title: Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase.
abstract: 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).
authors.affiliation: Institute of Child Health, University College London with Great Ormond Street Hospital for Children, NHS Trust, London WC1N 1EH, UK.
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.forename: Robert A H
authors.initials: RA
authors.lastname: Surtees
authors.forename: Michael P
authors.initials: MP
authors.lastname: Champion
authors.forename: Clare E
authors.initials: CE
authors.lastname: Beesley
authors.forename: Neil
authors.initials: N
authors.lastname: Dalton
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: Simon J R
authors.initials: SJ
authors.lastname: Heales
authors.forename: Anthony
authors.initials: A
authors.lastname: Briddon
authors.forename: Irene
authors.initials: I
authors.lastname: Scheimberg
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011732:Pyridoxal Phosphate / Q000494:pharmacology; D011734:Pyridoxaminephosphate Oxidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D011732:Pyridoxal Phosphate; D011734:Pyridoxaminephosphate Oxidase