{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T01:01:29Z","timestamp":1784682089322,"version":"3.55.0"},"reference-count":55,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T00:00:00Z","timestamp":1754092800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T00:00:00Z","timestamp":1754092800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Pyridox(am)ine 5\u2032\u2010phosphate oxidase (PNPO) deficiency is an ultrarare inherited neurometabolic disease, characterized by primarily neonatal\u2010onset B6\u2010responsive epileptic encephalopathies. Treatment often requires sustainable access to high\u2010quality pyridoxal\u20105\u2032\u2010phosphate (PLP, i.e., active vitamin B6), although some patients (also) respond to pyridoxine (PN). While PN is authorized as a medicinal product, PLP is not, and this forces reliance on lesser\u2010regulated food supplements, which risks dosing inaccuracies. This systematic review evaluates the effectiveness and safety of PLP in PNPO deficiency (PROSPERO, CRD42024542199). A systematic search was conducted in PubMed, Embase, and\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                    , with risk of bias assessed and observational evidence summarized using a narrative synthesis approach. A total of 30 studies were included reporting on 49 patients treated with PLP. Clinical seizure responsiveness following PLP therapy was observed in the majority of patients (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200938, 77.6%) and PLP treatment significantly improved survival (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) compared with untreated siblings with a similar phenotype. The majority of PLP\u2010responsive patients responded exclusively to PLP, with PN being attempted but ineffective in most of them (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200930\/33, 90.9%) Liver toxicity was the most frequently observed adverse event (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200910, 20.4%) and although the underlying pathophysiological mechanism remains unclear, it may be associated with high\u2010dose PLP. Therefore, regular liver disease screening is recommended during PLP therapy. This means that PLP remains the only effective therapy for achieving and maintaining seizure control in the majority of PNPO deficient patients, but the therapeutic window for optimal management is narrow. Thus, it is essential to ensure patient access to high\u2010quality and appropriate forms of PLP.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70074","type":"journal-article","created":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T11:53:42Z","timestamp":1754135622000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Effectiveness of Pyridoxal\u20105\u2032\u2010Phosphate in\n                    <scp>PNPO<\/scp>\n                    Deficiency: A Systematic Review"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3498-5747","authenticated-orcid":false,"given":"Nina N.","family":"Stolwijk","sequence":"first","affiliation":[{"name":"Medicines for Society (Medicijn voor de Maatschappij), Platform at Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"},{"name":"Department of Endocrinology and Metabolism. Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute Expertise Center for Inborn Errors of Metabolism, MetabERN, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6539-531X","authenticated-orcid":false,"given":"Laura","family":"van Dussen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism. Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute Expertise Center for Inborn Errors of Metabolism, MetabERN, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels D.","family":"Reijnhout","sequence":"additional","affiliation":[{"name":"Medicines for Society (Medicijn voor de Maatschappij), Platform at Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2025-5997","authenticated-orcid":false,"given":"Marion M. M. G.","family":"Brands","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Metabolic Diseases Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam UMC Location University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3664-162X","authenticated-orcid":false,"given":"Bregje","family":"Jaeger","sequence":"additional","affiliation":[{"name":"Department of Child Neurology Emma Children's Hospital, Amsterdam University Medical Centers  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7592-4302","authenticated-orcid":false,"given":"Peter T.","family":"Clayton","sequence":"additional","affiliation":[{"name":"Inborn Errors of Metabolism, Genetics and Genomic Medicine UCL Great Ormond Street Institute of Child Health  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0464-1078","authenticated-orcid":false,"given":"Carla E. M.","family":"Hollak","sequence":"additional","affiliation":[{"name":"Medicines for Society (Medicijn voor de Maatschappij), Platform at Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"},{"name":"Department of Endocrinology and Metabolism. Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute Expertise Center for Inborn Errors of Metabolism, MetabERN, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5027-5916","authenticated-orcid":false,"given":"Annet M.","family":"Bosch","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Metabolic Diseases Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam UMC Location University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.12701"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2022.04.011"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2010.12.006"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12060"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201070598\u20107"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi120"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12332"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13843"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17745"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2014_338"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2015_456"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2012.07.005"},{"key":"e_1_2_9_14_1","doi-asserted-by":"crossref","unstructured":"A.Ruiz J.Garc\u00eda\u2010Villoria A.Ormazabal et\u00a0al. \u201cA New Fatal Case of Pyridox(Am)ine 5\u2032\u2010Phosphate Oxidase (PNPO) Deficiency \u201d93 no.2(2008):216\u2013218 https:\/\/doi.org\/10.1016\/j.ymgme.2007.10.003.","DOI":"10.1016\/j.ymgme.2007.10.003"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13643\u2010016\u20100384\u20104"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjebm\u20102017\u2010110853"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100039\u20101697676"},{"key":"e_1_2_9_19_1","doi-asserted-by":"crossref","unstructured":"S.Bagci J.Zschocke G. 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