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Human Molecular Genetics Advance Access published online on March 16, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi120
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© The Author 2005. Published by Oxford University Press. All rights reserved

Article

Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase

Philippa B. Mills 1, Robert A.H. Surtees 1, Michael P. Champion 2, Clare E. Beesley 1, Neil Dalton 2, Peter J. Scambler 1, Simon J.R. Heales 3, Anthony Briddon 3, Irene Scheimberg 4, Georg F. Hoffmann 5, Johannes Zschocke 6, and Peter T. Clayton 1*

1 Institute of Child Health, University College London with Great Ormond Street Hospital for Children NHS Trust, London, WC1N 1EH, UK
2 Guy's and St Thomas's Hospital NHS Trust, London, SE1 9RT, UK
3 Neurometabolic Unit, National Hospital, Queen Square, London, WC1N 3BG, UK
4 Department of Histopathlogy, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, E1 1BB, UK
5 University Children's Hospital, Department of General Pediatrics, Division of Metabolic and Endocrine Diseases, D-69120 Heidelberg, Germany
6 Institute of Human Genetics, Ruprecht-Karls University, 69120 Heidelberg, Germany

* To whom correspondence should be addressed.
Peter T. Clayton, E-mail: p.clayton{at}ich.ucl.ac.uk


  Abstract

In the mouse, neurotransmitter metabolism can be regulated by modulation of the synthesis of pyridoxal 5'-phosphate, and failure to maintain pyridoxal phosphate levels results in epilepsy. This study of 5 patients with neonatal epileptic encephalopathy suggests that the same is true in man. Cerebrospinal fluid and urine analyses indicated reduced activity of aromatic L-amino acid decarboxylase and other pyridoxal phosphate-dependent enzymes. Seizures ceased with administration of pyridoxal phosphate, having been resistant to treatment with pyridoxine, suggesting a defect of pyridox(am)ine 5'-phosphate oxidase (PNPO). Sequencing of the PNPO gene identified homozygous missense, splice site and stop codon mutations. Expression studies in CHO cells showed that the splice site (IVS3-1g>a) and stop codon (X262Q) mutations were null activity mutations and that the missense mutation (R229W) markedly reduced pyridox(am)ine phosphate oxidase activity. Maintenance of optimal pyridoxal phosphate levels in the brain may be important in many neurological disorders in which neurotransmitter metabolism is disturbed (either as a primary or as a secondary phenomenon).


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