, we used infrared ion spectroscopy (IRIS) and were able to identify it as 2-oxopropylpiperidine-2-carboxylic acid (2-OPP), a previously unknown human metabolite. Interestingly, 2-OPP can be used as a highly diagnostic biomarker for PDE and was also shown to be chemically stable and suitable for inclusion in existing newborn screening protocols.

Furthermore, several biochemical and pathophysiological implications were also found related to 2-OPP: 2-OPP accumulates in the brains of patients and ALDH7A1 knock-out mice, and 2-OPP causes epilepsy-like behavior in a zebrafish. These findings suggest that 2-OPP is itself a likely contributor to aspects of neurotoxicity in PDE ALDH7A1. Finally, 2-OPP levels appears to be elevated in ketosis, emphasizing the importance of avoiding catabolism in PDE patients.

More information

Dr. Jonathan Martens

Dr. Karlien Coene
Translational Metabolic Laboratory – Radboudumc

Engelke U, et al. Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy. Journal of Clinical Investigation 131 15 (2021)