DeCure for Pyridoxal phosphate-responsive seizures
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for pyridoxal phosphate-responsive seizures — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePyridoxal phosphate-responsive seizures maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for pyridoxal phosphate-responsive seizures is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
What the evidence adds up to
Pyridoxal phosphate-responsive seizures are a rare condition caused by mutations in the PNPO gene, which encodes pyridox(am)ine 5'-phosphate oxidase. This enzyme converts pyridoxine phosphate and pyridoxamine phosphate into pyridoxal phosphate, a cofactor required for neurotransmitter synthesis. In a cohort of 82 individuals whose seizures reduced in frequency and severity after treatment with either pyridoxine or pyridoxal phosphate, sequencing identified three groups of patients with PNPO mutations and reduced enzyme activity: six patients with neonatal onset seizures that responded to pyridoxal phosphate, one patient with infantile spasms starting at five months that responded to pyridoxal phosphate, and eight patients whose seizures began before three months of age and responded to pyridoxine. Certain genotypes, such as R225H/C and D33V, appeared more likely to produce seizures that responded to pyridoxine. However, the same combination of mutations was seen in patients who did and did not respond to pyridoxine, indicating that the relationship between genotype and treatment response is not straightforward.
The clinical spectrum of PNPO deficiency is broader than initially reported. Some patients experienced worsening of symptoms when switched from pyridoxine to pyridoxal phosphate. Additional factors that may influence treatment response and outcome include prematurity, age at the time of the therapeutic trial, riboflavin status, and maternal supply of vitamin B6 to the foetus. Many PNPO mutations affected residues involved in binding flavin mononucleotide or pyridoxal phosphate, and many of these mutations retained residual enzyme activity. One sequence change, R116Q, predicted to affect flavin mononucleotide binding and dimerisation, showed high residual activity and was found in both the pyridoxal phosphate-responsive infantile spasms patient and the pyridoxine-responsive group. This variant has been reported in the 1000 Genomes project, raising the possibility that it could be a polymorphism or a common mutation that contributes to a susceptibility locus for genetic generalised epilepsy on chromosome 17q21.32.
Earlier work had ruled out mutations in the gene encoding glutamic acid decarboxylase as a cause of pyridoxine-dependent seizures. While linkage to chromosome 5q31 was demonstrated, no disease-causing gene in that region has been identified, and haplotype analysis of six affected kindreds showed genetic heterogeneity. Elevated pipecolic acid levels may serve as a diagnostic marker for patients with pyridoxine-dependent seizures. For neonatal epileptic encephalopathy unresponsive to pyridoxine and standard anticonvulsants, a trial of pyridoxal phosphate is recommended.
What remains missing is a clear understanding of why some patients with PNPO mutations respond to pyridoxine while others require pyridoxal phosphate, and why the same mutation can be associated with different responses. The role of modifying factors such as riboflavin status, prematurity, and maternal nutrition has not been systematically studied in a controlled trial. No large prospective trial has compared pyridoxine and pyridoxal phosphate head-to-head in genetically defined subgroups, and the long-term developmental outcomes for patients on each treatment are not well characterised. Funding for such trials and for the development of reliable, widely available biochemical and genetic diagnostic tests is lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain · 2014 · 182 citations · open access
Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome
AbstractThe 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.
Current Opinion in Neurology · 2006 · 85 citations
Pyridoxine-dependent seizures: new genetic and biochemical clues to help with diagnosis and treatment
AbstractPURPOSE OF REVIEW: Pyridoxine dependency is an uncommon but important cause of intractable seizures presenting in infancy and early childhood. This paper discusses recent clinical, biochemical and genetic studies and how the findings should change our approach in evaluating young patients with antiepileptic drug-resistant seizures. RECENT FINDINGS: Originally thought to be due to abnormal binding of pyridoxal phosphate to glutamic acid decarboxylase resulting in decreased gamma-aminobutyric acid, mutations in the gene encoding this enzyme have been ruled out. While linkage to 5q31 has been demonstrated, a disease-causing gene in that region has not been identified. Further haplotype analysis of six affected kindreds has demonstrated genetic heterogeneity for this rare disorder. Other studies demonstrate that some children with intractable seizures respond to pyridoxal phosphate rather than pyridoxine, including a rare form of neonatal epileptic encephalopathy shown to be due to mutations in the PNPO gene for pyridox(am)ine 5'-phosphate oxidase. While the biochemical explanation for this finding is not clear, elevated pipecolic acid levels may serve as a diagnostic marker for patients with pyridoxine-dependent seizures. SUMMARY: The results of these studies should prompt clinicians to adopt new strategies for diagnosis and therapy for young patients with intractable seizures. Levels of both pipecolic acid and certain metabolites shown to be elevated in patients with PNPO mutations should be measured, and therapeutic trials of pyridoxal phosphate as well as pyridoxine should be considered early in the course of the management of infants and young children with intractable seizures.
AbstractPyridox(am)ine-5'-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5'-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant treatment but responsive to pyridoxal phosphate is described. Pyridoxal phosphate should be considered in neonatal epileptic encephalopathy unresponsive to pyridoxine.
AbstractPyridox(am)ine-5'-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5'-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant treatment but responsive to pyridoxal phosphate is described. Pyridoxal phosphate should be considered in neonatal epileptic encephalopathy unresponsive to pyridoxine.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
