title: Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome.
abstract: The first described patients with pyridox(am)ine 5'-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5'-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5'-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5'-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5'-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5'-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5'-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin mononucleotide or pyridoxal 5'-phosphate and many of them showed residual enzyme activity. One sequence change (R116Q), predicted to affect flavin mononucleotide binding and binding of the two PNPO dimers, and with high residual activity was found in Groups (ii) and (iii). This sequence change has been reported in the 1000 Genomes project suggesting it could be a polymorphism but alternatively it could be a common mutation, perhaps responsible for the susceptibility locus for genetic generalized epilepsy on 17q21.32 (close to rs72823592). We believe the reduction in PNPO activity and B6-responsive epilepsy in the patients reported here indicates that it contributes to the pathogenesis of epilepsy.
authors.affiliation: 1 Clinical and Molecular Genetics Unit, UCL Institute of Child Health, 30 Guilford St, London WC1N 1EH, UK.
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.forename: Stephane S M
authors.initials: SS
authors.lastname: Camuzeaux
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Footitt
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Mills
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.forename: Laura
authors.initials: L
authors.lastname: Fisher
authors.forename: Krishna B
authors.initials: KB
authors.lastname: Das
authors.forename: Sophia M
authors.initials: SM
authors.lastname: Varadkar
authors.forename: Sameer
authors.initials: S
authors.lastname: Zuberi
authors.forename: Robert
authors.initials: R
authors.lastname: McWilliam
authors.forename: Tommy
authors.initials: T
authors.lastname: Stödberg
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
authors.forename: Oliver
authors.initials: O
authors.lastname: Maier
authors.forename: Sophie
authors.initials: S
authors.lastname: Calvert
authors.forename: Kate
authors.initials: K
authors.lastname: Riney
authors.forename: Nicole I
authors.initials: NI
authors.lastname: Wolf
authors.forename: John H
authors.initials: JH
authors.lastname: Livingston
authors.forename: Pronab
authors.initials: P
authors.lastname: Bala
authors.forename: Chantal F
authors.initials: CF
authors.lastname: Morel
authors.forename: François
authors.initials: F
authors.lastname: Feillet
authors.forename: Francesco
authors.initials: F
authors.lastname: Raimondi
authors.forename: Ennio
authors.initials: E
authors.lastname: Del Giudice
authors.forename: W Kling
authors.initials: WK
authors.lastname: Chong
authors.forename: Matthew
authors.initials: M
authors.lastname: Pitt
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D004777:Environment; D004827:Epilepsy / Q000235:genetics* / Q000628:therapy; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007223:Infant; D008297:Male; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009154:Mutation / Q000235:genetics*; D011732:Pyridoxal Phosphate / Q000627:therapeutic use; D011734:Pyridoxaminephosphate Oxidase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D011732:Pyridoxal Phosphate; D011734:Pyridoxaminephosphate Oxidase
keywords: epilepsy; pyridox(am)ine 5’-phosphate oxidase (PNPO); pyridoxal 5’-phosphate (PLP); pyridoxine; seizures