Abstract
Deficiency of pyridox(am)ine 5′-phosphate oxidase (PNPO, OMIM 610090) is a treatable autosomal recessive inborn error of metabolism. Neonatal epileptic encephalopathy and a low cerebrospinal fluid (CSF) pyridoxal 5′-phosphate level are the reported hallmarks of PNPO deficiency, but its clinical and biochemical spectra are not fully known. Case presentation: A girl born at 33 3/7 weeks of gestation developed seizures in the first hours of life. Her seizures initially responded to GABAergic agonists, but she subsequently developed a severe epileptic encephalopathy. Brain MRI and infectious and metabolic evaluations at birth, including urinary alpha-aminoadipic semialdehyde (AASA), were normal. Lumbar puncture at age 3 months showed: pyridoxal 5′-phosphate, 52 nmol/L (normal, 23–64); homovanillic acid, 392 nmol/L (normal, 450–1,132); 5-hydroxyindoleacetic acid, 341 nmol/L (normal, 179–711); and 3-ortho-methyldopa, 30 nmol/L (normal, below 300). The patient was not being treated with pyridoxine nor with pyridoxal 5′-phosphate at the time of the lumbar puncture. She died at age 14 months. A sequencing panel targeting 53 epilepsy-related genes revealed a homozygous missense mutation in PNPO (c.674G>A, p.R225H). Homozygosity was confirmed by parental testing. Expression studies of mutant p.R225H PNPO revealed greatly reduced activity. In conclusion, a normal CSF level of pyridoxal 5′-phosphate does not rule out PNPO deficiency.
Competing interests: None declared
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Acknowledgments
GAM and AML are supported by the Canadian Institutes for Health Research (CIHR).
PTC and PBM are supported by funding from Great Ormond Street Children’s Charity.
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Communicated by: Cornelis Jakobs, PhD
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Synopsis
Pyridoxal 5′-phosphate levels in cerebrospinal fluid may be normal in neonatal epileptic encephalopathy caused by pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency.
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Conflicts of Interest
Alina Levtova, Stephane Camuzeaux, Anne-Marie Laberge, Pierre Allard, Catherine Brunel-Guitton, Paola Diadori, Elsa Rossignol, Peter T. Clayton, Philippa B. Mills and Grant A. Mitchell declare no conflict of interest.
Keith Hyland is Vice President of Medical Neurogenetics, a company that measures pyridoxal 5′-phosphate in cerebrospinal fluid and performs sequencing of the PNPO gene.
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The investigations performed were done on a clinical basis. Consent was obtained from the family for the publication of this patient’s history.
Details of the Contributions of Individual Authors
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Writing and preparation of the manuscript: AL and GM
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Clinical management and investigation of the patient: AL, AML, PD, ER, GM
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Detailed review of the patient’s neurological and electrophysiological presentation: PD, ER
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cDNA cloning and expression studies of the mutant PNPO enzyme: SC, PC, PM
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Measurement of neurotransmitter metabolites and pyridoxal 5′-phosphate in cerebrospinal fluid and analysis of fluorescence chromatograms: KH
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Critical review of the manuscript: All authors.
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Levtova, A. et al. (2015). Normal Cerebrospinal Fluid Pyridoxal 5′-Phosphate Level in a PNPO-Deficient Patient with Neonatal-Onset Epileptic Encephalopathy. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 22. JIMD Reports, vol 22. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_413
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DOI: https://doi.org/10.1007/8904_2015_413
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