Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy
| Autor: | Ron A. Wevers, Levinus A. Bok, Erik de Vrieze, Thomas J. Boltje, Laura A. Tseng, Saadet Mercimek-Andrews, Tessa M.A. Peters, Keith Hyland, Marleen C. D. G. Huigen, Giel Berden, Clara D.M. van Karnebeek, Hilal H. Al-Shekaili, Floris P.J.T. Rutjes, Arno van Rooij, Sidney M. Gospe, Fred A. M. G. van Geenen, Sanne Broekman, Jasmin Mecinović, Jona Merx, Eduard A. Struys, Michèl A.A.P. Willemsen, Jos Oomens, Erwin van Wijk, Leo A.J. Kluijtmans, Laura A. Jansen, Udo Engelke, Purva Kulkarni, Jonathan Martens, Blair R. Leavitt, Rianne E. van Outersterp, Karlien L.M. Coene |
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| Přispěvatelé: | Laboratory Medicine, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Paediatrics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Paediatric Metabolic Diseases |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Spectrophotometry
Infrared Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] Synthetic Organic Chemistry Bioinformatics Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] Mice 03 medical and health sciences Epilepsy 0302 clinical medicine Animals Humans Metabolomics Medicine Child Pyridoxine-dependent epilepsy Zebrafish 030304 developmental biology Mice Knockout FELIX Molecular Structure and Dynamics 0303 health sciences Newborn screening business.industry Catabolism Neurotoxicity Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] General Medicine Aldehyde Dehydrogenase Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] medicine.disease 3. Good health Untargeted metabolomics Pipecolic Acids Biomarker (medicine) Female Organismal Animal Physiology Clinical Medicine Ketosis business Biomarkers 030217 neurology & neurosurgery |
| Zdroj: | Journal of Clinical Investigation, 131(15):e148272. The American Society for Clinical Investigation Engelke, U F H, van Outersterp, R E, Merx, J, van Geenen, F A M G, van Rooij, A, Berden, G, Huigen, M C D G, Kluijtmans, L A J, Peters, T M A, Al-Shekaili, H H, Leavitt, B R, de Vrieze, E, Broekman, S, van Wijk, E, Tseng, L A, Kulkarni, P, Rutjes, F P J T, Mecinović, J, Struys, E A, Jansen, L A, Gospe, S M, Mercimek-Andrews, S, Hyland, K, Willemsen, M A A P, Bok, L A, van Karnebeek, C D M, Wevers, R A, Boltje, T J, Oomens, J, Martens, J & Coene, K L M 2021, ' Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy ', Journal of Clinical Investigation, vol. 131, no. 15, e148272 . https://doi.org/10.1172/JCI148272 Journal of Clinical Investigation, 131 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, Mecinović, 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 2021, ' Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy ', Journal of Clinical Investigation, vol. 131, no. 15, e148272 . https://doi.org/10.1172/JCI148272 Journal of Clinical Investigation, 131, 15 J Clin Invest Journal of clinical investigation, 131(15):e148272. The American Society for Clinical Investigation |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/JCI148272 |
| Popis: | Contains fulltext : 237516.pdf (Publisher’s version ) (Open Access) BackgroundPyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine catabolism that presents with refractory epilepsy in newborns. Biallelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase/antiquitin, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important cofactor pyridoxal-5'-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but intellectual disability may still develop. Early diagnosis and treatment, preferably based on newborn screening, could optimize long-term clinical outcome. However, no suitable PDE-ALDH7A1 newborn screening biomarkers are currently available.MethodsWe combined the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy to discover and identify biomarkers in plasma that would allow for PDE-ALDH7A1 diagnosis in newborn screening.ResultsWe identified 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) as a PDE-ALDH7A1 biomarker, and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP) as a biomarker. The suitability of 2-OPP as a potential PDE-ALDH7A1 newborn screening biomarker in dried bloodspots was shown. Additionally, we found that 2-OPP accumulates in brain tissue of patients and Aldh7a1-knockout mice, and induced epilepsy-like behavior in a zebrafish model system.ConclusionThis study has opened the way to newborn screening for PDE-ALDH7A1. 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.FundingSociety for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), United for Metabolic Diseases (UMD), Stofwisselkracht, Radboud University, Canadian Institutes of Health Research, Dutch Research Council (NWO), and the European Research Council (ERC). |
| Databáze: | OpenAIRE |
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