{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T17:24:30Z","timestamp":1780507470403,"version":"3.54.1"},"reference-count":22,"publisher":"Georg Thieme Verlag KG","issue":"01","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neuropediatrics"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pyridoxal-5\u2032-phosphate (PLP) is in most patients the effective treatment for pyridox(am)ine-5\u2032-phosphate oxidase (PNPO) deficiency, a rare autosomal recessive cause of neonatal-onset developmental and epileptic encephalopathy. Although generally considered safe, long-term high-dose PLP exposure may have hepatotoxic effects, particularly in the absence of pharmaceutical-grade formulations.<\/jats:p>\n                  <jats:p>We report a series of four pediatric patients with vitamin B6\u2013dependent epilepsy who received long-term PLP therapy. Two had genetically confirmed PNPO deficiency, and two were later diagnosed with ALDH7A1 deficiency. All received high-dose oral PLP, with frequent changes in formulation due to availability issues.<\/jats:p>\n                  <jats:p>Three of the four patients developed hepatocellular carcinoma after several years of PLP treatment; one developed fully reversible severe hepatotoxicity. The shared exposure to prolonged high-dose PLP across all affected patients, despite differing metabolic conditions, suggests a possible role for PLP toxicity independent of the underlying metabolic disorder. Known toxic mechanisms include mitochondrial dysfunction, Schiff base\u2013mediated protein modification, and accumulation of reactive PLP degradation products. In two patients, the total PLP dose was successfully reduced by over 30% through increasing administration frequency, without loss of seizure control.<\/jats:p>\n                  <jats:p>These findings raise significant concerns about the long-term hepatic safety of oral PLP in patients with vitamin B6\u2013dependent epilepsies. As intravenous PLP is unfeasable for lifelong therapy, there is an urgent need for standardized, high-quality PLP preparations and exploration of alternative delivery routes such as intranasal administration. Regular hepatic monitoring should be implemented in all patients receiving chronic PLP therapy.<\/jats:p>","DOI":"10.1055\/a-2773-6076","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:38Z","timestamp":1767744038000},"page":"059-064","source":"Crossref","is-referenced-by-count":2,"title":["Hepatocellular Carcinoma: A Critical Complication in Patients Treated with Pyridoxal Phosphate"],"prefix":"10.1055","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2025-5997","authenticated-orcid":false,"given":"Marion M.","family":"Brands","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Metabolic Diseases, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chlo\u00e9","family":"de Puyraimond","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Reference Center for Inborn Errors of Metabolism, Necker Hospital, APHP, Universit\u00e9 Paris-Cit\u00e9, G2m Network, MetabERN, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidney M.","family":"Gospe Jr","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Pediatrics, University of Washington, Seattle, Washington, United States"},{"name":"Department of Pediatrics, Duke University, Durham, North Carolina, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel M.","family":"Schiff","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Reference Center for Inborn Errors of Metabolism, Necker Hospital, APHP, Universit\u00e9 Paris-Cit\u00e9, G2m Network, MetabERN, Paris, France"},{"name":"INSERM UMR _S1163, Institut Imagine, Universit\u00e9 Paris-Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bregje","family":"Jaeger","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Emma's Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart G.","family":"Koot","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine F.","family":"Raphael","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte M.","family":"Lubout","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Soto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, CH Auxerre, Auxerre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Delanne","sequence":"additional","affiliation":[{"name":"Department of Genetics, CHU Dijon Bourgogne, Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apolline","family":"Imbard","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, H\u00f4pital Necker-Enfants Malades, APHP, Paris, France"},{"name":"D\u00e9partement M\u00e9dicaments et Technologies pour La Sant\u00e9 (DMTS), Paris-Saclay University, CEA, Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Zempel","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Pediatrics, Washington University, St. Louis, Missouri, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathelijne C.","family":"Kraal","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Scheenstra","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T.","family":"Clayton","sequence":"additional","affiliation":[{"name":"Inborn Errors of Metabolism, Genetics and Genomic Medicine, UCL Great Ormond 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Wilson","year":"2019","journal-title":"J Inherit Metab Dis"},{"issue":"01","key":"ref4","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/jimd.12332","article-title":"Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to \u03b1-aminoadipic semialdehyde dehydrogenase deficiency","volume":"44","author":"C R Coughlin II","year":"2021","journal-title":"J Inherit Metab Dis"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.ejpn.2021.06.001","article-title":"Cognitive and neurological outcome of patients in the Dutch pyridoxine-dependent epilepsy (PDE-ALDH7A1) cohort, a cross-sectional study","volume":"33","author":"M Strijker","year":"2021","journal-title":"Eur J Paediatr Neurol"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1093\/brain\/awu051","article-title":"Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and 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