DeCure for Pyridoxine-dependent epilepsy caused by ALDH7A1 mutant
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for pyridoxine-dependent epilepsy caused by ALDH7A1 mutant — 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 modulePyridoxine-dependent epilepsy caused by ALDH7A1 mutant 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 pyridoxine-dependent epilepsy caused by aldh7a1 mutant 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.
Molecular view
aldehyde dehydrogenase 7 family member A1 (ALDH7A1) — ALDH7A1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet naddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6O4C · 1.7 Å · ligand NICOTINAMIDE-ADENINE-DINUCLEOTIDE (NAD). Experimental structure, not a prediction.
What the evidence adds up to
Pyridoxine-dependent epilepsy caused by ALDH7A1 mutations is a disorder of severe seizures that respond to daily pharmacological doses of pyridoxine, not to standard anticonvulsants. The underlying mechanism is deficient activity of α-aminoadipic semialdehyde dehydrogenase, leading to accumulation of α-aminoadipic semialdehyde and piperideine-6-carboxylic acid, which reacts with pyridoxal-phosphate. A 2010 study of 15 patients identified six missense, one nonsense, and five splice-site mutations, plus two small deletions; nine mutations accounted for 61% of alleles. Recurring mutations included E399Q (eight times), G477R (six times), R82X (two times), and c.1217_1218delAT (two times). Missense mutations clustered around exons 14, 15, and 16. A 2015 study found that among six patients with clinical and biochemical evidence of the disease but only one detectable mutation by sequence analysis, five had partial deletions of ALDH7A1, likely from Alu-Alu recombination. Over 70 mutations in ALDH7A1 have now been reported.
Three clinical phenotypes are described. Group 1 patients achieve complete seizure control with pyridoxine and have normal developmental outcome. Group 2 patients achieve complete seizure control but have developmental delay. Group 3 patients have persistent seizures despite pyridoxine and also have developmental delay. In the 2010 cohort, one patient was in group 1 and two were in group 2. Preliminary evidence suggests a genotype-phenotype correlation: group 1 patients may carry mutations with residual enzyme activity. However, patients with similar genotypes can have different outcomes, indicating nongenetic factors also contribute. A 2021 review states that seizure control is achieved by high-dose pyridoxine started as soon as possible, but that pyridoxine therapy does not prevent developmental delay in most cases. For such cases, supplementing arginine with pyridoxine and dietary lysine restriction is recommended.
What remains missing is a prospective trial that stratifies patients by genotype and measures developmental outcomes under standardised pyridoxine dosing, with or without arginine and lysine restriction. The rarity of the disorder makes such a trial difficult to fund and recruit for. Without that, the genotype-phenotype correlation remains preliminary, and the effect of adjunctive dietary interventions on developmental delay is not established by controlled evidence.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Inherited Metabolic Disease · 2020 · 118 citations · open access
Consensus guidelines for the diagnosis and management of pyridoxine‐dependent epilepsy due to α‐aminoadipic semialdehyde dehydrogenase deficiency
AbstractPyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.
Journal of Inherited Metabolic Disease · 2010 · 84 citations · open access
The genotypic and phenotypic spectrum of pyridoxine‐dependent epilepsy due to mutations in <i>ALDH7A1</i>
AbstractPyridoxine-dependent epilepsy is a disorder associated with severe seizures that may be caused by deficient activity of α-aminoadipic semialdehyde dehydrogenase, encoded by the ALDH7A1 gene, with accumulation of α-aminoadipic semialdehyde and piperideine-6-carboxylic acid. The latter reacts with pyridoxal-phosphate, explaining the effective treatment with pyridoxine. We report the clinical phenotype of three patients, their mutations and those of 12 additional patients identified in our clinical molecular laboratory. There were six missense, one nonsense, and five splice-site mutations, and two small deletions. Mutations c.1217_1218delAT, I431F, IVS-1(+2)T > G, IVS-2(+1)G > A, and IVS-12(+1)G > A are novel. Some disease alleles were recurring: E399Q (eight times), G477R (six times), R82X (two times), and c.1217_1218delAT (two times). A systematic review of mutations from the literature indicates that missense mutations cluster around exons 14, 15, and 16. Nine mutations represent 61% of alleles. Molecular modeling of missense mutations allows classification into three groups: those that affect NAD+ binding or catalysis, those that affect the substrate binding site, and those that affect multimerization. There are three clinical phenotypes: patients with complete seizure control with pyridoxine and normal developmental outcome (group 1) including our first patient; patients with complete seizure control with pyridoxine but with developmental delay (group 2), including our other two patients; and patients with persistent seizures despite pyridoxine treatment and with developmental delay (group 3). There is preliminary evidence for a genotype-phenotype correlation with patients from group 1 having mutations with residual activity. There is evidence from patients with similar genotypes for nongenetic factors contributing to the phenotypic spectrum.
Intragenic deletions of <i>ALDH7A1</i> in pyridoxine-dependent epilepsy caused by <i>Alu</i> - <i>Alu</i> recombination
AbstractOBJECTIVE: To investigate the role of intragenic deletions of ALDH7A1 in patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single identifiable mutation in ALDH7A1. METHODS: We designed a custom oligonucleotide array with high-density probe coverage across the ALDH7A1 gene. We performed array comparative genomic hybridization in 6 patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single detectable mutation in ALDH7A1 by sequence analysis. RESULTS: We found partial deletions of ALDH7A1 in 5 of 6 patients. Breakpoint analysis reveals that the deletions are likely a result of Alu-Alu recombination in all cases. The density of Alu elements within introns of ALDH7A1 suggests susceptibility to recurrent rearrangement. CONCLUSION: Patients with clinical pyridoxine-dependent epilepsy and a single identifiable mutation in ALDH7A1 warrant further investigation for copy number changes involving the ALHD7A1 gene.
Phytoma España: La revista profesional de sanidad vegetal · 2013 · 0 citations
Enfermedades fúngicas de la madera de la vid: estrategias de manejo
AbstractPyridoxine-dependent seizures (PDS) is a rare disorder characterized by seizures resistant to anticonvulsants but controlled by daily pharmacologic doses of pyridoxine. Mutations in the antiquitin (ALDH7A1) gene have recently reported to cause PDS in most of patients. We report the long-term follow-up in two PDS siblings carrying a novel ALDH7A1 mutation.
Journal of Pediatric Neurology · 2021 · 0 citations
ALDH7A1 Gene and Its Related Pyridoxine-Dependent Epilepsy
AbstractAbstract Despite being classically reported as caused by mutations in solute carriers genes (SLC2A1), it has been recently shown that also mutations in ALDH7A1 can cause pyridoxine-dependent epilepsy (PDE). ALDH7A1 is a gene encoding for the antiquitin, an enzyme that catalyzes the nicotinamide adenine dinucleotide-dependent dehydrogenation of L-α-aminoadipic semialdehyde/L-Δ1-piperideine 6-carboxylate. It is a highly treatable disorder, but nevertheless it is still not certain when to consider this diagnosis and how to test for it. It is possible to identify a classical form and an atypical one of PDE associated with more than 70 mutations of ALDH7A1 gene. The typical form is characterized by the onset of seizures within the first month of life and can be treated with pyridoxine in monotherapy, as they are not responsive to traditional anticonvulsant therapy. The atypical forms are equally pyridoxine-dependent, but are characterized by a later onset of seizures, sometimes up to the age of 3 years. Several brain abnormalities have been associated with ALDH7A1 mutations. Seizure control is achieved by the administration of high-dose pyridoxine, which must be started in the patient as soon as possible. However, it has been observed that pyridoxine therapy does not prevent developmental delay in most cases; in these cases, it can be recommended and useful to supplement arginine with pyridoxine therapy associated with a dietary restriction of lysine.
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.
