DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for 3-methylglutaconic aciduria — screening already-approved drugs against its 5-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease module3-methylglutaconic aciduria maps to a 5-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-methylglutaconic 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
ClpB family mitochondrial disaggregase (CLPB) — CLPB 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 atpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7XBK · 3.7 Å · ligand ADENOSINE-5'-TRIPHOSPHATE (ATP). Experimental structure, not a prediction.
What the evidence adds up to
3-methylglutaconic aciduria is not a single disease but a biochemical finding that appears in several distinct inborn errors of metabolism. A 2013 classification proposal distinguishes primary 3-methylglutaconic aciduria, caused by 3-methylglutaconyl-CoA hydratase deficiency (AUH defect), from secondary forms where the origin of the aciduria remains unknown. The secondary group includes Barth syndrome (TAZ defect), MEGDEL syndrome (SERAC1 defect), Costeff syndrome (OPA3 defect), DCMA syndrome (DNAJC19 defect), and TMEM70 defect. Patients with significant and consistent 3-methylglutaconic aciduria who do not fit any known syndrome are labelled "not otherwise specified (NOS) 3-MGA-uria" until the underlying mechanism is identified.
A 2008 leucine loading test in 21 patients with different inborn errors of metabolism showed that urinary 3-methylglutaconic acid levels increased only in patients with an AUH defect. This supports the hypothesis that in all other subtypes the aciduria is independent of leucine catabolism, and provides a simple biochemical test to distinguish primary from secondary forms in clinical care.
A 2020 case report describes a 13-year-old boy with 3-methylglutaconic aciduria and a duplication in region 5q23.3q31.1. His main symptoms were myopathy, weakness, spastic paresis mostly in the lower limbs, and intellectual disability. Elevated 3-methylglutaconic acid was found in urine and ammonia in plasma. Next-generation sequencing revealed no pathological mutation, and he was diagnosed with 3-methylglutaconic aciduria type IV with duplication 5q.
A 1993 review notes that the most common clinical syndromes associated with 3-methylglutaconic aciduria were already recognised at that time, but the underlying pathomechanisms for most subtypes were not understood. What remains missing is a clear molecular explanation for the secondary forms, a systematic way to classify the growing number of NOS cases, and any evidence that altering leucine intake or any other intervention changes clinical outcomes. No drug treatment is mentioned in any of 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.
Journal of Inherited Metabolic Disease · 2013 · 104 citations
Inborn errors of metabolism with 3‐methylglutaconic aciduria as discriminative feature: proper classification and nomenclature
AbstractIncreased urinary 3-methylglutaconic acid excretion is a relatively common finding in metabolic disorders, especially in mitochondrial disorders. In most cases 3-methylglutaconic acid is only slightly elevated and accompanied by other (disease specific) metabolites. There is, however, a group of disorders with significantly and consistently increased 3-methylglutaconic acid excretion, where the 3-methylglutaconic aciduria is a hallmark of the phenotype and the key to diagnosis. Until now these disorders were labelled by roman numbers (I-V) in the order of discovery regardless of pathomechanism. Especially, the so called "unspecified" 3-methylglutaconic aciduria type IV has been ever growing, leading to biochemical and clinical diagnostic confusion. Therefore, we propose the following pathomechanism based classification and a simplified diagnostic flow chart for these "inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature". One should distinguish between "primary 3-methylglutaconic aciduria" formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, AUH defect) due to defective leucine catabolism and the--currently known--three groups of "secondary 3-methylglutaconic aciduria". The latter should be further classified and named by their defective protein or the historical name as follows: i) defective phospholipid remodelling (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome) and ii) mitochondrial membrane associated disorders (OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect). The remaining patients with significant and consistent 3-methylglutaconic aciduria in whom the above mentioned syndromes have been excluded, should be referred to as "not otherwise specified (NOS) 3-MGA-uria" until elucidation of the underlying pathomechanism enables proper (possibly extended) classification.
Distribution of ostracode assemblages along the nearshore and offshore areas of Malabar coast, Kerala (west coast of India)
AbstractCurrently, six inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature are known. The "Primary 3-methylglutaconic aciduria," 3-methylglutaconyl-CoA hydratase deficiency or AUH defect, is a disorder of leucine catabolism. For all other subtypes, also denoted "Secondary 3-methylglutaconic acidurias" (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome, OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect, "not otherwise specified (NOS) 3-MGA-uria"), the origin of 3-methylglutaconic aciduria remains enigmatic but is hypothesized to be independent from leucine catabolism. Here we show the results of leucine loading test in 21 patients with different inborn errors of metabolism who present with 3-methylglutaconic aciduria. After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect. This strongly supports the hypothesis that 3-methylglutaconic aciduria is independent from leucine breakdown in other inborn errors of metabolism with 3-methylglutaconic aciduria and also provides a simple test to discriminate between primary and secondary 3-methylglutaconic aciduria in regular patient care.
Coincidence of 3-methylglutaconic aciduria and duplication 5q – a case report and literature review
Abstract3-methylglutaconic aciduria includes a heterogeneous group of inborn errors of metabolism. The disease may have various clinical presentations, as can duplication 5q. We present the case of a 13-year-old boy with 3-methylglutaconic aciduria and duplication 5q. The main symptoms included myopathy, weakness, spastic paresis intensified mostly in the lower limbs, and intellectual disability. Additional studies showed elevated levels of 3-methylglutaconic acid in urine and ammonia in plasma. A duplication in region 5q23.3q31.1 was found in array-based comparative genomic hybridization. Next-generation sequencing did not reveal any pathological mutation. On the basis of the clinical picture and the results of biochemical and genetic tests 3-methylglutaconic aciduria type IV with duplication 5q was diagnosed.
Galter Health Sciences Library, Northwestern University · 1993 · 0 citations · open access
Syndromes of 3-Methylglutaconic Aciduria
AbstractThe most common clinical syndromes associated with 3-methyl-glutaconic (MGC) aciduria are reviewed by researchers from various centers; Courtwright and Summers Metabolic Disease Center and Baylor Research Institute, Dallas, TX; Shaare Zedek Medical Center, Jerusalem; Free University of Amsterdam; Loewenstein Hospital, Tel-Aviv Univ, Raanana, Israel; and Kennedy Krieger Institute, Baltimore, MD.
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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