TY - JOUR
T1 - Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy
AU - Engelke, Udo F.H.
AU - Van Outersterp, Rianne E.
AU - Merx, Jona
AU - Van Geenen, Fred A.M.G.
AU - Van Rooij, Arno
AU - Berden, Giel
AU - Huigen, Marleen C.D.G.
AU - Kluijtmans, Leo A.J.
AU - Peters, Tessa M.A.
AU - Al-Shekaili, Hilal H.
AU - Leavitt, Blair R.
AU - De Vrieze, Erik
AU - Broekman, Sanne
AU - Van Wijk, Erwin
AU - Tseng, Laura A.
AU - Kulkarni, Purva
AU - Rutjes, Floris P.J.T.
AU - Mecinović, Jasmin
AU - Struys, Eduard A.
AU - Jansen, Laura A.
AU - Gospe, Sidney M.
AU - Mercimek-Andrews, Saadet
AU - Hyland, Keith
AU - Willemsen, Michel A.A.P.
AU - Bok, Levinus A.
AU - Van Karnebeek, Clara D.M.
AU - Wevers, Ron A.
AU - Boltje, Thomas J.
AU - Oomens, Jos
AU - Martens, Jonathan
AU - Coene, Karlien L.M.
N1 - Funding Information:
This research was partly funded by a Stimuleringsbeurs from the Society for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), a catalyst grant from United for Metabolic Diseases (UMD-CG-2020-004), and a Stofwisselkracht grant under the project name "Innovative diagnostics in cerebrospinal fluid of patients with neurometabolic disorders" (all to KLMC). Also, parts of this work were financially supported by an Interfaculty Collaboration Grant from Radboud University Nijmegen (to KLMC, RAW, JO, and J Martens), and an Operating Grant from Canadian Institutes of Health Research (to HHAS and BRL). The authors also gratefully acknowledge the Dutch Research Council, division Natural Sciences, for the support of the FELIX Laboratory (grant numbers VICI 724.011.002, TTW 15769, TKI-LIFT 731.017.419, and Rekentijd 2019.062, all to JO). This work was also supported by an ERC-Stg grant (GlycoEdit, 758913) awarded to TJB. We are indebted to Siebolt de Boer, Joris Reintjes, and Ed van der Heeft for technical assistance, and to Dawn Cordeiro for assistance in CSF sample distribution. We would also like to thank our colleagues from the newborn screening laboratory at Elisabeth Tweesteden Ziekenhuis (ETZ) Tilburg, Netherlands, for helpful discussions on newborn screening methodology. This research made use of metabolomics infrastructure that is part of the NWO-funded Netherlands X-omics initiative, project 184.034.019.
Funding Information:
This research was partly funded by a Stimuleringsbeurs from the Society for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), a catalyst grant from United for Metabolic Diseases (UMD-CG-2020-004), and a Stofwisselkracht grant under the project name “Innovative diagnostics in cerebrospinal fluid of patients with neurometabolic disorders” (all to KLMC). Also, parts of this work were financially supported by an Interfaculty Collaboration Grant from Radboud University Nijmegen (to KLMC, RAW, JO, and J Martens), and an Operating Grant from Canadian Institutes of Health Research (to HHAS and BRL). The authors also gratefully acknowledge the Dutch Research Council, division Natural Sciences, for the support of the FELIX Laboratory (grant numbers VICI 724.011.002, TTW 15769, TKI-LIFT 731.017.419, and Rekentijd 2019.062, all to JO). This work was also supported by an ERC-Stg grant (GlycoEdit, 758913) awarded to TJB. We are indebted to Siebolt de Boer, Joris Reintjes, and Ed van der Heeft for technical assistance, and to Dawn Cordeiro for assistance in CSF sample distribution. We would also like to thank our colleagues from the newborn screening laboratory at Elisabeth Tweesteden Ziekenhuis (ETZ) Tilburg, Netherlands, for helpful discussions on newborn screening methodology. This research made use of metabolomics infrastructure that is part of the NWO-funded Netherlands X-omics initiative, project 184.034.019.
Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/8
Y1 - 2021/8
N2 - Background. Pyridoxine-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. Methods. We 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. Results. We 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. Conclusion. This 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.
AB - Background. Pyridoxine-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. Methods. We 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. Results. We 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. Conclusion. This 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.
UR - http://www.scopus.com/inward/record.url?scp=85111823821&partnerID=8YFLogxK
U2 - 10.1172/JCI148272
DO - 10.1172/JCI148272
M3 - Article
C2 - 34138754
AN - SCOPUS:85111823821
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 15
M1 - e148272
ER -