DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for glutaric acidemia type 3 — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleGlutaric acidemia type 3 maps to a 2-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
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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 glutaric acidemia type 3 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
electron transfer flavoprotein subunit alpha (ETFA) — ETFA 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 faddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2A1U · 2.11 Å · ligand FLAVIN-ADENINE DINUCLEOTIDE (FAD). Experimental structure, not a prediction.
What the evidence adds up to
Glutaric acidemia type 3 is not mentioned in any of the provided abstracts. All abstracts concern glutaric acidemia type 1 (GA1) or, in one case, type 2. No data on glutaric acidemia type 3 are available from these sources.
For glutaric acidemia type 1, the abstracts describe an autosomal recessive disorder caused by mutations in the GCDH gene, leading to accumulation of glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine. The disease can present in early childhood with encephalitis-like crises between three months and three years, or later from age six. About 25% of cases have a subacute course in the first year of life with psychomotor delay, hyperkinetic syndrome, and spasticity. Outcome is dominated by dystonia, feeding problems, seizures, and reduced life expectancy. One expression study found that four missense mutations (p.Arg138Gly, p.Met263Val, p.Arg402Trp, p.Glu414Lys) were enzymatically inactive except p.Met263Val, which retained 10% activity. Reduced intramitochondrial stability and impaired formation of GCDH complexes were observed.
Neonatal screening for GA1 uses glutarylcarnitine in dried blood spots by tandem mass spectrometry. A 2006 review notes that patients with a mild biochemical phenotype (low excretors) can be missed, and that diagnostic and therapeutic procedures must be optimised before screening can be regarded as reliable for all patients. A 2021 study of six low-excretor GA1 patients found that five had normal newborn screening results; three of those five later presented clinically with GA1 symptoms. Urine organic acid analysis was diagnostic in only 33% of these patients, plasma glutarylcarnitine was elevated in 67%, and urine glutarylcarnitine in 80%. The authors conclude that the low-excretor phenotype is not protective against adverse outcomes and that false negative newborn screening results require high clinical vigilance.
A 2014 case report describes three symptomatic adult siblings with GA1 diagnosed after a healthy newborn in the family had a low carnitine level on screening. All three had low plasma carnitine, elevated glutaric acid, pronounced 3-hydroxyglutaric aciduria, undetectable GCDH activity in lymphocytes, and two pathogenic GCDH mutations. A 2022 clinical case report reiterates that GA1 causes progressive neurological motor disorders, hyperkinesis with spasticity, high disability and mortality, and that timely therapy is needed to prevent disability. One abstract on glutaric aciduria type 2 describes a 10-year-old girl with rhabdomyolysis and acute renal failure treated with carnitine and riboflavin, but this is a different disease.
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 · 2006 · 46 citations
Neonatal screening for glutaric aciduria type I: Strategies to proceed
AbstractAcute encephalopathic crisis in glutaric aciduria type I results in an unfavourable disease course and poor outcome, dominated by dystonia, feeding problems, seizures and reduced life expectancy. A conditio sine qua non for the prevention of irreversible brain damage is timely diagnosis and start of therapy, i.e. before the onset of neurological disease. As there are no specific clinical signs or symptoms that allow a reliable detection of these patients before the manifestation of encephalopathic crises, neonatal screening programmes for glutaric aciduria type I have been established in some countries using analysis of glutarylcarnitine in dried blood spots by tandem mass spectrometry. This article summarizes recent strategies, pitfalls and shortcomings of mass screening for glutaric aciduria type I, focusing on the relevant risk of missing patients with a mild biochemical phenotype (i.e. low excretors). Furthermore, it evaluates a binary strategy--using glutarylcarnitine as primary variable and glutarylcarnitine/acylcarnitine ratios as secondary variable--to improve the diagnostic sensitivity and specificity of neonatal screening for glutaric aciduria type I. An optimization of diagnostic as well as therapeutic procedures must be achieved before screening for glutaric aciduria type I can be regarded as reliable and beneficial for all patients.
Human Molecular Genetics · 2008 · 43 citations · open access
Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH)
AbstractGlutaric aciduria type 1 (GA1) is an autosomal recessive neurometabolic disorder caused by mutations in the glutaryl-CoA dehydrogenase gene (GCDH), leading to an accumulation and high excretion of glutaric acid and 3-hydroxyglutaric acid. Considerable variation in severity of the clinical phenotype is observed with no correlation to the genotype. We report here for the first time on expression studies of four missense mutations c.412A > G (p.Arg138Gly), c.787A > G (p.Met263Val), c.1204C > T (p.Arg402Trp) and c.1240G > A (p.Glu414Lys) identified in GA1 patients in mammalian cells. Biochemical analyses revealed that all mutants were enzymatically inactive with the exception of p.Met263Val which showed 10% activity of the expressed wild-type enzyme. Western blot and pulse-chase analyses demonstrated that the amount of expressed p.Arg402Trp protein was significantly reduced compared with cells expressing wild-type protein which was due to rapid intramitochondrial degradation. Upon cross-linkage the formation of homotetrameric GCDH was strongly impaired in p.Met263Val and p.Arg402Trp mutants. In addition, GCDH appears to interact with distinct heterologous polypeptides to form novel 97, 130 and 200 kDa GCDH complexes. Molecular modeling of mutant GCDH suggests that Met263 at the surface of the GCDH protein might be part of the contact interface to interacting proteins. These results indicate that reduced intramitochondrial stability as well as the impaired formation of homo- and heteromeric GCDH complexes can underlie GA1.
The low excretor phenotype of glutaric acidemia type I is a source of false negative newborn screening results and challenging diagnoses
AbstractAbstract Background Glutaric acidemia type I (GA1) is an organic acidemia that is often unrecognized in the newborn period until patients suffer an acute encephalopathic crisis, which can be mistaken for nonaccidental trauma. Presymptomatic identification of GA1 patients is possible by newborn screening (NBS). However, the biochemical “low‐excretor” (LE) phenotype with nearly normal levels of disease metabolites can be overlooked, which may result in untreated disease and irreversible neurological sequelae. The LE phenotype is also a potential source of false negative (FN) NBS results that merits further investigation. Methods Samples from six LE GA1 patients were analyzed by biochemical and molecular methods and newborn screen outcomes were retrospectively investigated. Results Five LE GA1 patients were identified that had normal NBS results and three of these presented clinically with GA1 symptoms. One additional symptomatic patient was identified who did not undergo screening. Semiquantitative urine organic acid analysis was consistent with a GA1 diagnosis in two (33%) of the six patients, while plasma glutarylcarnitine was elevated in four (67%) of the six and urine glutarylcarnitine was elevated in four (80%) of five patients. Five GCDH variants were identified in these patients; three of which have not been previously linked to the biochemical LE phenotype. Conclusions The data presented here raise awareness of potential FN NBS results for LE GA1 patients. The LE phenotype is not protective against adverse clinical outcomes, and the possibility of FN NBS results calls for high vigilance amongst clinicians, even in the setting of a normal NBS result.
Screening of a healthy newborn identifies three adult family members with symptomatic glutaric aciduria type I
AbstractWe report three adult sibs (one female, two males) with symptomatic glutaric acidura type I, who were diagnosed after a low carnitine level was found by newborn screening in a healthy newborn of the women. All three adults had low plasma carnitine, elevated glutaric acid levels and pronounced 3-hydroxyglutaric aciduria. The diagnosis was confirmed by undetectable glutaryl-CoA dehydrogenase activity in lymphocytes and two pathogenic heterozygous mutations in the GCDH gene (c.1060A > G, c.1154C > T). These results reinforce the notion that abnormal metabolite levels in newborns may lead to the diagnosis of adult metabolic disease in the mother and potentially other family members.
World Journal of Clinical Cases · 2018 · 8 citations · open access
Glutaric acidemia type II patient with thalassemia minor and novel electron transfer flavoprotein-A gene mutations: A case report and review of literature
AbstractGlutaric acidemia type II (GAII), also known as multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAII with novel electron transfer flavoprotein (ETF)-A mutations in a 2-year-old female with thalassemia minor. The patient developed an episode of hypoglycemia and hypotonicity on the postnatal first day. Laboratory investigations revealed elevations of multiple acyl carnitines indicating glutaric acidemia type II in newborn screening analysis. Urinary organic acids were evaluated for the confirmation and revealed a high glutaric acid excretion. Genetic analysis revealed two novel mutations in the ETF-A gene, which are considered to be compound heterozygote. At the 8 mo of life ketone therapy was added, which significantly increased the neuromotor development. The patient had been closely followed for two years with carnitine, riboflavin, coenzyme Q10, and ketone supplementation in addition to a high carbohydrate diet. Although the patient had comorbidity like thalassemia minor, her neuromotor development was normal for her age and had no major health problems. This specific case expands the previously reported spectrum of this disease.
Alborz University Medical Journal · 2020 · 0 citations · open access
Glutaric Aciduri Type II, with Rhabdomyolysis and Acute Renal Failure Presentation in 10 Years Old Girl
AbstractIntroduction: Myopathy and rhabdomyolysis are not common in children and, if not detected and do not treated it will be associated with high mortality and morbidity rate. The causes of rhabdomyolysis include hypokalemia, trauma, viral myositis, poisoning, rheumatoid diseases, and metabolic myopathies. Rhabdomyolysis treatment includes rapid supportive care and treatment of the underlying disease leading to rhabdomyolysis. Case Presentation: 10-year-old girl with progressive muscle weakness was admitted in Pediatric Intensive Care Unit (PICU) with acute renal failure and respiratory failure. The laboratory results showed myoglobinuria, high CPK, LDH. The initial diagnosis was severe rhabdomyolysis. In addition to fluid therapy and diuretic, she was treated with carnitine and riboflavin with possible glutaric aciduria type II. The patient showed progressive improvement after a few days. Result of plasma acyl carnitine and urine organic acid analysis stablished the diagnosis of glutaric aciduria type II.
L O Badalyan Neurological Journal · 2022 · 0 citations · open access
Glutaric acidemia type 1 (clinical cases)
AbstractGlutaric aciduria type 1 (glutaryl-CoA dehydrogenase deficiency, glutaric acidemia type 1) (OMIM 231670) is an autosomal recessive disease caused by mutations in the gene encoding the enzyme glutaryl-CoA dehydrogenase (GCDH). Glutaryl-CoA dehydrogenase (GCDH) plays an important role in the degradation metabolism of L-lysine, L-hydroxylysine and L-tryptophan. The insufficiency or absence of the enzyme leads to the accumulation of by-products of degradation of such amino acids as glutaric acid, 3-hydroxyglutaric acid, glutarylcarnitine (C5DC-acylcarnitine) and glutaconic acid. The accumulation of glutaric acid and 3-OH-glutaric acid causes neurotoxicity. Glutaric aciduria type 1 can manifest itself in early childhood with encephalitis-like crises: from three months to three years as GA-1 with infantile onset or from the age of six years as the late onset of GA-1. It is characterized by progressive neurological motor disorders, with the appearance of various types of hyperkinesis in combination with spasticity, a high incidence of disability and mortality. In about 25% of cases, the disease has a subacute course and manifests over the first year of life with a delay in psychomotor development, the gradual development of hyperkinetic syndrome, and spasticity. Awareness of doctors and alertness regarding diseases from the group of hereditary metabolic diseases will help to carry out therapy in a timely manner both in the acute period and in the appointment of long-term therapy to prevent disability of patients.
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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