DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for D,L-2-hydroxyglutaric aciduria — 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 moduleD,L-2-hydroxyglutaric aciduria 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 d,l-2-hydroxyglutaric aciduria 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
A mouse model of L-2-hydroxyglutaric aciduria was created by deleting the L-2-hydroxyglutarate dehydrogenase gene (l2hgdh-/-). These mice accumulated L-2-hydroxyglutarate in tissues, reaching about 3.5 μmol/g in brain and testis. Male mice excreted 30% more L-2-hydroxyglutarate than females, which the authors attribute to lactate dehydrogenase C activity in testes. In cultured embryonic fibroblasts from these mice, down-regulating mitochondrial malate dehydrogenase reduced formation of L-2-hydroxyglutarate. Brain concentrations of lysine and arginine were markedly increased; saccharopine was depleted and glutamine decreased by about 40%. L-2-hydroxyglutarate inhibited lysine-α-ketoglutarate reductase with a Ki of about 0.8 mM. Brain pathology showed significant spongiosis, with vacuolar lesions mostly affecting oligodendrocytes and myelin sheaths. Neurobehavioral testing indicated a deficit in learning capacity. The authors conclude that L-2-hydroxyglutaric aciduria is a disorder of metabolite repair and that accumulated L-2-hydroxyglutarate exerts toxic effects through enzyme inhibition and glial cell swelling.
Clinical descriptions of the human disease are limited. A 2012 report describes a 9-year-old boy presenting with behaviour disorder, seizure, and poor school performance, diagnosed by elevated L-2-hydroxyglutaric acid in urine, plasma, or cerebrospinal fluid. A 2022 case report describes two sisters, aged 12 and 13, from a consanguineous Caucasian family. The authors note that only 295 events have been described in the literature up to that date. A 2008 report of an infant with D-2-hydroxyglutaric aciduria (a different stereoisomer) mentions mildly dysmorphic facies, developmental delay, generalised hypotonia, myoclonic seizures, cortical blindness, and dilated cardiomyopathy requiring treatment. Muscle biopsy showed excessive glycogen and subsarcolemmal cylindrical spirals. The authors state that valproic acid is contraindicated for treating epilepsy in D-2-hydroxyglutaric aciduria because of the metabolism of that disease.
No drug treatment is tested or recommended in any of these abstracts. The mouse model provides a tool for studying the biochemical consequences of L-2-hydroxyglutarate accumulation, but no therapeutic intervention is reported. What is still missing is any clinical trial, any tested drug, any attempt to reduce L-2-hydroxyglutarate levels in patients, and any clear understanding of which patients might benefit from which approach. The small number of described cases (fewer than 300) makes patient stratification difficult, and funding for a rare neurometabolic disease is limited.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PLoS ONE · 2015 · 61 citations · open access
A Mouse Model of L-2-Hydroxyglutaric Aciduria, a Disorder of Metabolite Repair
AbstractThe purpose of the present work was to progress in our understanding of the pathophysiology of L-2-hydroxyglutaric aciduria, due to a defect in L-2-hydroxyglutarate dehydrogenase, by creating and studying a mouse model of this disease. L-2-hydroxyglutarate dehydrogenase-deficient mice (l2hgdh-/-) accumulated L-2-hydroxyglutarate in tissues, most particularly in brain and testis, where the concentration reached ≈ 3.5 μmol/g. Male mice showed a 30% higher excretion of L-2-hydroxyglutarate compared to female mice, supporting that this dicarboxylic acid is partially made in males by lactate dehydrogenase C, a poorly specific form of this enzyme exclusively expressed in testes. Involvement of mitochondrial malate dehydrogenase in the formation of L-2-hydroxyglutarate was supported by the commensurate decrease in the formation of this dicarboxylic acid when down-regulating this enzyme in mouse l2hgdh-/- embryonic fibroblasts. The concentration of lysine and arginine was markedly increased in the brain of l2hgdh-/- adult mice. Saccharopine was depleted and glutamine was decreased by ≈ 40%. Lysine-α-ketoglutarate reductase, which converts lysine to saccharopine, was inhibited by L-2-hydroxyglutarate with a Ki of ≈ 0.8 mM. As low but significant activities of the bifunctional enzyme lysine-α-ketoglutarate reductase/saccharopine dehydrogenase were found in brain, these findings suggest that the classical lysine degradation pathway also operates in brain and is inhibited by the high concentrations of L-2-hydroxyglutarate found in l2hgdh-/- mice. Pathological analysis of the brain showed significant spongiosis. The vacuolar lesions mostly affected oligodendrocytes and myelin sheats, as in other dicarboxylic acidurias, suggesting that the pathophysiology of this model of leukodystrophy may involve irreversible pumping of a dicarboxylate in oligodendrocytes. Neurobehavioral testing indicated that the mice mostly suffered from a deficit in learning capacity. In conclusion, the findings support the concept that L-2-hydroxyglutaric aciduria is a disorder of metabolite repair. The accumulation of L-2-hydroxyglutarate exerts toxic effects through various means including enzyme inhibition and glial cell swelling.
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AbstractAn infant girl was demonstrated to have D-2-hydroxyglutaric aciduria, the fifth case described and the first with muscle biopsy of this rare organic aciduria that differs clinically and genetically from the more common L-2-hydroxyglutaric aciduria. Her clinical features included mildly dysmorphic facies, developmental delay, generalized hypotonia, myoclonic seizures, cortical blindness, and dilated cardiomyopathy requiring treatment. Muscle biopsy demonstrated only excessive glycogen histochemically, but ultrastructural examination revealed subsarcolemmal cylindrical spirals and normal mitochondria. Because of the metabolism of D-2-hydroxyglutaric aciduria, we regard valproic acid as contraindicated in the treatment of epilepsy in this disease.
AbstractL-2-hydroxyglutaric aciduria is a rare, autosomal recessive inherited neurometabolic disease affecting the central nervous system. The disease is characterized by mental retardation, behavior disorder, ataxia, epileptic seizures and macrocephaly. Brain magnetic resonance imaging reveals alterations in the bilateral symmetric basal ganglia, subcortical white matter and dentat nuclei. Diagnosis is confirmed by increased levels of L-2-hydroxyglutaric acid in urine, plasma or cerebrospinal fluid. In this report, a 9-year-old boy presented with behavior disorder, seizure, and failure in school performance and was diagnosed with L-2-hydroxyglutaric aciduria. This report discusses this rare disease and new therapeutic approaches.
American Journal of Medical Case Reports · 2022 · 0 citations · open access
Case Report: L-2-Hydroxyglutaric Aciduria in Sibling Sisters
AbstractOur case report presents one of the rarely seen disorders L-2-hydroxyglutaric aciduria. Very little information is given in the literature and it remained undiagnosed until the 1980s. According to our information, only 295 events have been described in the literature till date. Our case report describes the disease manifestations, clinical pictures, and a review of the relevant literature on L-2-hydroxyglutaric aciduria. Our patients were females aged 12 and 13 years, respectively, which were born in consanguineous and Caucasian descent family.
AbstractA group of genetic disorders characterized by elevated urinary concentrations of 2hydroxyglutaric acid.T hree different types have been identified based on the steroisomeric composition of the elevated alpha-hydroxyglutaric acid metabolites.Additionally, the disease may be categorized by the genetic mutation that is causative.Genes associated with 2-hydroxyglutaric aciduria are L2HGDH, D2HGDH, IDH2, and/or SLC25A1.Generally, there is nervous system involvement, but the clinical manifestations are variable and are dependent on the specific type of defect present.
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.
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