DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for 3-hydroxy-3-methylglutaric 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 module3-hydroxy-3-methylglutaric 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 3-hydroxy-3-methylglutaric 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.
Molecular view
3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) — HMGCL 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 3hgdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2CW6 · 2.1 Å · ligand 3-HYDROXYPENTANEDIOIC ACID (3HG). Experimental structure, not a prediction.
What the evidence adds up to
3-hydroxy-3-methylglutaric aciduria was diagnosed in a newborn infant of consanguineous parents who presented at 5 days of life with hyperammonemia, hypoglycemia, and metabolic acidosis without ketonuria. A profound deficiency of 3-hydroxy-3-methylglutaryl-coenzyme A lyase was found in cultured skin fibroblasts, with intermediate enzyme levels in the parents. The disorder is an extremely rare genetic metabolic condition of leucine metabolism.
A 2014 case report described a 4-year-old intubated female patient admitted to intensive care with status epilepticus, hypoglycemia, and severe metabolic acidosis. Urine gas chromatography-mass spectrometry showed markedly elevated 3-methylglutaric acid, 3-hydroxy-3-methylglutaryl-CoA, and 3-hydroxyisovaleric acid. After acute management, dietary therapy was the main intervention. Total daily calories were increased from 1400 kcal (targeted 60–80% of needs) to 2100–2200 kcal (targeted 100%), with a macronutrient ratio of 13% protein, 24% lipid, and 63% carbohydrate. Lifelong protein restriction was essential, with total daily protein given at 1.5–2 g/kg/day. Daily leucine dose was 1000 mg (suggested dose 700–900 mg/day), representing 1.5% of total protein. Food avoidance focused on milk, meat, cheese, fish, poultry, eggs, beans, and nutlets, with partial restriction of sprouts, radish, red bean, and mungbean. Unlimited foods included vegetables, low-protein starches, and low-leucine foods such as potato powder. The patient’s major protein source was a special formula (I-Valex I and II). Daily oral L-carnitine was prescribed to increase excretion of organic acid. The ability to recognise food labelling was taught to parents, the patient, and school nurses.
Two abstracts on 2-hydroxyglutaric aciduria and L-2-hydroxyglutaric aciduria are included but describe a different disorder. They note elevated urinary 2-hydroxyglutaric acid, variable nervous system involvement, and association with genes L2HGDH, D2HGDH, IDH2, and SLC25A1. These abstracts do not report any drug treatment or outcomes relevant to 3-hydroxy-3-methylglutaric aciduria.
What is still missing are controlled trials of any pharmacological intervention, systematic data on long-term outcomes with dietary therapy alone, and any evidence that L-carnitine or other adjuncts alter survival or neurological development. No drug has been tested in a trial for this disease. Patient stratification by residual enzyme activity or genotype is not addressed in the available literature.
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 Neurogenetics · 1984 · 23 citations
3-Hydroxy-3-Methylglutaric Aciduria
Abstract3-Hydroxy-3-methylglutaric aciduria was found in a newborn infant whose parents are first cousins. The patient presented at 5 days of life with hyperammonemia, hypoglycemia, and metabolic acidosis. There was no ketonuria. Diagnosis was made by analysis of the pattern of organic acids excreted in the urine. A profound deficiency in activity of 3-hydroxy-3-methylglutaryl-coenzyme A lyase was found in cultured skin fibroblasts. The parents had intermediate levels of enzyme activity.
Tzu Chi Medical Journal · 2014 · 1 citations · open access
Dietary therapy for a patient affected with 3-hydroxy-3-methylglutaric aciduria
Abstract3-Hydroxy-3-methylglutaric aciduria (OMIM 246450) is an extremely rare genetic metabolic disorder of leucine caused by deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase). Affected patients present with life-threatening metabolic acidosis, hyperammonemia, and nonketotic hypoglycemia. Optimal outcome for patients depends on early diagnosis and treatment, prompt management of acute metabolic decompensation during the chronic stage, and long-term interprofessional health care programs. Nutritionists play a pivotal role in the care of metabolic disorders throughout the rest of a patient’s life. A 4-year-old intubated Bunun tribe female patient was admitted to the pediatric intensive care unit of the Buddhist Tzu Chi General Hospital (Hualien, Taiwan) due to status epilepticus, hypoglycemia, and severe metabolic acidosis. Results of urine gas chromatography with mass spectrometry revealed markedly elevated 3-methylglutaric acid, 3-hydroxy-3-methylglutaryl-CoA, and 3-hydroxyisovaleric acid, a finding consistent with a diagnosis of HMG-CoA lyase deficiency. She received an interdisciplinary health care program after acute management. Dietary therapy was the major part of the transdisciplinary health delivery process. Total daily calories were increased from 1400 kcal/day (targeted 60e80%) to 2100e2200 kcal/day (targeted 100%). The ratio of protein lipid and carbohydrate was 13%:24%:63% as recommended for healthy children. Lifelong protein restriction was essential. Total daily protein was given at a dose of 1.5e2 g/kg/day (target: above 50 g/day after the age of 4 years) and was administered at different growth and developmental stages. The daily leucine dose was 1000 mg (suggested dose ¼ 700e900 mg/day), 1.5% of the total protein amount was designed for her. Because leucine is an essential amino acid, close monitoring of optimal serum levels through blood sampling should be reached for better growth and development. Food avoidance was a major focus on restriction of protein from milk, meat, cheese, fish, poultry (including egg), beans, and nutlets, and even any foods containing milk and egg. Partial limited foods included sprouts (alfalfa, clover), radish, red bean, and murgbean. Unlimited fruits included vegetables and low protein starch such as green bean noodles, rice flour, pearl sago, lotus root powder, cornstarch, and corn flour, and low leucine foods such as potato powder were advised. The patient’s major protein source was from a special formula (I-Valex I and II; Abbott, Chicago, USA). Other nutrients such as multivitamins and minerals were prescribed. Daily oral L-carnitine was also prescribed to increase excretion of organic acid. The ability to recognize food labeling was taught to the parents, the patient, and school nurses. Servings for daily dietary content (Table 1) and sample meal plans were designed (Table 2).
L-2-Hydroxyglutaric Aciduria – a Rare Type of Organic Aciduria Presenting as Seizures and Developmental Delay in a Filipino Child
AbstractL-2-hydroxyglutaric aciduria (L-2-HGA) is a rare, autosomal recessive organic aciduria with increased levels of L-2hydroxyglutaric acid in the urine and other body fluids. Clinical presentation includes developmental delay, epilepsy, and typical neuroimaging findings. This is a report of the clinical, neuroimaging, and biochemical findings of the first diagnosed case of L-2-hydroxyglutaric aciduria in the Philippines. This paper likewise reaffirms the importance of locally available biochemical tests in diagnosing inborn error of metabolism.
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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