DeCure for Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency — 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 moduleMitochondrial short-chain Enoyl-Coa hydratase 1 deficiency 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 mitochondrial short-chain enoyl-coa hydratase 1 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
enoyl-CoA hydratase, short chain 1 (ECHS1) — ECHS1 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 8ZRU · 2.18 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, caused by recessive mutations in ECHS1, produces a severe and heterogeneous mitochondrial encephalopathy. In a 2015 study of ten unrelated individuals, all had encephalopathy, nine of nine had deafness, six of nine had epilepsy, six of ten had optic atrophy, and four of ten had cardiomyopathy. Disease onset was in the first year of life, and the course ranged from neonatal death to survival into adulthood. Serum lactate was elevated, and brain MRI showed white matter changes or a Leigh-like pattern. Patient fibroblasts showed reduced ECHS1 protein and reduced 2-enoyl-CoA hydratase activity. Urinary 2-methyl-2,3-dihydroxybutyrate was significantly increased, indicating impaired valine oxidation. The authors speculated that both the beta-oxidation defect and the block in valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder.
A 2019 case report described a patient with typical Leigh syndrome and compound heterozygous ECHS1 variants. A valine-restricted diet was started at six months of age and N-acetylcysteine supplementation at nine months. The authors reported subsequent improvement in growth and slow progress in developmental milestones. However, at 15 months the patient aspirated during a breakthrough seizure and died soon after from related complications. The report states that no proven treatments were available at the time, and that a valine-restricted diet and N-acetylcysteine could be safely administered with potential for clinical improvement, but the patient still died in infancy.
A 2023 study focused on validating variants of uncertain significance in ECHS1. The authors constructed a high-throughput assay using ECHS1 knockout cells expressing cDNA containing VUS, and performed multiomics analysis including RNA-seq and proteome analysis on patient samples. This approach identified novel loss-of-function variants, revealed the effect of VUS in compound heterozygous states, and uncovered a synonymous substitution (p.P163=) that causes splicing abnormality. The multiomics analysis complemented diagnosis in some cases that the VUS validation system could not resolve. The study did not report any new treatment or survival data.
What remains missing is any controlled trial of valine restriction or N-acetylcysteine, and the single published attempt ended in death before age two. No therapy has shown a clear survival benefit. The disorder is ultra-rare, which hampers recruitment for trials. Patient stratification by residual enzyme activity or by specific mutation type might clarify who could benefit from metabolic interventions, but that work has not been done. Funding for natural history studies and for preclinical testing of alternative metabolic or chaperone strategies is lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annals of Clinical and Translational Neurology · 2015 · 119 citations · open access
Deficiency of <scp>ECHS</scp>1 causes mitochondrial encephalopathy with cardiac involvement
AbstractOBJECTIVE: Short-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency. METHODS: Using exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay. RESULTS: Patients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, in vitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial β-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation. INTERPRETATION: In conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the β-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches.
ECHS1 Mutations Cause Combined Respiratory Chain Deficiency Resulting in Leigh Syndrome
AbstractThe human ECHS1 gene encodes the short-chain enoyl coenzyme A hydratase, the enzyme that catalyzes the second step of β-oxidation of fatty acids in the mitochondrial matrix. We report on a boy with ECHS1 deficiency who was diagnosed with Leigh syndrome at 21 months of age. The patient presented with hypotonia, metabolic acidosis, and developmental delay. A combined respiratory chain deficiency was also observed. Targeted exome sequencing of 776 mitochondria-associated genes encoded by nuclear DNA identified compound heterozygous mutations in ECHS1. ECHS1 protein expression was severely depleted in the patient's skeletal muscle and patient-derived myoblasts; a marked decrease in enzyme activity was also evident in patient-derived myoblasts. Immortalized patient-derived myoblasts that expressed exogenous wild-type ECHS1 exhibited the recovery of the ECHS1 activity, indicating that the gene defect was pathogenic. Mitochondrial respiratory complex activity was also mostly restored in these cells, suggesting that there was an unidentified link between deficiency of ECHS1 and respiratory chain. Here, we describe the patient with ECHS1 deficiency; these findings will advance our understanding not only the pathology of mitochondrial fatty acid β-oxidation disorders, but also the regulation of mitochondrial metabolism.
American Journal of Medical Genetics Part A · 2019 · 26 citations · open access
Case report and novel treatment of an autosomal recessive Leigh syndrome caused by short‐chain enoyl‐CoA hydratase deficiency
AbstractShort chain enoyl-CoA hydratase (SCEH) deficiency leads to a severe form of autosomal recessive Leigh syndrome with inevitable neurological decline and early mortality. SCEH is most notably involved in valine catabolism, a deficiency of which results in various metabolic alterations, including increased levels of the highly reactive metabolite 2-methacrylyl-CoA. With no proven treatments available to date, it has been speculated that patients may respond to a valine restricted diet and/or N-acetylcysteine supplementation, as suggested by early studies of a very similar inborn error of metabolism, 3-hydroxyisobutyryl-CoA hydrolase deficiency. We describe a patient with typical Leigh syndrome clinical findings and identified compound heterozygous variants in ECSH1. Valine-restricted diet was initiated at 6 months of age and N-acetylcysteine supplementation at 9 months with subsequent improvement in growth and slow progress in developmental milestones. However, at 15 months, the patient aspirated during a breakthrough seizure from which he did not recover and died soon after from related complications. This report highlights some of the challenges that remain in the management and treatment of SCEH deficiency, while demonstrating that a valine restricted diet and N-acetylcysteine can be safely administered with the potential for clinical improvement.
Strategic validation of variants of uncertain significance in <i>ECHS1</i> genetic testing
AbstractBackground Enoyl-CoA hydratase short-chain 1 (ECHS1) is an enzyme involved in the metabolism of branched chain amino acids and fatty acids. Mutations in the ECHS1 gene lead to mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, resulting in the accumulation of intermediates of valine. This is one of the most common causative genes in mitochondrial diseases. While genetic analysis studies have diagnosed numerous cases with ECHS1 variants, the increasing number of variants of uncertain significance (VUS) in genetic diagnosis is a major problem. Methods Here, we constructed an assay system to verify VUS function for ECHS1 gene. A high-throughput assay using ECHS1 knockout cells was performed to index these phenotypes by expressing cDNAs containing VUS. In parallel with the VUS validation system, a genetic analysis of samples from patients with mitochondrial disease was performed. The effect on gene expression in cases was verified by RNA-seq and proteome analysis. Results The functional validation of VUS identified novel variants causing loss of ECHS1 function. The VUS validation system also revealed the effect of the VUS in the compound heterozygous state and provided a new methodology for variant interpretation. Moreover, we performed multiomics analysis and identified a synonymous substitution p.P163= that results in splicing abnormality. The multiomics analysis complemented the diagnosis of some cases that could not be diagnosed by the VUS validation system. Conclusions In summary, this study uncovered new ECHS1 cases based on VUS validation and omics analysis; these analyses are applicable to the functional evaluation of other genes associated with mitochondrial disease.
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.
