Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome
| العنوان: | Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome |
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| المؤلفون: | Mills, Philippa B, Camuzeaux, Stephane S M, Footitt, Emma J, Mills, Kevin A, Gissen, Paul, Fisher, Laura, Das, Krishna B, Varadkar, Sophia M, Zuberi, Sameer, McWilliam, Robert, Stödberg, Tommy, Plecko, Barbara, Baumgartner, Matthias R, Maier, Oliver, Calvert, Sophie, Riney, Kate, Wolf, Nicole I, Livingston, John H, Bala, Pronab, Morel, Chantal F, Feillet, François, Raimondi, Francesco, Del Giudice, Ennio, Chong, W Kling, Pitt, Matthew, Clayton, Peter T |
| المساهمون: | University of Zurich, Clayton, Peter T, UCL Institute of Child Health, Great Ormond Street Hospital for Children [London] (GOSH), Royal Hospital for Sick Children, Glasgow, Astrid Lindgren Children's Hospital, Karolinska University Hospital [Stockholm], University Children’s Hospital Zurich, Department of Child Neurology, Development and Rehabilitation [Hospital of Eastern Switzerland], Children's Hospital of Eastern Switzerland St.Gallen, Mater Children's Private Hospital [Brisbane], Dept. of Neurology, VU University Medical Center, Children's Hospital of Leeds, Airedale General Hospital NHS Foundation Trust, University Health Network, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), 'Federico II' University of Naples Medical School, Pediatric surgery, NCA - Brain mechanisms in health and disease, P. B., Mill, S. S. M., Camuzeaux, E. J., Footitt, K. A., Mill, P., Gissen, L., Fisher, K. B., Da, S. M., Varadkar, S., Zuberi, R., Mcwilliam, T., Stodberg, B., Plecko, M. R., Baumgartner, O., Maier, S., Calvert, K., Riney, N. I., Wolf, J. H., Livingston, P., Bala, C. F., Morel, F., Feillet, Raimondi, Francesco, DEL GIUDICE, Ennio, W. K., Chong, M., Pitt, P. T., Clayton |
| المصدر: | Mills, P B, Camuzeaux, S S M, Footitt, E J, Mills, K A, Gissen, P, Fisher, L, Das, K B, Varadkar, S M, Zuberi, S, McWilliam, R, Stodberg, T, Plecko, B, Baumgartner, M R, Maier, O, Calvert, S, Riney, K, Wolf, N I, Livingston, J H, Bala, P, Morel, C F, Feillet, F, Raimondi, F, Del Giudice, E, Chong, W K, Pitt, M & Clayton, P T 2014, ' Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome ', Brain, vol. 137, pp. 1350-1360 . https://doi.org/10.1093/brain/awu051Test Brain Brain-A Journal of Neurology Brain-A Journal of Neurology, Oxford University Press (OUP), 2014, 137 (5), pp.1350-1360. ⟨10.1093/brain/awu051⟩ Brain, 137, 1350-1360. Oxford University Press |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Male, [SDV]Life Sciences [q-bio], chemical and pharmacologic phenomena, 610 Medicine & health, Environment, Transfection, Young Adult, immune system diseases, Humans, Child, pyridoxine, seizures, Epilepsy, pyridoxal 5’-phosphate (PLP), food and beverages, Infant, pyridox(am)ine 5’-phosphate oxidase (PNPO), Electroencephalography, Original Articles, Pyridoxaminephosphate Oxidase, nervous system diseases, 2728 Neurology (clinical), 10036 Medical Clinic, Child, Preschool, Pyridoxal Phosphate, Mutation, Mutagenesis, Site-Directed, lipids (amino acids, peptides, and proteins), Anticonvulsants, Female, HeLa Cells |
| الوصف: | Mutations in PNPO are a known cause of neonatal onset seizures that are resistant to pyridoxine but responsive to pyridoxal phosphate (PLP). Mills et al. show that PNPO mutations can also cause neonatal onset seizures that respond to pyridoxine but worsen with PLP, as well as PLP-responsive infantile spasms. 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. |
| وصف الملف: | Brain-2014-Mills-brain_awu051.pdf - application/pdf |
| اللغة: | English |
| تدمد: | 0006-8950 1460-2156 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::32a23f3d512a09839e593e237bb2655fTest https://doi.org/10.5167/uzh-94354Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.pmid.dedup....32a23f3d512a09839e593e237bb2655f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00068950 14602156 |
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