DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for 3-methylglutaconic aciduria type 1 — 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-methylglutaconic aciduria type 1 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-methylglutaconic aciduria type 1 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
AU RNA binding methylglutaconyl-CoA hydratase (AUH) — AUH 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 1HZD · 2.2 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Of 388 patients referred for suspected metabolic disorder who showed 3-methylglutaconic aciduria on routine screening, 3% of all urine samples had the finding. In a separate cohort of 591 patients with 50 different genetically proven mitochondrial disorders, 11% had 3-methylglutaconic aciduria. It was more frequent in ATPase-related disorders and in mitochondrial DNA depletion or deletion, but not in single respiratory chain complex deficiencies. The finding was a consistent feature only in patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 and TMEM70. The original type I, now called primary 3-methylglutaconic aciduria, is caused by 3-methylglutaconyl-CoA hydratase deficiency (AUH defect) and arises from defective leucine catabolism. The other types are secondary and arise from defective phospholipid remodelling (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome) or mitochondrial membrane associated disorders (OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect). Patients with significant and consistent 3-methylglutaconic aciduria who do not fit these categories are labelled not otherwise specified (NOS) 3-MGA-uria.
A case report describes a 13-year-old boy with 3-methylglutaconic aciduria and a duplication in region 5q23.3q31.1, diagnosed as type IV. His main symptoms were myopathy, weakness, spastic paresis worse in the lower limbs, and intellectual disability. He had elevated 3-methylglutaconic acid in urine and elevated ammonia in plasma. Next-generation sequencing found no pathological mutation. The 1962 abstract on orotic aciduria describes a different disease — megaloblastic anaemia with urinary orotic acid — and is not about 3-methylglutaconic aciduria.
No therapy, no clinical trial, and no drug repurposing data appear in any of these abstracts. What is missing is any prospective trial that tests a treatment in patients with confirmed AUH deficiency or any of the secondary 3-methylglutaconic aciduria syndromes, and any systematic attempt to stratify patients by the underlying genetic defect before measuring outcomes.
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.
Journal of Inherited Metabolic Disease · 2013 · 93 citations · open access
3‐Methylglutaconic aciduria—lessons from 50 genes and 977 patients
AbstractElevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11% presented 3-methylglutaconic aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.
Quantification of 3-methylglutaconic acid in urine, plasma, and amniotic fluid by isotope-dilution gas chromatography/mass spectrometry
AbstractA method is described for quantification of the trace metabolite, 3-methylglutaconic acid, by isotope-dilution gas chromatography/mass spectrometry using synthetic 3-[2,4,6-13C3]methylglutaconic acid. Results are shown for quantification of 3-methylglutaconic acid in plasma, urine, cerebrospinal fluid and amniotic fluid for both normal controls and patients with different forms of 3-methylglutaconic aciduria. A simple method for the synthesis and purification of 3-[2,4,6-13C3]methylglutaconic acid is also described.
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.
Studies on the Enzymatic Defect of Orotic Aciduria.
Abstracts1 April 1962Studies on the Enzymatic Defect of Orotic Aciduria.L. H. Smith Jr., M.D.L. H. Smith Jr., M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-56-4-678_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptOrotic aciduria is a rare metabolic disease characterized by megaloblastic anemia, resistant to the usual hematinic agents, and the presence of large amounts of urinary orotic acid, a pyrimidine nucleotide precusor. Studies on the surviving siblings and the parents of the propositus of orotic aciduria have demonstrated decreased erythrocyte activities of orotidylic pyrophosphorylase and orotidylic decarboxylase, enzymes which convert orotic acid into uridylic acid. The pattern of inheritance is consistent with that of an autosomal recessive trait. TwoEntamoeba colimutants and a neurospora crassa mutant with somewhat analogous enzyme defects have been studied as examples of "microbiological orotic aciduria."... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Boston, Mass. (BS) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 April 1962Volume 56, Issue 4Page: 678-678KeywordsEnzymesMegaloblastic anemiaMetabolic disorders Issue Published: 1 April 1962 PDF DownloadLoading ...
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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