DeCure for Developmental and epileptic encephalopathy, 88
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for developmental and epileptic encephalopathy, 88 — 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 moduleDevelopmental and epileptic encephalopathy, 88 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 developmental and epileptic encephalopathy, 88 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
malate dehydrogenase 1 (MDH1) — MDH1 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 mlidrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7RM9 · 1.65 Å · ligand MALONATE ION (MLI). Experimental structure, not a prediction.
What the evidence adds up to
A 2015 review noted that childhood epileptic encephalopathies show marked genetic heterogeneity and a high frequency of de novo mutations, listing the genes then known to be involved. A 2023 review on childhood epilepsy stated that many children with pharmacoresistant epilepsy beginning in early infancy progress to developmental epileptic encephalopathy, which is associated with intellectual, behavioural and motor disabilities; these children do not show remission and require comprehensive medical care into adulthood.
A 2024 case report described a patient with developmental and epileptic encephalopathy carrying a synonymous variant in the ATP6AP2 gene (c.858G>A, p.Ala286=). The patient began having tonic seizures at 3.5 months of age; magnetic resonance imaging showed impaired brain white matter development and reduced left hippocampal volume. Electroencephalography showed multifocal interictal epileptiform discharges. Treatment with various anti-seizure medications yielded unsatisfactory results, and the disorder eventually developed into epileptic spasms. An in vitro splicing assay showed the variant caused a deletion in exon 8 and corresponding protein truncation. A review of previously reported ATP6AP2-related DEE patients found that synonymous variants in this gene can cause early DEE onset, progressive changes in early-life MRI, and exon skipping.
A 2018 case report described a six-year-old girl with early infantile epileptic encephalopathy type 13 carrying a heterozygous missense mutation in the SCN8A gene (c.5616G>A, p.Arg1872Gln). She had complex partial seizures from the left temporal lobe beginning at 4 months of age, which were difficult to control with medication and evolved to generalised tonic-clonic seizures after age 3. Seizures occurred as rarely as once every 5–10 months, but neurodevelopment became severely delayed. The authors suggested this SCN8A mutation has a primary neurodegenerative effect leading to brain atrophy and intellectual disability partially independent of its epileptogenic effect.
What is still missing are treatments that reliably control seizures or prevent the progressive neurodevelopmental decline in these genetically defined encephalopathies. No trial has yet tested a drug specifically for ATP6AP2-related DEE or for the SCN8A p.Arg1872Gln mutation. Patient stratification by precise genetic diagnosis is possible but not yet linked to any proven therapy, and funding for such targeted trials remains scarce.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Arquivos de Neuro-Psiquiatria · 2015 · 17 citations · open access
Recent developments in the genetics of childhood epileptic encephalopathies: impact in clinical practice
AbstractRecent advances in molecular genetics led to the discovery of several genes for childhood epileptic encephalopathies (CEEs). As the knowledge about the genes associated with this group of disorders develops, it becomes evident that CEEs present a number of specific genetic characteristics, which will influence the use of molecular testing for clinical purposes. Among these, there are the presence of marked genetic heterogeneity and the high frequency of de novo mutations. Therefore, the main objectives of this review paper are to present and discuss current knowledge regarding i) new genetic findings in CEEs, ii) phenotype-genotype correlations in different forms of CEEs; and, most importantly, iii) the impact of these new findings in clinical practice. Accompanying this text we have included a comprehensive table, containing the list of genes currently known to be involved in the etiology of CEEs.
Frontiers in Neurology · 2024 · 4 citations · open access
Synonymous variants in the ATP6AP2 gene may lead to developmental and epileptic encephalopathy
AbstractObjective To the literature, variants in the ATP6AP2 gene may cause abnormal nervous system development and associated neurological symptoms. Methods We report a patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G > A (p.Ala286=) synonymous variant. In addition, an overview of reported patients with the same variant were collected and summarized to compare our findings. Results The patient started experiencing tonic seizures at 3.5 months of age, and magnetic resonance imaging (MRI) indicated impaired brain white matter development and reduced left hippocampal volume. Furthermore, electroencephalography showed multifocal interictal epileptiform discharges. Treatment with various anti-seizure medications yielded unsatisfactory results, and the disorder eventually developed into epileptic spasms. An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. A review of previously reported ATP6AP2 -related DEE patients found that synonymous variants in the ATP6AP2 gene can cause early DEE onset, progressive changes in early-life MRI, and exon skipping in all ATP6AP2 -related DEE patients. Significance We found that synonymous variants in ATP6AP2 may have significant pathogenicity and are highly correlated with DEE. Due to increased isoform production, ATP6AP2 synonymous variants may cause nervous system developmental disorders by competitively reducing the generation of full-length transcripts, resulting in defects in ATP6AP2 -related physiological processes.
<i>SCN8A</i> p.Arg1872Gln mutation in early infantile epileptic encephalopathy type 13: Review and case report
AbstractEarly infantile epileptic encephalopathy (EIEE) is a disorder with variable genetic heterogeneity. Symptoms are mostly presented with generalised epileptic seizures with an infantile onset and progressive neurodevelopmental delay. Early infantile epileptic encephalopathy13 is caused by mutations in the SCN8A gene, which encodes the neuronal voltage-gated sodium channel α subunit (Nav1.6) and plays a major role in neuronal excitability. Describing the wide clinical variability of previously reported cases of patients carrying the same mutation, we demonstrate the complexity of the disease and the necessity of correctly correlating the phenotype with the genotype. Here, we present a minireview and a case report of EIEE13 involving the rare p.Arg1872Gln mutation in the SCN8A gene. We used targeted next-generation sequencing to examine a six-year-old girl with complex partial seizures from the left temporal lobe since 4 months of age. The condition was difficult to control with medication and the seizures evolved to generalised tonic-clonic seizures after the age of 3 years. Neurodevelopment in the child became severely delayed although seizures were as rare as 1 in every 5–10 months. А heterozygous missense mutation in the SCN8A gene (NM_014191.3:c.5616G > A, NP_055006.1:p.Arg1872Gln) was found. The variant was validated by Sanger sequencing. We suggest that this SCN8A mutation has a primary neurodegenerative effect leading to brain atrophy and intellectual disability (with or without autism) that is partially independent of its epileptogenic effect. Our results demonstrate that the application of large panels with clinically-associated genes is essential for identifying rare mutations in individuals with disorders of unknown etiology.
AbstractChildhood epilepsy is characterized by specific epilepsy syndromes that occur during each developmental age. These "age-dependent" epilepsy syndromes are clinically categorized into a self-limited epilepsy group with good prognosis and high prevalence rate and a pharmacoresistant epilepsy group with poor prognosis despite low prevalence rates. Many children develop pharmacoresistant epilepsy beginning in early infancy and progress to developmental epileptic encephalopathy, which is associated with intellectual, behavioral, and/or motor disabilities. These children do not show remission in epilepsy and are transitioned to the adult service and require comprehensive medical care.
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.
