| Literature DB >> 34138754 |
Udo Fh Engelke1, Rianne E van Outersterp2, Jona Merx3, Fred Amg van Geenen2, Arno van Rooij1, Giel Berden2, Marleen Cdg Huigen1, Leo Aj Kluijtmans1, Tessa Ma Peters1,4, Hilal H Al-Shekaili5, Blair R Leavitt5, Erik de Vrieze6, Sanne Broekman6, Erwin van Wijk6, Laura A Tseng7, Purva Kulkarni1, Floris Pjt Rutjes3, Jasmin Mecinović3,8, Eduard A Struys9, Laura A Jansen10, Sidney M Gospe11,12, Saadet Mercimek-Andrews13,14, Keith Hyland15, Michèl Aap Willemsen16, Levinus A Bok17, Clara Dm van Karnebeek7,18,19, Ron A Wevers1, Thomas J Boltje3, Jos Oomens2,20, Jonathan Martens2, Karlien Lm Coene1.
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).Entities:
Keywords: Diagnostics; Epilepsy; Genetic diseases; Metabolism
Year: 2021 PMID： 34138754 PMCID： PMC8321577 DOI： 10.1172/JCI148272
Source DB: PubMed Journal: J Clin Invest ISSN： 0021-9738 Impact factor: 14.808