DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for 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 moduleL-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 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
L-2-hydroxyglutaric aciduria is a rare autosomal recessive neurometabolic disorder. By 2022, only about 295 cases had been described in the literature. The disease was first reported in 1980 in a child from Morocco. The clinical phenotype is variable but cerebellar symptoms and mental deficiency have been present in almost all patients. Other features include choreiform movements, seizures, macrocephaly, speech and mental retardation, and developmental regression presenting in infancy or childhood. One report describes a 9-year-old boy who presented with behaviour disorder, seizure, and failure in school performance. Two brothers have been reported with cervical spine stenosis. Brain magnetic resonance imaging shows alterations in the bilateral symmetric basal ganglia, subcortical white matter and dentate nuclei.
The biochemical defect was identified in 2004. A FAD-dependent enzyme that specifically oxidises L-2-hydroxyglutarate to alpha-ketoglutarate exists in rat tissues, mainly in liver and kidney but also at lower levels in heart and brain. The liver enzyme is mitochondrial and membrane-bound. A human gene on chromosome 14q22.1, encoding a hypothetical protein homologous to bacterial FAD-dependent malate dehydrogenases and targeted to mitochondria, was found to be in a region homozygous in patients from two consanguineous families. Three mutations — Lys-71-Glu, Glu-176-Asp, and removal of exon 9 — were identified in homozygous state in patients from three distinct families and cosegregated with the disease. The gene most likely encodes L-2-hydroxyglutarate dehydrogenase. The pathological findings are therefore attributed to a toxic effect of L-2-hydroxyglutarate on the central nervous system.
No therapeutic trial data are reported in these abstracts. The 2012 report mentions new therapeutic approaches but provides no specific results. No drug is named, no survival or response rates are given, and no intervention has been tested in a controlled manner. The underlying metabolic defect was originally thought to involve an unidentified step in the lysine catabolic pathway, but the 2004 work points instead to a defect in the direct oxidation of L-2-hydroxyglutarate.
What is still missing is any clinical trial testing a specific treatment, any evidence of drug efficacy in patients, and any systematic patient stratification by genotype or phenotype. Funding for natural history studies and for preclinical work on substrate reduction or enzyme replacement has not been reported in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Proceedings of the National Academy of Sciences · 2004 · 194 citations · open access
A gene encoding a putative FAD-dependent <scp>l</scp> -2-hydroxyglutarate dehydrogenase is mutated in <scp>l</scp> -2-hydroxyglutaric aciduria
AbstractThe purpose of this study was to identify the biochemical and genetic defect in L-2-hydroxyglutaric aciduria, a neurometabolic disorder characterized by the presence of elevated concentrations of L-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid. Evidence is provided for the existence in rat tissues of a FAD-dependent enzyme catalyzing specifically the oxidation of L-2-hydroxyglutarate to alpha-ketoglutarate. This enzyme is mainly expressed in liver and kidney but also at lower levels in heart, brain, and other tissues. Subcellular fractionation indicates that the liver enzyme is present in mitochondria, where it is bound to membranes. Based on this information, a database search led to the identification of a gene encoding a human hypothetical protein homologous to bacterial FAD-dependent malate dehydrogenases and targeted to mitochondria. The gene encoding this protein, present on chromosome 14q22.1, was found to be in a region homozygous in patients with L-2-hydroxyglutaric aciduria from two consanguineous families. Three mutations that replaced a highly conserved residue (Lys-71-Glu and Glu-176-Asp) or removed exon 9 were identified in homozygous state in patients from three distinct families and were found to cosegregate with the disease. It is concluded that L-2-hydroxyglutarate is normally metabolized to alpha-ketoglutarate in mammalian tissues and that L-2-hydroxyglutaric aciduria is caused by mutations in the gene that most likely encodes L-2-hydroxyglutarate dehydrogenase. The pathological findings observed in this metabolic disorder must therefore be due to a toxic effect of L-2-hydroxyglutarate on the central nervous system.
L-2-hydroxyglutaric aciduria presenting as migraine
AbstractL-2 hydroxyglutaric aciduria is a rare inborn error of metabolism, first described in 1980 in a child from Morocco.1 It has now been identified in almost 50 patients. The clinical phenotype is variable, including cerebellar ataxia, choreiform movements, seizures, macrocephaly, speech and mental retardation, and developmental regression presenting in infancy or childhood.1,2⇓ Two brothers have been reported with cervical spine stenosis.3 Cerebellar symptoms and mental deficiency have been present in almost all patients. There is increased urinary excretion of L-2 hydroxyglutaric aciduria, as well as increased concentrations in CSF and to a lesser extent in plasma. The underlying metabolic defect is unknown and is thought to involve an unidentified step in the lysine catabolic pathway.2 …
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.
Internal Medicine · 2025 · 0 citations · open access
Successful Treatment of 2-hydroxyglutaric Aciduria Diagnosed in Adulthood, Three Decades After the Onset: A Case Report and Literature Review
Abstract2-Hydroxyglutaric aciduria is a rare genetic metabolic disorder, especially in Japan. Although magnetic resonance images show characteristic abnormalities in the subcortical white matter, some cases have been diagnosed in adulthood, namely many decades after onset. We herein report the case of a bedridden 37-year-old 2-hydroxyglutaric aciduria male patient who was diagnosed three decades after onset. Despite this, combination treatment with riboflavin and levocarnitine improved his condition, thus allowing him to walk by himself. Considering our case and the previous literature, we emphasize the importance of correctly diagnosing and treating patients with 2-hydroxyglutaric aciduria.
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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