DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for ethylmalonic encephalopathy — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleEthylmalonic encephalopathy maps to a 3-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 ethylmalonic encephalopathy 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
ETHE1 persulfide dioxygenase (ETHE1) — ETHE1 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4CHL · 2.61 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Ethylmalonic encephalopathy is a rare autosomal recessive metabolic disorder caused by mutations in the ETHE1 gene on chromosome 19q13. In a 2005 study, frameshift, stop, splice site, and missense mutations of ETHE1 were found in all 29 patients with typical ethylmalonic encephalopathy, while no ETHE1 mutations were identified in 11 patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria who did not have the full syndrome. The ETHE1 protein is thought to be a mitochondrial matrix thioesterase acting on an unknown substrate, and the precise pathogenesis remains only partly understood. A 2008 report noted that by 2007 only about 35 patients, mostly of Mediterranean descent, had been described since the first report in 1991.
A 2001 therapeutic trial described three Korean girls, the first Asian cases, who received riboflavin and/or coenzyme Q10. The authors reported slight improvement in motor functions, cognitive behaviours, and chronic mucoid diarrhoea after treatment, but stated that the precise pathogenesis had not been fully elucidated and that riboflavin treatment may be helpful. No controlled trial data exist. No other drug treatments are reported in these abstracts.
The substrate of the ETHE1 enzyme is still unknown, and the molecular mechanisms of the disease are only partly understood despite identification of the gene defect. What is missing is a clear biochemical target for drug development, any randomised or controlled clinical trial data, and a sufficiently large and genetically defined patient population to stratify for potential treatment effects.
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 Medical Genetics · 2005 · 89 citations
<i>ETHE1</i> mutations are specific to ethylmalonic encephalopathy
AbstractMutations in ETHE1, a gene located at chromosome 19q13, have recently been identified in patients affected by ethylmalonic encephalopathy (EE). EE is a devastating infantile metabolic disorder, characterised by widespread lesions in the brain, hyperlactic acidaemia, petechiae, orthostatic acrocyanosis, and high levels of ethylmalonic acid in body fluids. To investigate to what extent ETHE1 is responsible for EE, we analysed this gene in 29 patients with typical EE and in 11 patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria (non-EE EMA). Frameshift, stop, splice site, and missense mutations of ETHE1 were detected in all the typical EE patients analysed. Western blot analysis of the ETHE1 protein indicated that some of the missense mutations are associated with the presence of the protein, suggesting that the corresponding wild type amino acid residues have a catalytic function. No ETHE1 mutations were identified in non-EE EMA patients. Experiments based on two dimensional blue native electrophoresis indicated that ETHE1 protein works as a supramolecular, presumably homodimeric, complex, and a three dimensional model of the protein suggests that it is likely to be a mitochondrial matrix thioesterase acting on a still unknown substrate. Finally, the 625G-->A single nucleotide polymorphism in the gene encoding the short chain acyl-coenzyme A dehydrogenase (SCAD) was previously proposed as a co-factor in the aetiology of EE and other EMA syndromes. SNP analysis in our patients ruled out a pathogenic role of SCAD variants in EE, but did show a highly significant prevalence of the 625A alleles in non-EE EMA patients.
Journal of Inherited Metabolic Disease · 2001 · 21 citations
Therapeutic trial in the first three Asian cases of ethylmalonic encephalopathy: Response to riboflavin
AbstractThree Korean girls with ethylmalonic encephalopathy, the first Asian cases, were identified. In all three cases, we observed slight improvement in motor functions, cognitive behaviours and chronic mucoid diarrhoea after treatment with riboflavin and/or coenzyme Q10 treatment. The precise pathogenesis of ethylmalonic encephalopathy has not been fully elucidated, but riboflavin treatment may be helpful.
A severe case of encephalopathy with ethylmalonic aciduria and generalized vasculopathy
AbstractEthylmalonic Encephalopathy (EE) is a rare autosomal recessive metabolic disorder presumably restricted to the Mediterranean region caused by mutations in the ETHE-1 gene on chromosome 19q13. EE is characterized by clinical features including psychomotor retardation, hypotonia, petechiae, acrocyanosis, as well as a typical metabolic profile in body fluids and a typical neuroradiologic pattern. Despite the identification of the underlying gene defect the pathomechanism of EE is only partly understood. ETH1 enzyme is localised in the mitochondrial matrix, the substrate(s) are still unknown.
Neuropediatrics · 2007 · 0 citations · open access
Lessons to Learn from Rare Inborn Errors of Metabolism
AbstractThis issue contains a most interesting and comprehensive case report by D. Zafeiriou and co-authors [13] on one of the very rare inborn errors of metabolism - ethylmalonic encephalopathy (EE). Since the first description in 1991 by Burlina et al. [3] only about 35 patients, mostly of Mediterranean descent, have been described. Knowledge on very rare inborn errors of metabolism may not only contribute to our every day clear-up rate of unexplained cases, but may also improve our understanding of the molecular pathomechanisms involved in CNS disease. The delineation of ethylmalonic encephalopathy has been intriguing and despite the identification of the underlying gene defect by Tiranti et al. in 2004 [10], the molecular mechanisms are only partly understood today.
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.
