Abstract
We report the case of a 4-year-old boy with pyridoxamine 5-phosphate oxidase deficiency, now the second reported case to develop hepatic cirrhosis. He presented with an encephalopathy in the first 1.5 h of life and received a first dose of PLP at 40 h of life. PNPO gene sequencing identified homozygosity for a novel variant in exon 7, c.637C>T (p.Pro213Ser). Persistent elevations in alanine transferase and aspartate transferase combined with an echogenic liver on ultrasound prompted performance of a liver biopsy which demonstrated hepatic cirrhosis. This is the second reported case of hepatic cirrhosis in PNPO deficiency. The pathogenesis is unclear but may be related to epigenetic activation of purinergic signaling in the hepatic stellate cells. PNPO deficiency may in time prove to be a suitable candidate for consideration of therapeutic orthotropic liver transplantation in select patients.
Competing interests: None declared
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References
Bagci S, Zschocke J, Hoffmann GF et al (2008) Pyridoxal phosphate-dependent neonatal epileptic encephalopathy. Arch Dis Child Fetal Neonatal Ed 93(2):F151–F152
Bian EB, Zhao B, Huang C et al (2013) New advances of DNA methylation in liver fibrosis, with special emphasis on the crosstalk between microRNAs and DNA methylation machinery. Cell Signal 25(9):1837–1844
Blomhoff R, Wake K (1991) Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. FASEB J 5(3):271–277
Boers SJ, Visser G, Smit PG, Fuchs SA (2014) Liver transplantation in glycogen storage disease type I. Orphanet J Rare Dis 9:47
Brown S, Kim Y, Kim S et al (2001) Actions of a series of PPADS analogs at P2X1 and P2X3 receptors. Drug Dev Res 53(4):281–291
Clayton PT (2006) B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis 29(2–3):317–326
Dranoff JA, Ogawa M, Kruglov EA, et al (2004) Expression of P2Y nucleotide receptors and ectonucleotidases in quiescent and activated rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 287(2):G417–G424
Dranoff JA, Kruglov EA, Abreu-Lanfranco O, Nguyen T, Arora G, Jain D (2007) Prevention of liver fibrosis by the purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate (PPADS). Vivo 21(6):957–965
Friedman SL (2000) Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 275:2247–2250
Hoffmann GF, Schmitt B, Windfuhr M et al (2007) Pyridoxal 5′-phosphate may be curative in early-onset epileptic encephalopathy. J Inherit Metab Dis 30(1):96–99
Khayat M, Korman SH, Frankel P et al (2008) PNPO deficiency: an under diagnosed inborn error of pyridoxine metabolism. Mol Genet Metab 94(4):431–434
Lewindon PJ, Shepherd RW, Walsh MJ et al (2011) Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy. Hepatology 53(1):193–201
Mann D (2014) Epigenetics in liver disease. Hepatology 60(4):1418–1425
Mazariegos G, Shneider B, Burton B et al (2014) Liver transplantation for pediatric metabolic disease. Mol Genet Metab 111(4):418–427
Mills PB, Surtees RA, Champion MP et al (2005) Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5′-phosphate oxidase. Hum Mol Genet 14(8):1077–1086
Mills PB, Camuzeaux SS, Footitt EJ et al (2014) Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. Brain 137(Pt 5):1350–1360
Pearl PL, Hyland K, Chiles J, McGavin CL, Yu Y, Taylor D (2013) Partial pyridoxine responsiveness in PNPO deficiency. JIMD Rep 9:139–142
Plecko B, Paul K, Mills P et al (2014) Pyridoxine responsiveness in novel mutations of the PNPO gene. Neurology 82(16):1425–1433
Porri S, Fluss J, Plecko B, Paschke E, Korff CM, Kern I (2014) Positive outcome following early diagnosis and treatment of pyridoxal-5′-phosphate oxidase deficiency: a case report. Neuropediatrics 45(1):64–68
Ruiz A, García-Villoria J, Ormazabal A et al (2008) A new fatal case of pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency. Mol Genet Metab 93(2):216–218
Schmitt B, Baumgartner M, Mills PB, Clayton PT, Jakobs C, Keller E, Wohlrab G (2010) Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency. Dev Med Child Neurol 52(7):e133–e142
Sudarsanam A, Singh H, Wilcken B et al (2014) Cirrhosis associated with pyridoxal 5'-phosphate treatment of pyridoxamine 5′-phosphate oxidase deficiency. JIMD Rep 17:67–70
Tu ZH, Shang DS, Jiang JC et al (2012) Liver transplantation in Crigler-Najjar syndrome type I disease. Hepatobiliary Pancreat Dis Int 11(5):545–548
Veerapandiyan A, Winchester SA, Gallentine WB, Smith EC, Kansagra S, Hyland K, Mikati MA (2011) Electroencephalographic and seizure manifestations of pyridoxal 5′-phosphate-dependent epilepsy. Epilepsy Behav 20(3):494–501
Ware TL, Earl J, Salomons GS, Struys EA, Peters HL, Howell KB, Pitt JJ, Freeman JL (2014) Typical and atypical phenotypes of PNPO deficiency with elevated CSF and plasma pyridoxamine on treatment. Dev Med Child Neurol 56(5):498–502
Yao H, Li J (2015) Epigenetic modifications in fibrotic diseases: implications for pathogenesis and pharmacological targets. J Pharmacol Exp Ther 352(1):2–13
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Communicated by: Ertan Mayatepek, MD
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David Coman, Peter Lewindon, Peter Clayton, and Kate Riney declare that they have no conflicts of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
Author Contributions
A/Prof David Coman is a metabolic physician and involved in the care of the patients and has coordinated the manuscript development and design.
A/Prof Peter Lewindon is a pediatric gastroenterologist who is involved in the patients’ care and has been involved in the manuscript development.
Professor Peter Clayton is a metabolic physician who has provided invaluable clinical advice on the patients and has been involved in the manuscript development.
Dr. Kate Riney is a pediatric neurologist, is the primary caregiver for the patient, and has been involved in the manuscript development.
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Coman, D., Lewindon, P., Clayton, P., Riney, K. (2015). PNPO Deficiency and Cirrhosis: Expanding the Clinical Phenotype?. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 25. JIMD Reports, vol 25. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_456
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DOI: https://doi.org/10.1007/8904_2015_456
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