DeCure for Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for long chain 3-hydroxyacyl-CoA dehydrogenase deficiency — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleLong chain 3-hydroxyacyl-CoA dehydrogenase deficiency maps to a 3-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 long chain 3-hydroxyacyl-coa dehydrogenase 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 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
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is a rare autosomal recessive disorder of fatty acid oxidation. In a cohort of 50 patients, the mean age of clinical presentation was 5.8 months, with 15% presenting in the neonatal period. 78% presented with hypoketotic hypoglycaemia, the classic acute metabolic derangement, while 22% presented with chronic problems including failure to thrive, feeding difficulties, cholestatic liver disease, or hypotonia. In retrospect, most patients (82%) who presented with an acute crisis had also suffered from a combination of chronic non-specific symptoms beforehand. Mortality in this series was 38%, with all deaths occurring before or within three months of diagnosis. Among survivors, morbidity remained high, with recurrent metabolic crises and muscle problems despite therapy. The authors concluded that early diagnosis is difficult in the absence of the classical metabolic derangement, and that while survival can be improved by prompt diagnosis, morbidity remains alarmingly high under current treatment regimes.
A separate 1991 case report describes a 16-year-old girl with a short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency, a different enzyme defect, who presented with recurrent myoglobinuria, hypoketotic hypoglycaemic encephalopathy, and hypertrophic/dilatative cardiomyopathy. Enzyme activity in muscle was markedly decreased with acetoacetyl-CoA as substrate (2.48 mumol/min/gm versus normal 6.90 ± 1.80), but was normal with longer-chain substrates, and activity was normal in fibroblasts, suggesting a tissue-specific defect. This is a distinct disorder from LCHAD deficiency and does not provide treatment data for the long-chain form.
A 1998 review summarises fatty acid oxidation disorders including short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and long-chain fatty acid transport deficiency, but provides no new clinical or outcome data for LCHAD deficiency. A 2014 case report from China describes medium-chain acyl-CoA dehydrogenase deficiency in a 2-year-old, confirmed by genetic analysis showing compound heterozygosity for a missense mutation and a 4-bp deletion in the ACADM gene. This is a different disorder and offers no information on LCHAD deficiency.
What remains missing for LCHAD deficiency is a prospective trial testing any specific intervention beyond the current supportive regimes. No abstract reports a randomised or controlled study of any drug. The existing data are retrospective, from a single centre, and show that even with diagnosis and therapy, morbidity and mortality remain high. No abstract describes a successful repurposed drug, a biomarker-stratified trial, or a funded effort to test one.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PEDIATRICS · 2002 · 194 citations
Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: Clinical Presentation and Follow-Up of 50 Patients
AbstractOBJECTIVES: To assess the mode of presentation, biochemical abnormalities, clinical course, and effects of therapy in patients of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. BACKGROUND: LCHAD deficiency is a rare, autosomal recessive inborn error of fatty acid oxidation. Although case reports and small series of patients have been published, these may not give a true picture of the clinical and biochemical spectrum associated with this disorder. To improve the early recognition and management of this potentially lethal disorder, we have reviewed a large cohort of LCHAD-deficient patients. METHODS: A questionnaire was sent to the referring physicians of 61 unselected patients with LCHAD deficiency diagnosed in our center. The standardized questionnaire requested information about the clinical signs and symptoms at presentation, the clinical history, family history, pregnancy, biochemical parameters at presentation, treatment, and clinical outcome. RESULTS: Questionnaires on 50 patients (82%) were returned and included in this study. The mean age of clinical presentation was 5.8 months (range: 1 day-26 months). Seven (15%) of the patients presented in the neonatal period. Thirty-nine patients (78%) presented with hypoketotic hypoglycemia, the classical features of a fatty acid oxidation disorder. Eleven patients (22%) presented with chronic problems, consisting of failure to thrive, feeding difficulties, cholestatic liver disease, and/or hypotonia. In retrospect, most (82%) of the patients presenting with an acute metabolic derangement also suffered from a combination of chronic nonspecific symptoms before the metabolic crises. Mortality in this series was high (38%), all dying before or within 3 months after diagnosis. Morbidity in the surviving patients is also high, with recurrent metabolic crises and muscle problems despite therapy. CONCLUSIONS: LCHAD deficiency often presents with a combination of chronic nonspecific symptoms. Early diagnosis is difficult in the absence of the classical metabolic derangement. Survival can be improved by prompt diagnosis, but morbidity remains alarmingly high despite current therapeutic regimes.
Short‐chain<scp>L</scp>‐3‐hydroxyacyl‐CoA dehydrogenase deficiency in muscle: A new cause for recurrent myoglobinuria and encephalopathy
AbstractWe report on a 16-year-old girl with short-chain L-3-hydroxyacyl-coenzyme A (CoA) dehydrogenase deficiency resulting in juvenile-onset recurrent myoglobinuria, hypoketotic hypoglycemic encephalopathy, and hypertrophic/dilatative cardiomyopathy. Urinary organic acids showed traces of 3-hydroxy-dodecanedioic acids and small amounts of suberic, sebacic, and adipic acids. There was a marked decrease in L-3-hydroxyacyl-CoA dehydrogenase activity in muscle with acetoacetyl-CoA as substrate (2.48 mumol/min/gm; normal = 6.90 +/- 1.80 mumol/min/gm of tissue; n = 11), contrasting with normal L-3-hydroxyacyl-CoA dehydrogenase activity with 3-ketooctanoyl-CoA and 3-ketopalmitoyl-CoA as substrates. Short-chain L-3-hydroxyacyl-CoA dehydrogenase activity was normal in fibroblasts, suggesting a tissue-specific defect.
Current Opinion in Pediatrics · 1998 · 74 citations
Clinical and biochemical features of fatty acid oxidation disorders
AbstractInborn errors of fatty acid oxidation (FAO) represent a group of metabolic disorders that has brought forward many interesting developments, as highlighted by the rapid pace of discovery of new defects and by the recognition of an ever-increasing spectrum of clinical phenotypes. This review includes a clinical and biochemical summary of the FAO disorders known to date, a synopsis of four recently discovered defects (short-chain 3-hydroxy acyl-CoA [coenzyme A] dehydrogenase deficiency, medium-chain 3-ketoacyl-CoA thiolase deficiency, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency, and long-chain fatty acid transport deficiency) and of two susceptibility variations in the short-chain acyl-CoA dehydrogenase gene, and guidelines for the biochemical work-up of candidate patients.
Journal of Pediatric Endocrinology and Metabolism · 2014 · 6 citations
First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China
AbstractMedium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is an autosomal recessive inborn error of mitochondrial fatty acid β-oxidation, caused by mutations in the ACADM gene. As it is the most commonly inherited disorder of the mitochondrial fatty acid oxidation in Caucasians, there are no related reports in China diagnosed by molecular genetic testing. We report here the case of a 2-year-old female patient who had hepatomegaly and abnormal liver function with a common illness, and who had been healthy before. A marked increase found in the concentration of C8-carnitine with the help of tandem mass spectrometry (MS/MS) profile, as well as the presence of hexanoylglycine and cyclohepta acyl glycinate as shown in the urinary gas chromatography/mass spectrometry (GC/MS) were suggestive of MCADD, a diagnosis that was confirmed by genetic analysis that showed compound heterozygosity for a missense mutation, c.362C>T(p.Thr121Ile), and a 4-bp deletion, c.448-453delCTGA, in the medium-chain acyl-coenzyme A dehydrogenase (MCAD) gene, also named ACADM gene. There are no related reports in China. This report broadens the phenotype and genotype of MCADD in China and underlines the difficulty of diagnosis.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
