Journal Article

Neonatal epileptic encephalopathy caused by mutations in the <i>PNPO</i> gene encoding pyridox(am)ine 5′-phosphate oxidase

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

in Human Molecular Genetics

Volume 14, issue 8, pages 1077-1086
Published in print April 2005 | ISSN: 0964-6906
Published online March 2005 | e-ISSN: 1460-2083 | DOI:
Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5′-phosphate oxidase

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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).

Journal Article.  6914 words.  Illustrated.

Subjects: Genetics and Genomics

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