Liver Transplantation in PNPO Deficiency: Management Challenges and Biological Lessons

Pyridox(am)ine 5' Phosphate Oxidase deficiency (PNPO) presents with refractory epilepsy responsive to treatment with pyridoxal 5' phosphate (PLP) or pyridoxine. A 15-year-old boy with PNPO deficiency and cirrhosis underwent orthotopic liver transplantation for hepatocellular carcinoma without extra-hepatic disease. Pre-transplant, the boy was cognitively normal with well controlled epilepsy on PLP 50 mg/kg/day. Continuous EEG monitoring was used pre-operatively and post-operatively to identify encephalopathy resulting from PLP deficiency. B6 vitamers (pyridoxine [PN], pyridoxamine [PM], pyridoxal [PL] and phosphorylated forms [PNP, PMP, PLP]) were assayed at times of encephalopathy (symptoms and/or EEG) and for pharmacokinetics. Doses of PLP were titrated to prevent encephalopathy and limit side effects. The intraoperative/immediate postoperative periods were managed with intravenous PLP at a dose which could be reduced to 7.8 mg/kg/day before encephalopathy recurred. Post-transplant, transition to oral PLP (100 mg/kg/day) led to fulminant hepatic impairment, which improved when IV dosing resumed. Subsequent transition to full oral PLP dosing took 9 months with a final dose of 24 mg/kg/day oral PLP. PLP showed dose dependent hepatotoxicity with associated rises in alpha-fetoprotein levels. Gradual PLP dose changes and frequent oral dosing minimised encephalopathy episodes and hepato-toxicity. Six years post-transplant, liver biopsy showed moderate portal fibrosis (Ishak fibrosis stage 2/6, LAFSc score 3/9). Encephalopathy/seizures were associated with lower plasma PL concentrations (40 times above physiological levels); but high plasma PLP concentrations did not prevent encephalopathy. Despite liver transplantation, requirements for supraphysiologic doses of PLP continued, suggesting impaired neuronal PLP salvage is the major factor determining PLP requirements in PNPO deficiency.