ArticleThe Journal of clinical investigation2021
Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 62 citations in OpenAlex.
- Action Spectroscopy of Mass-Selected Ions-From Principles to Applications.Journal of mass spectrometry : JMS · 2026Review
- A Novel Multimodal LC-MS/MS Panel for the Comprehensive Diagnosis of Neurometabolic Disorders in CSF.Journal of inherited metabolic disease · 2026Article
- Classical and Emerging Biomarkers in Pyridoxine-Dependent Epilepsy (PDE-ALDH7A1): Implications for Early Diagnosis and Therapeutic Development.Biomolecules · 2026Review
- Untargeted Metabolomics for Diagnosis, Monitoring, and Understanding the Pathophysiology of Inherited Metabolic Disorders.Journal of inherited metabolic disease · 2026Review
- The associations between epilepsy, metabolism, and their clinical implications.Frontiers in endocrinology · 2026Review
- LongitudinalFrontiers in molecular biosciences · 2026Article
- Targeting AASS alleviates neurotoxicity and improves mitochondrial function in astrocyte models for pyridoxine-dependent epilepsy.Molecular therapy. Nucleic acids · 2025Article
- Lactic acidosis, rhabdomyolysis, and hyperammonemia: Atypical presentation in a new patient with PDE-ALDH7A1 defect.Molecular genetics and metabolism reports · 2025Article
- Semi-Targeted Nuclear Magnetic Resonance Metabolomics via Parahydrogen-Induced Hyperpolarization for Enhanced Sensitivity to Metabolic Composition.Journal of the American Chemical Society · 2025Article
- Advancing Neonatal Screening for Pyridoxine-Dependent Epilepsy-ALDH7A1 Through Combined Analysis of 2-OPP, 6-Oxo-Pipecolate and Pipecolate in a Butylated FIA-MS/MS Workflow.International journal of neonatal screening · 2025Article
- Structure Elucidation for MALDI Mass Spectrometry Imaging Using Infrared Ion Spectroscopy.Analytical chemistry · 2025Article
- Identification and enrichment of potential pathways in the buffy coat of patients with DRE using non-targeted metabolomics integrated with GEO Datasets.European journal of medical research · 2025Article
- New treatment for pyridoxine-dependent epilepsy due to ALDH7A1 deficiency: first proof-of-principle of upstream enzyme inhibition in the mouse.Brain communications · 2025Article
- Feasibility of newborn screening for pyridoxine-dependent epilepsy.Molecular genetics and metabolism · 2025Article
- Assessment of urinary 6-oxo-pipecolic acid as a biomarker for ALDH7A1 deficiency.Journal of inherited metabolic disease · 2025Article
- Precision diagnosis and treatment of vitamin metabolism-related epilepsy.Acta epileptologica · 2024Review
- Alterations in serum metabolomics during the first seizure and after effective control of epilepsy.Scientific reports · 2024Article
- Dietary management for pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency, a follow-on from the international consortium guidelines.JIMD reports · 2024Article
- AnAnalytical chemistry · 2023Article
- Pyridoxine-dependent epilepsy: Current perspectives and questions for future research.Annals of the Child Neurology Society · 2023Article
Corrections and comments
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Authors and funding
31 authors at 7 institutions in 4 countries.
Funding
Abstract
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).
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