DeCure for 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for 3-hydroxy-3-methylglutaryl-CoA synthase deficiency — 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-methylglutaryl-CoA synthase deficiency 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-methylglutaryl-coa synthase deficiency 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 synthase 2 (HMGCS2) — HMGCS2 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 hmgdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2WYA · 1.7 Å · ligand 3-HYDROXY-3-METHYLGLUTARYL-COENZYME A (HMG). Experimental structure, not a prediction.
What the evidence adds up to
3-hydroxy-3-methylglutaryl-CoA synthase deficiency is a rare inborn error of ketone body synthesis caused by mutations in the HMGCS2 gene. Fewer than 30 patients had been described by 2018. A 2025 study of 19 Vietnamese patients from 14 unrelated families is the largest single case series reported. Among those 19 patients, 16 were symptomatic and three were asymptomatic. The first acute episode occurred between 10 days and 28 months of age. Triggers included poor feeding (93.8%), vomiting (56.3%), diarrhea (25.0%), and fever (18.8%). During the first episode, 81.3% presented with lethargy or coma, 68.8% with rapid breathing, 56.3% with hepatomegaly, 37.5% with shock, and 18.8% with seizures. All symptomatic patients had elevated plasma transaminases; 75% had metabolic acidosis, 56.3% had hypoglycemia, and 31.3% had elevated ammonia. Low free carnitine was found in seven cases, dicarboxylic aciduria in two, and ketonuria in two. Abnormal brain MRI was seen in three patients.
Genetic analysis in the Vietnamese cohort identified seven HMGCS2 variants, including a novel one, c.407A>T (p.D136V). Two variants, c.559+1G>A and c.1090T>A (p.F364I), were common, present in 57.9% and 55.5% of cases respectively. Earlier work on mitochondrial HMG-CoA synthase deficiency described two new missense mutations, c.334C>T (p.R112W) and c.430G>T (p.V144L), and extended the study to ten missense variants. Enzymatic assays showed that three mutant proteins retained some activity but seven had none. One patient homozygous for a mutation retaining 70% of enzyme activity still developed symptoms, suggesting that even modest impairment can cause disease. Molecular dynamics modelling indicated that maintaining the dimerization surface is crucial for enzyme activity.
A separate 2018 case report described an 8-month-old girl with seizures, acidosis, hypoglycemia, abnormal liver function, myocardial injury, and coagulation dysfunction, who was found to have a homozygous c.1502G>A (p.R501Q) mutation in HMGCS2. Urine organic acid analysis showed a significant increase in 4-hydroxy-6-methyl-2-pyranone. The 2025 Vietnamese study reported that after diagnosis, management with high glucose infusion, avoidance of prolonged fasting, and enteral carbohydrate or glucose during illness reduced acute relapses. All 19 patients were alive at follow-up, aged five months to 14 years, with normal physical development.
The condition is also related to 3-methylglutaconic aciduria type I, caused by mutations in the AUH gene, which encodes 3-methylglutaconyl-CoA hydratase. In one study, five patients from four families had mutations in AUH, including c.80delG, R197X, IVS8-1G>A, A240V, and c.613_614insA. One patient detected by neonatal screening and homozygous for an N-terminal frameshift mutation remained asymptomatic at age two years, indicating that complete absence of the enzyme can be compatible with normal development in some cases. What remains missing is a clear understanding of why some patients with these enzyme deficiencies develop severe symptoms while others do not; the external or genetic factors that trigger clinical problems are unknown. Larger, prospective studies with standardised metabolic monitoring and long-term neurodevelopmental follow-up are needed, as are better biochemical markers to allow earlier diagnosis before acute crises occur.
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 Mass Spectrometry · 1978 · 67 citations
Abnormal metabolites of isoleucine in a patient with propionyl-CoA carboxylase deficiency
AbstractA number of previously unrecognized abnormal metabolites have been identified and quantitated in the urine of a patient with an inherited deficiency of propionyl-CoA carboxylase. These included the isoleucine metabolites 2-methyl-3-hydroxybutyric acid and 2-methylacetoacetic acid. These isomers 3-hydroxyvaleric acid and 3-oxovaleric acid were found, which may be products of the condensation of propionyl-CoA with acetyl-CoA catalyzed by 3-oxoacyl-CoA thiolases. Following a load of isoleucine, 2-methylbutyrylglycine was identified. This metabolite has not previously been observed in man.
Human Mutation · 2003 · 52 citations · open access
Mutations in theAUH gene cause 3-methylglutaconic aciduria type I
AbstractThe conversion of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA is the only step in leucine catametabolism yet to be characterized at enzyme and DNA levels. The deficiency of the putative mitochondrial enzyme 3-methylglutaconyl-CoA hydratase associates with the rare organic aciduria 3-methylglutaconic aciduria type I (MGA1), but neither the enzyme nor its gene have been described in any organism. Here we report that human 3-methylglutaconyl-CoA hydratase is identical with a previously described RNA-binding protein (designated AUH) possessing enoyl-CoA hydratase activity. Molecular analyses in five patients from four independent families revealed homozygosity or compound heterozygosity for mutations in the AUH gene; most mutations are predicted to completely abolish protein function. Mutations identified include c.80delG, R197X, IVS8-1G>A, A240V, and c.613_614insA. Clinical severity of MGA1 in published patients has been quite variable. Included in the present study is an additional patient with MGA1 who was detected by neonatal screening and has remained asymptomatic up to his present age of 2 years. The boy is homozygous for an N-terminal frameshift mutation in the AUH gene. Complete absence of 3-methylglutaconyl-CoA hydratase/AUH appears to be compatible with normal development in some cases. Further work is required to identify external or genetic factors associated with development of clinical problems in patients with MGA1.
International Journal of Molecular Sciences · 2018 · 27 citations · open access
Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients
AbstractMitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mitochondrial HMG-CoA synthase deficiency or mHS deficiency, OMIM #605911) is an inborn error of metabolism that affects ketone body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycemia and dicarboxylic aciduria. The diagnosis is difficult due to the relatively unspecific clinical and biochemical presentation, and fewer than 30 patients have been described. This work describes three new patients with mHS deficiency and two missense mutations c.334C>T (p.R112W) and c.430G>T (p.V144L) previously not reported. We developed a new method to express and measure the activity of the enzyme and in this work the study is extended to ten new missense variants including those of our patients. Enzymatic assays showed that three of the mutant proteins retained some but seven completely lacked activity. The identification of a patient homozygous for a mutation that retains 70% of enzyme activity opens the door to a new interpretation of the disease by demonstrating that a modest impairment of enzyme function can actually produce symptoms. This is also the first study employing molecular dynamics modelling of the enzyme mutations. We show that the correct maintenance of the dimerization surface is crucial for retaining the structure of the active center and therefore the activity of the enzyme.
[Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase deficiency: a case report and literature review].
AbstractMitochondrial 3-hydroxy-3-methylglutaryl CoA synthase deficiency (HMCSD) is caused by HMGCS2 gene mutation. This paper reports the clinical and genetic features of an infant with this disease. The 8-month-old female infant was admitted to the hospital with diarrhea for 1 week and fever and convulsion for 1 day. The child presented with seizures, acidosis, hypoglycemia, abnormal liver function, myocardial injury and coagulation dysfunction. The new homozygous mutation c.1502G>A(p.R501Q) in the HMGCS2 gene was found in the infant by genetic testing. The mutant gene was found to be harmful by bioinformatics software analysis. Urine organic acid analysis indicated that 4-hydroxy-6-methyl-2-pyranone was significantly increased, which was consistent with the results of genetic testing. The infant was definitely diagnosed with HMCSD.
Mitochondrial HMG-CoA Synthase Deficiency in Vietnamese Patients
AbstractBackground: Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D) is a rare metabolic disorder that impairs the body's ability to produce ketone bodies and regulate energy metabolism. Diagnosing HMGCS2D is challenging because patients typically remain asymptomatic unless experiencing fasting or illness. Due to the absence of reliable biochemical markers, genetic testing has become the definitive method for diagnosing HMGCS2D. Methods: This study included 19 patients from 14 unrelated families diagnosed with HMGCS2D in our department between October 2018 and October 2024. The clinical presentations, biochemical findings, molecular characteristics, and management strategies were systematically summarized and analyzed. Results: Of the 19 cases studied, 16 were symptomatic and three were asymptomatic. The onset of the first acute episode occurred between 10 days and 28 months of age. Triggers for the initial crisis in the symptomatic cases included poor feeding (93.8%), vomiting (56.3%), diarrhea (25.0%), and fever (18.8%). Clinical manifestations during the first episode were lethargy/coma (81.3%), rapid breathing (68.8%), hepatomegaly (56.3%), shock (37.5%), and seizures (18.8%). Biochemical abnormalities observed included elevated plasma transaminases (100%), metabolic acidosis (75%), hypoglycemia (56.3%), and elevated plasma ammonia levels (31.3%). Additionally, low free carnitine levels were found in seven cases, elevated C2 levels in one case, dicarboxylic aciduria in two cases, and ketonuria in two cases. Abnormal brain MRI findings were detected in three patients. Genetic analysis revealed seven HMGCS2 gene variants across the 19 cases. Notably, a novel variant, c.407A>T (p.D136V), was identified and has not been reported in any existing databases. Two common variants, c.559+1G>A and c.1090T>A (p.F364I), were present in 11 out of 19 cases (57.9%) and 10 out of 19 cases (55.5%), respectively. Implementation of high glucose infusion and proactive management strategies—such as preventing prolonged fasting and providing enteral carbohydrate/glucose infusion during illness—effectively reduced the rate of acute relapses following accurate diagnosis. Currently, all 19 patients are alive, with ages ranging from five months to 14 years, and exhibit normal physical development. Conclusions: To the best of our knowledge, this study represents the first reported cases of HMGCS2D in Vietnamese patients. Our findings contribute to a broader understanding of the clinical phenotype and expand the known spectrum of HMGCS2 gene variants, enhancing current knowledge of this rare metabolic disorder.
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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