Human Molecular Genetics Advance Access originally published online on March 16, 2005
Human Molecular Genetics 2005 14(8):1077-1086; doi:10.1093/hmg/ddi120
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Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase
1Institute of Child Health, University College London with Great Ormond Street Hospital for Children NHS Trust, London WC1N 1EH, UK, 2Guy's and St Thomas's Hospital NHS Trust, London SE1 9RT, UK, 3Neurometabolic Unit, National Hospital, Queen Square, London WC1N 3BG, UK, 4Department of Histopathlogy, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London E1 1BB, UK, 5Division of Metabolic and Endocrine Diseases, Department of General Pediatrics, University Children's Hospital, D-69120 Heidelberg, Germany and 6Institute of Human Genetics, Ruprecht-Karls University, 69120 Heidelberg, Germany
* To whom correspondence should be addressed. Tel: +44 2079052628; Fax: +44 2074046191; Email: p.clayton{at}ich.ucl.ac.uk
Received January 19, 2005; Revised February 15, 2005; Accepted March 3, 2005
In the mouse, neurotransmitter metabolism can be regulated by modulation of the synthesis of pyridoxal 5'-phosphate and failure to maintain pyridoxal phosphate (PLP) levels results in epilepsy. This study of five 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 PLP-dependent enzymes. Seizures ceased with the administration of PLP, 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 Chinese hamster ovary 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 PLP 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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