DeCure for Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 — 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 moduleProgressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 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
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 progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant 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
DNA polymerase gamma, catalytic subunit (POLG) — POLG 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 dcpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8D33 · 2.46 Å · ligand 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE (DCP). Experimental structure, not a prediction.
What the evidence adds up to
In a 2014 study of 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia, 78 (67%) had a single mitochondrial DNA deletion, 12 (10%) had a point mutation of mitochondrial DNA, and 26 (22%) had mutations in POLG, C10orf2, or RRM2B, or had multiple mitochondrial DNA deletions without an identified nuclear gene defect. Among 77 patients who had neurophysiological studies, 16 (21%) had a large-fibre peripheral neuropathy. The prevalence of peripheral neuropathy was 2% in patients with a single mitochondrial DNA deletion, compared with 44% in those with a point mutation and 52% in those with a nuclear DNA defect. Binomial logistic regression identified peripheral neuropathy as the only independent predictor of a nuclear DNA defect, with an odds ratio of 8.43. Peripheral neuropathy had a specificity of 91% and a negative predictive value of 83% for a nuclear DNA defect.
A 2006 study sequenced POLG1, C10ORF2, and ANT1 in 38 sporadic progressive external ophthalmoplegia patients with multiple mitochondrial DNA deletions. Causative mutations were found in approximately 10% of cases; two unrelated individuals had a novel premature stop codon mutation in POLG1. No mutations were found in C10ORF2 or ANT1. The authors concluded that in most patients the primary nuclear genetic defect likely affects other unknown genes important for mitochondrial DNA maintenance.
A 2023 report described 8 adult patients with classical features of mitochondrial ophthalmologic and/or muscle disease and multiple mitochondrial DNA deletions isolated to muscle. Age at onset ranged from 18 to 61 years. Ocular manifestations included bilateral optic neuropathy in one patient, bilateral optic disc cupping without optic neuropathy in two, ptosis in four, and ocular motility deficits in two. Five patients had generalised weakness. Pathogenic mitochondrial DNA variants were not found in blood or buccal samples from any patient, but 7 of 8 had multiple mitochondrial DNA deletions in muscle tissue. One patient had a single deletion. Heteroplasmy was below 15% for all deletions except one at 50–60%. None of the patients had a known nuclear gene variant associated with mitochondrial DNA maintenance.
A 2023 case report describes a 16-year-old female with progressive external ophthalmoplegia and histological features consistent with the condition. The report states that ptosis and ophthalmoplegia are unresponsive to anticholinergics and that there is no effective treatment, though corrective surgery for ptosis is palliative. The same review notes that genotype-phenotype correlations in mitochondrial diseases can be imprecise, with multiple genes associated with classic syndromes and the same genetic variant producing different clinical presentations. What remains missing are prospective studies that stratify patients by nuclear genotype, funding for trials of any emerging therapy in this specific phenotype, and diagnostic algorithms that incorporate peripheral neuropathy testing to reduce reliance on muscle biopsy.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain · 2014 · 46 citations · open access
Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia
AbstractProgressive external ophthalmoplegia is a common clinical feature in mitochondrial disease caused by nuclear DNA defects and single, large-scale mitochondrial DNA deletions and is less frequently associated with point mutations of mitochondrial DNA. Peripheral neuropathy is also a frequent manifestation of mitochondrial disease, although its prevalence and characteristics varies considerably among the different syndromes and genetic aetiologies. Based on clinical observations, we systematically investigated whether the presence of peripheral neuropathy could predict the underlying genetic defect in patients with progressive external ophthalmoplegia. We analysed detailed demographic, clinical and neurophysiological data from 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia. Seventy-eight patients (67%) had a single mitochondrial DNA deletion, 12 (10%) had a point mutation of mitochondrial DNA and 26 (22%) had mutations in either POLG, C10orf2 or RRM2B, or had multiple mitochondrial DNA deletions in muscle without an identified nuclear gene defect. Seventy-seven patients had neurophysiological studies; of these, 16 patients (21%) had a large-fibre peripheral neuropathy. The prevalence of peripheral neuropathy was significantly lower in patients with a single mitochondrial DNA deletion (2%) as compared to those with a point mutation of mitochondrial DNA or with a nuclear DNA defect (44% and 52%, respectively; P<0.001). Univariate analyses revealed significant differences in the distribution of other clinical features between genotypes, including age at disease onset, gender, family history, progressive external ophthalmoplegia at clinical presentation, hearing loss, pigmentary retinopathy and extrapyramidal features. However, binomial logistic regression analysis identified peripheral neuropathy as the only independent predictor associated with a nuclear DNA defect (P=0.002; odds ratio 8.43, 95% confidence interval 2.24-31.76). Multinomial logistic regression analysis identified peripheral neuropathy, family history and hearing loss as significant predictors of the genotype, and the same three variables showed the highest performance in genotype classification in a decision tree analysis. Of these variables, peripheral neuropathy had the highest specificity (91%), negative predictive value (83%) and positive likelihood ratio (5.87) for the diagnosis of a nuclear DNA defect. These results indicate that peripheral neuropathy is a rare finding in patients with single mitochondrial DNA deletions but that it is highly predictive of an underlying nuclear DNA defect. This observation may facilitate the development of diagnostic algorithms. We suggest that nuclear gene testing may enable a more rapid diagnosis and avoid muscle biopsy in patients with progressive external ophthalmoplegia and peripheral neuropathy.
Mitochondria and the eye—manifestations of mitochondrial diseases and their management
AbstractHistorically, distinct mitochondrial syndromes were recognised clinically by their ocular features. Due to their predilection for metabolically active tissue, mitochondrial diseases frequently involve the eye, resulting in a range of ophthalmic manifestations including progressive external ophthalmoplegia, retinopathy and optic neuropathy, as well as deficiencies of the retrochiasmal visual pathway. With the wider availability of genetic testing in clinical practice, it is now recognised that genotype-phenotype correlations in mitochondrial diseases can be imprecise: many classic syndromes can be associated with multiple genes and genetic variants, and the same genetic variant can have multiple clinical presentations, including subclinical ophthalmic manifestations in individuals who are otherwise asymptomatic. Previously considered rare diseases with no effective treatments, considerable progress has been made in our understanding of mitochondrial diseases with new therapies emerging, in particular, gene therapy for inherited optic neuropathies.
<i>POLG1</i> , <i>C10ORF2</i> , and <i>ANT1</i> mutations are uncommon in sporadic progressive external ophthalmoplegia with multiple mitochondrial DNA deletions
AbstractThe authors sequenced POLG1, C10ORF2, and ANT1 in 38 sporadic progressive external ophthalmoplegia patients with multiple mitochondrial DNA (mtDNA) deletions. Causative mutations were identified in approximately 10% of cases, with two unrelated individuals harboring a novel premature stop codon mutation (1356T>G). None had a mutation in C10ORF2 or ANT1. In the majority of patients, the primary nuclear genetic defect is likely to affect other unknown genes important for mtDNA maintenance.
Journal of Neuro-Ophthalmology · 2023 · 2 citations
Myopathy and Ophthalmologic Abnormalities in Association With Multiple Skeletal Muscle Mitochondrial DNA Deletions
AbstractBACKGROUND: Establishing a molecular diagnosis of mitochondrial diseases due to pathogenic mitochondrial DNA (mtDNA) variants can be difficult because of varying levels of tissue heteroplasmy, and identifying these variants is important for clinical management. Here, we present clinical and molecular findings in 8 adult patients with classical features of mitochondrial ophthalmologic and/or muscle disease and multiple mtDNA deletions isolated to muscle. METHODS: The patients were identified via a retrospective review of patients seen in both a tertiary ophthalmology center and a genetics clinic with a clinical diagnosis of chronic progressive external ophthalmoplegia, optic nerve abnormalities, and/or mitochondrial myopathy. Age at onset of symptoms ranged from 18 to 61 years. Ocular manifestations included bilateral optic neuropathy in one patient, bilateral optic disc cupping without optic neuropathy in 2 patients, ptosis in 4 patients, and ocular motility deficits in 2 patients. Five patients had generalized weakness. RESULTS: Pathogenic variants in mtDNA were not found in the blood or buccal sample from any patient, but 7 of 8 patients had multiple mtDNA deletions identified in muscle tissue. One patient had a single mtDNA deletion identified in the muscle. Heteroplasmy was less than 15% for all of the identified deletions, with the exception of one deletion that had a heteroplasmy of 50%-60%. None of the patients were found to have a nuclear gene variant known to be associated with mitochondrial DNA maintenance. CONCLUSIONS: mtDNA deletions were identified in adult patients with ophthalmologic and/or musle abnormalities and may underlie their clinical presentations.
Indian Journal of Pathology and Microbiology · 2023 · 0 citations · open access
Progressive external ophthalmoplegia – A case report
AbstractProgressive external ophthalmoplegia is a slowly progressive hereditary mitochondrial myopathy. Most mitochondrial disorders overlap clinically, enzymatically, and genetically. The most common enzyme defect is the combined deficit of complexes I and IV. Progressive external ophthalmoplegia particularly affects the extraocular muscles and is characterised by ophthalmoplegia, and bilateral ptosis. The ptosis and ophthalmoplegia is unresponsive to anticholinergics, with no effective treatment, but corrective surgery for ptosis as a palliative one. In this article, we report a rare case of a 16-year-old female with characterstic histological features consistent with progressive external ophthalmoplegia.
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.
