Pyridoxal 5 '-phosphate may be curative in early-onset epileptic encephalopathy

University of Bonn, Bonn, North Rhine-Westphalia, Germany
Journal of Inherited Metabolic Disease (Impact Factor: 4.14). 03/2007; 30(1):96-9. DOI: 10.1007/s10545-006-0508-4
Source: PubMed

ABSTRACT Neonatal epileptic encephalopathy can be caused by inborn errors of metabolism. These conditions are often unresponsive to treatment with conventional antiepileptic drugs. Six children with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency presented with neonatal epileptic encephalopathy. Two were treated with pyridoxal 5'-phosphate (PLP) within the first month of life and showed normal development or moderate psychomotor retardation thereafter. Four children with late or no treatment died or showed severe mental handicap. All of the children showed atypical biochemical findings. Prompt treatment with PLP in all neonates and infants with epileptic encephalopathy should become mandatory, permitting normal development in at least some of those affected with PNPO deficiency.

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Available from: Beat Steinmann, Jun 29, 2014
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    • "Mutations in PNPO known to be associated with neonatal epileptic encephalopathy for which expression studies have shown reduced enzyme activity are: IVS3-1g4a, X262Q, R229W (Mills et al., 2005) and R95H (Khayat et al., 2008). Other probable neonatal epileptic encephalopathy-causing PNPO mutations include R95C, D33V, c.246delT (Hoffmann et al., 2007), A174X (Ruiz et al., 2008), R225C (Veerapandiyan et al., 2011) and G118R (Pearl et al., 2012). The effects of R229W on PNPO catalytic function and crystal structure have been studied by Musayev et al. (2009). "
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    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.
    Brain 03/2014; 137(5). DOI:10.1093/brain/awu051 · 10.23 Impact Factor
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    • "Seizures in Patient 12 (D33V in combination with R116Q and R225C) also responded well to treatment with pyridoxine . Conversely seizures in Patient 2 (homozygous D33V) failed to respond to a 10-day trial of 100 mg pyridoxine/day and previously reported patients [Patient 4; homozygous D33V (Goyal et al., 2013) and Patient 3; heterozygous D33V/heterozy- gous c.246delT (Hoffmann et al., 2007)] failed to respond to shorter trials of pyridoxine. Perhaps Patient 2 did not respond to pyridoxine because she was breast fed; breast feeding can be associated with a relative deficiency of riboflavin (Hovi et al., 1979) or perhaps because she has a second genetic factor compromising PLP homeostasis or neurotransmitter metabolism. "
    Brain 01/2014; · 10.23 Impact Factor
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    • "The investigators found no therapeutic response with pyridoxine and folinic acid when used without PLP (the latter compound discussed in some detail later). In some instances, the above recommended PLP dose may have to be increased to effectively treat the disease [6]. As noted by Wang et al., [73], it may also require concomitant use of PLP and AEDs to effectively treat the disorder. "
    Miscellanea on Encephalopathies - A Second Look, 04/2012; , ISBN: 978-953-51-0558-9
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