24 June 2021

Karlien Coene, theme Metabolic Disorders, together with the group of Jos Oomens and Jonathan Martens at the Radboud FELIX laboratory, published the discovery of novel biomarkers for pyridoxine-dependent epilepsy in the Journal of Clinical Investigation, based on the unique combination of untargeted metabolomics and infrared ion spectroscopy.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1), also known as antiquitin deficiency, is an inborn error of lysine metabolism that presents with severe epilepsy in newborns. The biochemical result of this genetic condition is inactivation of vitamin B6, an important co-factor for many enzymatic processes in the human body. Vitamin B6 supplementation resolves epilepsy in patients, and additional lysine reduction therapy ensures optimal cognitive outcome, however, only when started in the first months of life. Ideally, early diagnosis through newborn screening would allow for pre-symptomatic detection of patients and early initiation of personalized treatment, however, so far no suitable blood-based biomarkers were available for this purpose.

By joining forces between the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy, the research team was able to discover a novel biomarker for PDE-ALDH7A1, 2-oxopropylpiperidine-2-carboxylic acid, in short 2-OPP. This biomarker was shown to be compatible with newborn screening workflows. Additionally, it was shown that 2-OPP accumulates in brain tissue of patients and aldh7a1 knock-out mice, and induced epilepsy-like behavior in a zebrafish model system, which may indicate that 2-OPP itself contributes to ongoing neurotoxicity in PDE-ALDH7A1. As 2-OPP formation appears to increase upon ketosis, this knowledge translates directly into clinical practice, emphasizing the importance of avoiding catabolism in PDE-ALDH7A1 patients.

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