Stolwijk Nina N, van Dussen Laura, Reijnhout Niels D, Brands Marion M M G, Jaeger Bregje, Clayton Peter T, Hollak Carla E M, Bosch Annet M
Medicines for Society (Medicijn voor de Maatschappij), Platform at Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
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.
J Inherit Metab Dis. 2025 Sep;48(5):e70074. doi: 10.1002/jimd.70074.
Pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency is an ultrarare inherited neurometabolic disease, characterized by primarily neonatal-onset B6-responsive epileptic encephalopathies. Treatment often requires sustainable access to high-quality pyridoxal-5'-phosphate (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-regulated 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 ClinicalTrials.gov, 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 = 38, 77.6%) and PLP treatment significantly improved survival (p < 0.001) compared with untreated siblings with a similar phenotype. The majority of PLP-responsive patients responded exclusively to PLP, with PN being attempted but ineffective in most of them (n = 30/33, 90.9%) Liver toxicity was the most frequently observed adverse event (n = 10, 20.4%) and although the underlying pathophysiological mechanism remains unclear, it may be associated with high-dose 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-quality and appropriate forms of PLP.
磷酸吡哆（醛/胺）5'-氧化酶（PNPO）缺乏症是一种极为罕见的遗传性神经代谢疾病，主要特征为新生儿期起病的维生素B6反应性癫痫性脑病。治疗通常需要持续获取高质量的磷酸吡哆醛（PLP，即活性维生素B6），尽管部分患者对吡哆醇（PN）也有反应。虽然PN被批准为药品，但PLP并非如此，这使得人们不得不依赖监管较松的食品补充剂，存在剂量不准确的风险。本系统评价评估了PLP治疗PNPO缺乏症的有效性和安全性（国际前瞻性系统评价注册库，CRD42024542199）。在PubMed、Embase和ClinicalTrials.gov进行了系统检索，采用叙述性综合方法评估偏倚风险并总结观察性证据。共纳入30项研究，报告了49例接受PLP治疗的患者。大多数患者（n = 38，77.6%）在PLP治疗后临床癫痫反应良好，与具有相似表型的未治疗同胞相比，PLP治疗显著提高了生存率（p < 0.001）。大多数对PLP有反应的患者仅对PLP有反应，尝试使用PN但大多数患者无效（n = 30/33，90.9%）。肝毒性是最常观察到的不良事件（n = 10，20.4%），尽管潜在的病理生理机制尚不清楚，但可能与高剂量PLP有关。因此，建议在PLP治疗期间定期进行肝病筛查。这意味着PLP仍然是大多数PNPO缺乏症患者实现和维持癫痫控制的唯一有效疗法，但最佳管理的治疗窗口较窄。因此，确保患者能够获得高质量和合适形式的PLP至关重要。
